National Academies Press: OpenBook

Adverse Effects of Vaccines: Evidence and Causality (2012)

Chapter: 4 Measles, Mumps, and Rubella Vaccine

« Previous: 3 Evaluating Biological Mechanisms of Adverse Events
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

4

Measles, Mumps, and Rubella Vaccine

INTRODUCTION

Measles

Measles is caused by a single-stranded, negative-sense nonsegmented RNA virus of the genus Morbillivirus and the family Paramyxoviridae that encodes at least eight structural proteins (Gershon, 2010a). The virus is easily inactivated by extremes of pH, heat, and sunlight (Strebel et al., 2008). As the only natural hosts for the wild virus, humans transmit measles through aerosolized respiratory fluids or droplet nuclei (Babbott and Gordon, 1954; de Jong, 1965).

The incubation period of the measles virus is 10 to 12 days (CDC, 1998). The prodromal stage, during which the infected individual is most contagious, lasts 2 to 4 days and manifests as conjunctivitis, fever, malaise, and tracheobronchitis (Strebel et al., 2008). This period is followed by 4 days of fever as high as 105°F (Strebel et al., 2008). Rash is preceded by Koplik’s spots that appear on the lining of the cheeks and lips and may persist for 1 to 2 days after the onset of rash (Strebel et al., 2008). The rash, which occurs 14 days after exposure, starts on the head and spreads to the trunk and extremities over 3 to 4 days, before fading (Strebel et al., 2008). Individuals are infectious for as long as 4 days before and after the onset of rash (Strebel et al., 2008).

Serious complications of measles include pneumonia, postinfectious encephalitis, subacute sclerosing panencephalitis (SSPE), and death (Johnson et al., 1984; Miller, 1987; Strebel et al., 2008). These complications are

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

associated with a fever lasting more than 2 days after the onset of rash (Strebel et al., 2008). Measles-related mortality is highest for infants, young children, and adults with decreased risk in older children and adolescents (CDC, 1998). Other complications include acute otitis media, appendicitis, hepatitis, myocarditis, and thrombocytopenia (Kempe and Fulginiti, 1965).

Although recognized as a disease for approximately 2,000 years, the first major advance in the study of measles was in 1846 when Parnum observed measles cases in the Faroe Islands. Parnum confirmed the infectious nature of measles, defined the 2-week incubation period, and noted that individuals infected with measles did not become ill after subsequent exposure to the virus (Strebel et al., 2008). In 1954, Enders and Peebles propagated measles virus in human renal tissues (Enders and Peebles, 1954). Nine years later, in 1963, the first live, attenuated vaccine was licensed for use in the United States (Enders, 1962). The Edmonston B virus strain that was passaged at 35–36°C through primary renal cells, primary human amnion cells, and embryonic chicken cells a total of 59 times was used in many vaccines (Strebel et al., 2008). In 1965 and 1968, the Schwarz and Moraten (more attenuated strain derived from Ender’s attenuated Edmonston measles virus) strains were also licensed in the United States. These strains were developed from the Edmonston B strain and were passaged at 32°C an additional 85 and 40 times, respectively (Strebel et al., 2008). The Schwarz and Moraten strains were shown to cause less severe and less frequent side effects (Andelman et al., 1963; Hilleman et al., 1968; Schwarz, 1964; Schwarz and Anderson, 1965; Schwarz et al., 1967; Strebel et al., 2008). Today, the only strain licensed in the United States is the more attenuated, live Ender’s Edmonston strain (Moraten strain) (CDC, 1998).

Prior to the licensure of a measles vaccine, an average of 400,000 measles cases were reported each year, although the actual incidence was estimated to be 3.5 million based on the size of the annual birth cohort, and the fact that nearly 100 percent of the population was infected during childhood (CDC, 1998). With the licensure of the vaccine, the measles burden has been reduced by more than 99 percent, and in 1998, the Centers for Disease Control and Prevention (CDC) indicated that 95 and 98 percent of children vaccinated at age 12 and 15 months, respectively, developed measles antibodies (CDC, 1998).

Mumps

Mumps is an acute viral infection caused by an enveloped, negative-sense RNA virus of the genus Rubulavirus (Litman and Baum, 2010). The virus is composed of 15,384 nucleotides that encode seven genes, one of which is the SH protein that has been used to identify at least 12 mumps virus strains (Jin et al., 2000; Plotkin and Rubin, 2008). Mumps is transmit-

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

ted by direct contact with infectious respiratory secretions, droplet nuclei, or fomites that are then transferred to the nose and mouth (Litman and Baum, 2010).

The average incubation period of the mumps virus is 16 to 18 days but can range from 2 to 4 weeks (Litman and Baum, 2010). Fifteen to 20 percent of mumps infections are asymptomatic; 50 percent of cases have nonspecific symptoms such as anorexia, headache, fever, and malaise, or present primarily as respiratory infections; and only 30 to 40 percent demonstrate the classic salivary gland tenderness and enlargement (parotitis) (CDC, 1998). Asymptomatic infection is more common in adults, while parotitis occurs most often in children age 2 to 9 years (CDC, 1998). Children younger than 5 years old more commonly manifest symptoms of lower respiratory disease (Plotkin and Rubin, 2008). Complications of mumps infection are possible without the presence of parotitis. In 1958, Philip et al. (1959) observed testicular and mammary inflammation in 5 percent of postpubertal men and 31 percent of women over 15 years of age. Pancreatitis occurs in 4 percent of cases, and although it has not been proven, evidence suggests an association between mumps infection and diabetes mellitus (Sultz et al., 1975). Neurological complications are more common in adults and occur three times more often in men than in women (Plotkin and Rubin, 2008). These complications include mumps meningitis, cerebellar ataxia, transverse myelitis and poliomyelitis-like disease, cranial nerve palsies, hydroencephalitis, and encephalitis, which occurs in less than 0.3 percent of cases, but is responsible for more than 50 percent of mumps-related fatalities (Bray, 1972; Cohen et al., 1992; Kilham et al., 1949; Lahat et al., 1993; Oldfelt, 1949; Oran et al., 1995; Plotkin and Rubin, 2008; Timmons and Johnson, 1970). Hearing loss due to infection of the endolymph is also a potential complication of mumps infection (Tanaka et al., 1988). Short-term, high-frequency deafness occurs in approximately 4 percent of mumps cases, and permanent hearing loss occurs in only 1 per 20,000 cases and is usually unilateral (Litman and Baum, 2010; Plotkin and Rubin, 2008). Mumps arthropathy, more common in men than women, occurs most often in young adults (Plotkin and Rubin, 2008). It may manifest as arthralgias, polyarticular migratory arthritis, and monoarticular arthritis (Gordon and Lauter, 1984; Harel et al., 1990). Myocarditis is rare and generally self-limited, although some fatal cases have been reported (Chaudary and Jaski, 1989; Roberts and Fox, 1965).

Johnson and Goodpasture (1934) identified the causative agent of mumps in 1934, and in 1945 Habel and Enders successfully cultivated the virus in chick embryos (Enders, 1946; Habel, 1945). The first inactivated mumps vaccine was developed in 1946 and tested in humans in 1951 (Habel, 1946, 1951). The first live, attenuated vaccine was developed in the 1960s in the United States and former Soviet Union (Plotkin and Rubin,

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

2008; Weibel et al., 1967). In the United States, mumps vaccines are manufactured using the Jeryl Lynn strain mumps virus that was isolated from the throat of Jeryl Lynn Hilleman in the 1960s (Plotkin and Rubin, 2008). The vaccine is currently licensed in the mono-, tri-, and tetravalent forms, although the monovalent, Mumpsvax (Merck and Co., Inc.), is no longer available in the United States.

Prior to the licensing of a live-attenuated mumps vaccine, mumps outbreaks occurred every 2 to 5 years, with peak incidence from January through May (Anderson and Seward, 2008; Litman and Baum, 2010). Since the introduction of the vaccine, the incidence of mumps infection has been reduced greatly, evidenced by a 99 percent decrease in mumps infection from 1968 to 1995 (CDC, 1998).

Rubella

Rubella, also known as German measles, is caused by an enveloped, positive-sense RNA togavirus of the genus Rubivirus (Gershon, 2010b). The rubella virus genome consists of approximately 9,800 nucleotides, and the virus can be divided into two clades and at least seven genotypes (Zheng et al., 2003). Maturing by budding from the cell membrane (Murphy et al., 1968), rubella virus is relatively unstable and vulnerable to chemical inactivation, extremes of pH and heat, lipid solvents, and ultraviolent light (Gershon, 2010b).

Rubella is spread through contact with infectious respiratory secretions, and replication occurs in the nasopharynx of the infected individual (Plotkin and Reef, 2008). Rubella infections are subclinical in 25 to 50 percent of cases (CDC, 1998). In those cases in which clinical illness develops, the beginning of the 12- to 23-day incubation period is largely asymptomatic (CDC, 1998; Plotkin and Reef, 2008). By the end of the second week virus can be isolated from the blood and symptoms of conjunctivitis, low-grade fever, lymphadenopathy, and malaise are present (Plotkin and Reef, 2008). A rash follows spreading downwards from the face before fading within 1 to 3 days (Plotkin and Reef, 2008). Rubella illness in a child or adult is usually benign although arthritis and arthralgia has been observed in association with viral replication in the synovial cavity of the joints (Plotkin and Reef, 2008). Other complications of rubella include encephalitis, Guillain-Barré syndrome (GBS), progressive rubella panencephalitis, and thrombocytopenia (Gershon, 2010b; Plotkin and Reef, 2008).

Rubella virus infection during pregnancy can lead to congenital rubella infection in neonates. The disease outcome is directly correlated to the age of the fetus at the time of infection with younger fetuses experiencing more severe disease (Gershon, 2010b). Infections within the first 2 months of pregnancy can cause multiple congenital defects or spontaneous abortion in

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

65 to 85 percent of women (Gershon, 2010b). Infections in the third month and fourth month are associated with a single defect in 30 to 35 percent and 10 percent of cases, respectively (Gershon, 2010b). Commonly associated defects include transient thrombocytopenia purpura and meningoencephalitis, as well as permanent and developmental manifestations such as hearing loss, pulmonic stenosis, mental retardation, and behavioral disorders (Gershon, 2010b). Other less common manifestations include myocardial abnormalities, hepatitis, and seizure disorders (Gershon, 2010b). Studies have also shown that diabetes mellitus occurs 50 times more frequently in children with congenital rubella, and insulin-dependent diabetes has been reported in 40 percent of adults who were congenitally infected with rubella during the 1942 rubella epidemic (Gershon, 2010b).

Clinically described as early as the 1700s, rubella was considered a disease of children and young adults and was given little attention until 1941 when Gregg discovered an association between maternal rubella infection and congenital cataracts (Gregg, 1941). Parkman and colleagues and Weller and Neva isolated the causative agent of rubella in 1962 (Parkman et al., 1962; Weller and Neva, 1962). By 1970, three rubella virus strains were licensed for use in vaccines in the Untied States: Cendehill (grown in rabbit kidney), HPV-77 (grown in dog kidney), and HPV-77 (grown in duck embryo) (HPV-77DE) (Hilleman et al., 1969; Meyer et al., 1969; Prinzie et al., 1969). HPV-77DE was used as the rubella component of the first MMR vaccine, but was later replaced with RA 27/3 after studies showed RA 27/3 induced higher antibody levels, more persistent seropositivity, more resistance to reinfection, and greater herd immunity (Fogel et al., 1978; Gershon et al., 1980; Klock and Rachelefsky, 1973). Today, RA 27/3 is the only rubella virus strain available for use in vaccines in the United States.

Measles-, Mumps-, and Rubella-Containing Vaccines

In the United States, measles, mumps, and rubella (MMR) vaccine is a live, attenuated virus vaccine and is manufactured by Merck & Co., Inc. Although Merck is licensed to produce monovalent measles, mumps, and rubella vaccines—Attenuvax, Meruvax, and Mumpsvax, respectively— currently, these vaccines are no longer available in the United States. The combination vaccine, M-M-R II (Merck), contains greater than 1,000 TCID50 of a more attenuated line of measles virus derived from Ender’s attenuated Edmonston strain, greater than 12,500 TCID50 of Jeryl Lynn mumps virus, and greater than 1,000 TCID50 of Wistar Institute RA 27/3 rubella virus, in addition to sorbitol, sodium phosphate, sucrose, sodium chloride, hydrolyzed gelatin, human albumin, fetal bovine serum, and neomycin (Merck & Co., Inc., 2007). The vaccine does not contain a preservative. In 2005 the Food and Drug Administration (FDA) licensed the tetravalent measles, mumps,

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

rubella, and varicella (MMRV) vaccine, ProQuad (Merck). ProQuad contains greater than 3.0 log10 TCID50 of a more attenuated line of measles virus derived from Ender’s attenuated Edmonston strain, greater than 4.3 log10 TCID50 of Jeryl Lynn mumps virus, greater than 3.0 log10 TCID50 of Wistar Institute RA 27/3 rubella virus, and greater than 3.99 log10 plaque-forming units (PFUs) of Oka/Merck varicella zoster virus (VZV)—the equivalent to that found in varicella virus vaccines (see Chapter 5) (Merck & Co., Inc., 2009). ProQuad also does not contain a preservative.

The Advisory Committee on Immunization Practices (ACIP) recommends that all children receive two subcutaneous doses of the MMR or MMRV vaccine without preference. The first dose is scheduled between 12 and 15 months of age and is followed by a second dose between 4 and 6 years of age prior to kindergarten or first grade. The ACIP also recommends that adults born after 1956 and all women of childbearing age who are not pregnant receive at least one dose of the MMR vaccine in the absence of prior immunity (CDC, 1998). The vaccine is contraindicated in those with hypersensitivity to any component of the vaccine including gelatin, pregnant women, those with allergies to neomycin, febrile respiratory illness or other active febrile infection, and the immunosuppressed. According to the National Immunization Survey, from 2005 to 2009 more than 90 percent of children aged 19 to 35 months had received at least one dose of the MMR vaccine (CDC, 2010).

The committee focused on virus strains used in licensed U.S. vaccines. On occasion, the committee reviewed other virus strains that were sufficiently similar to U.S. strains. This will be noted in the text. The committee was not charged with reviewing the MMRV vaccine.

MEASLES INCLUSION BODY ENCEPHALITIS

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of measles inclusion body encephalitis after the administration of MMR vaccine.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between MMR vaccine and measles inclusion body encephalitis.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Mechanistic Evidence

The committee identified five publications reporting measles inclusion body encephalitis after the administration of measles or MMR vaccine. Freeman et al. (2004) and Kim et al. (1992) demonstrated wild-type measles virus in their patients. These cases did not contribute to the weight of mechanistic evidence.

Described below are three publications reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Bitnun et al. (1999) describe a 21-month-old boy presenting with status epilepticus, fever, irritability, and vomiting 9 months after receiving an MMR containing the Moraten strain of measles. Serology was positive for antimeasles IgM and IgG; the cerebrospinal fluid (CSF) was not positive for these antibodies. The patient died when ventilatory support was withdrawn 51 days after admission. Evaluation of the patient’s immune system revealed depressed proliferative responses to mitogens and antigens and depressed CD8 cell numbers. Measles hemagglutinin and matrix proteins were observed by immunohistochemical staining performed on biopsied brain tissue. Furthermore, intracytoplasmic and intranuclear inclusions with the appearance of paramyxovirus neucleocapsids were revealed by electron microscopy. Reverse-transcription polymerase chain reaction (RT-PCR) amplified measles RNA from the patient’s brain tissue. PCR analysis of the N gene and sequence analysis of the F gene from viral material isolated in the biopsied brain tissue was identical to the Moraten measles vaccine strain.

Baram et al. (1994) describe a 22-month-old girl who presented with focal and generalized myoclonic seizures, clumsiness, falling, head drop, and right arm jerk 4 months after receiving a measles, mumps, and rubella vaccine. The patient’s history included a febrile illness with rash at the age of 5 weeks. The patient died of aspiration pneumonia at 25.5 months of age, 3.5 months after the onset of symptoms. Upon autopsy, inclusion bodies were identified and found to contain helical nucleocapsid tubules. Measles virus was amplified, by PCR, from the patient’s brain.

Poon et al. (1998) described a 2-year-old boy, diagnosed with human immunodeficiency virus (HIV), presenting with generalized convulsive seizures lasting 40 minutes 9 months after receiving a measles, mumps, and rubella vaccine. Despite treatment the patient continued to develop partial and generalized seizures. The patient presented with a fever, lymphadenopathy, hepatosplenomegaly, and delayed language and motor skills upon physical and developmental examination. Tests were negative for herpes simplex virus, cytomegalovirus, respiratory syncytial virus, Toxoplasma, and cryptococal organisms. The patient died 4 months after admission for pneumonia. Electron microscopic observation of a fine-needle aspiration

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

biopsy of the right temporal region showed intranuclear inclusions corresponding to the configuration and size of measles virus.

Weight of Mechanistic Evidence

Measles inclusion body encephalitis is a complication of wild-type measles infection that develops months to years after the initial acute measles infection (Reuter and Schneider-Schaulies, 2010). Furthermore, measles inclusion body encephalitis is confined to immunodeficient patients and is inevitably fatal (Reuter and Schneider-Schaulies, 2010). The committee considers the effects of natural infection one type of mechanistic evidence.

In addition, the three publications described above presented clinical evidence sufficient for the committee to conclude the vaccine was a contributing cause of measles inclusion body encephalitis after administration of a measles-containing vaccine. The publications reported either intranuclear inclusions corresponding to measles virus or the isolation of measles virus from the brain; vaccine strain measles virus was identified by PCR in one publication.

The latencies between vaccination and the development of measles inclusion body encephalitis in the publications described above were 4 and 9 months, suggesting persistent viral infection as the mechanism. Direct viral infection may also contribute to the symptoms of measles inclusion body encephalitis; however, the publications did not provide evidence linking this mechanism to MMR vaccine.

The committee assesses the mechanistic evidence regarding an association between the measles vaccine and measles inclusion body encephalitis in individuals with demonstrated immunodeficiencies as strong based on one case presenting definitive clinical evidence.

The committee assesses the mechanistic evidence regarding an association between the mumps or rubella vaccine and measles inclusion body encephalitis as lacking.

Causality Conclusion

Conclusion 4.1: The evidence convincingly supports a causal relationship between MMR1vaccine and measles inclusion body encephalitis in individuals with demonstrated immunodeficiencies.

___________

1 The committee attributes causation to the measles component of the vaccine.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

ENCEPHALITIS AND ENCEPHALOPATHY

Epidemiologic Evidence

The committee reviewed 13 studies to evaluate the risk of encephalitis or encephalopathy after the administration of measles or MMR vaccine. Nine studies (Bino et al., 2003; D’Souza et al., 2000; Fescharek et al., 1990; Katz, 1969; Landrigan and Witte, 1973; Patja et al., 2000; Stetler et al., 1985; Vahdani et al., 2005; Weibel et al., 1998) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations. One controlled study (Griffin et al., 1991) had very serious methodological limitations that precluded its inclusion in this assessment. The study by Griffin et al. (1991) was unable to find any cases of encephalopathy following MMR immunization, so no conclusions could be drawn from this analysis.

The three remaining controlled studies (Makela et al., 2002; Ray et al., 2006; Ward et al., 2007) contributed to the weight of epidemiologic evidence and are described below.

Makela et al. (2002) conducted a retrospective cohort study in 535,544 children (1 to 7 years of age) who received an MMR vaccination in Finland from November 1982 to June 1986. Vaccination data were collected from a National Public Health Institute cohort that included the child’s social security number, age at vaccination, and the year and month of vaccination. The nationwide hospital discharge register was linked to the vaccination data using the social security number of each child. The investigators reviewed the hospital discharge register for cases of encephalitis or encephalopathies (referred to as encephalitis) following vaccination; records with a defined cause unrelated to vaccination were excluded. Cases of encephalitis that occurred within 3 months of vaccination were validated with information from the patients’ medical records and the exact dates of vaccination were verified. The number of events observed within the 3-month postvaccina-tion risk period was compared to the events observed during the control period, which was defined as subsequent 3-month postvaccination intervals until 24 months was reached. A total of 199 children were hospitalized for encephalitis during the study period; 9 occurred within 3 months of MMR vaccination, 110 occurred after the 3 months following vaccination, and 80 occurred before MMR vaccination. The analysis did not find an increase of encephalitis hospitalizations within 3 months of vaccination (p = .28). The authors concluded that MMR vaccination does not increase the risk of encephalitis in children.

Ray et al. (2006) conducted a case-control study in children (0 to 6 years of age) enrolled in four health maintenance organizations (HMOs) participating in the Vaccine Safety Datalink (VSD) from January 1981

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

through December 1995. The cases were defined as patients hospitalized with a primary or secondary diagnosis of encephalopathy, encephalitis, or Reye syndrome, and who were enrolled in the HMO at least 60 days before hospitalization (or since birth for patients under 60 days of age). The medical records of all cases were reviewed by a neurologist, who was blind to vaccination status, to confirm patients met the case definition. A total of 452 encephalopathy cases were identified and categorized according to whether the encephalopathy etiology was known, unknown, or suspected but unconfirmed. One to three controls were matched to each case on age (within 7 days), sex, HMO location, and length of enrollment in the HMO. Vaccination histories were obtained from the medical records and stratified into time windows; the cases and controls had similar vaccination rates. Odds ratios were calculated for MMR vaccination within the specified time windows and included all cases, cases with unknown or suspected but unconfirmed diagnoses, or cases with only suspected but unconfirmed diagnoses. None of the comparisons found a statistically significant increase in risk, meaning all 95% confidence intervals (CIs) for odds ratios included 1. In fact, most of the point estimates of the odds ratios in these comparisons were less than 1. The highest odds ratio point estimate was 1.23 (95% CI, 0.51–2.98) for cases of unknown or suspected encephalopathy within 90 days of MMR vaccination. The authors concluded that MMR vaccination is not associated with an increased risk of encephalopathy owing to the absence of a consistent time association between vaccination and encephalopathy onset.

Ward et al. (2007) conducted a self-controlled case series study in children (2 to 35 months of age) residing in the United Kingdom or Ireland between October 1998 and September 2001. MMR vaccines with the Jeryl Lynn or RIT 4385 mumps component, and Moraten or Schwarz measles component were in use during the study period. The British Pediatric Surveillance Unit distributed monthly surveillance surveys to pediatricians in order to identify children with encephalitis, or suspected severe illness with fever and seizures. The questionnaires were reviewed by a physician to confirm patients met the case definition of severe neurologic disease (encephalitis or febrile seizures). Vaccination histories of confirmed cases were obtained from the child’s general practitioner by the Immunization Department, Health Protection Agency, Centre for Infections, London. The risk periods considered were 6–11 days and 15–35 days after MMR vaccination; each child was categorized as having been vaccinated or unvaccinated, and with disease or without disease based on dates of vaccine administration and disease episodes during these time periods. A total of 107 children (12 to 35 months of age) with confirmed severe neurologic disease were included in the analysis for MMR vaccine. The relative risk of severe neurologic disease within 6 to 11 days after MMR vaccination was

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

5.68 (95% CI, 2.31–13.97) and within 15 to 35 days after MMR vaccination was 1.34 (95% CI, 0.52–3.47). While a significant increased risk of disease was observed during the 6 to 11 day postvaccination period, three of the six cases received MMR and meningococcal C conjugate vaccine on the same day, and four of the six cases reported complex febrile seizures combined with encephalopathy. The authors concluded that administration of MMR vaccine is associated with an increased risk of severe neurologic disease within 6 to 11 days of vaccination, but attributed the risk to the inclusion of cases with complex febrile seizures. Furthermore, the study included two vaccine formulations, one of which is not available in the United States, and the association of these vaccines with encephalitis was not analyzed separately.

Weight of Epidemiologic Evidence

Two of the three studies detailed above showed no significant increased risk of encephalopathy after MMR vaccination. Makela et al. (2002) found only 9 of the 199 cases were diagnosed within their defined risk period of 0–3 months, a rate no higher than during the control periods of this cohort study. All control periods were after vaccination, which weakens the results of this study. Of the three studies, the study by Ray et al. (2006) investigated the largest number of cases with 452 that were then matched to controls, and was the only study judged to have negligible limitations. The authors considered different risk intervals and different categories of diagnosis but did not find evidence of an increased risk. The last paper by Ward et al. (2007) showed a significant increase of neurologic disease—but the illnesses were predominantly complex febrile seizures with recovery except in one patient, not other forms of encephalopathy (the association of MMR vaccination and seizures is discussed in a subsequent section). The study also combined assessments for two vaccine formulations, one of which is not available in the United States. Thus, two of the three studies—of which only one had negligible limitations—found no association between MMR vaccine and encephalitis or encephalopathy. A third study did find an increase in risk, but the association was with febrile seizures, which are arbitrarily discussed in another section of the report. See Table 4-1 for a summary of the studies that contributed to the weight of epidemiologic evidence.

The committee has limited confidence in the epidemiologic evidence, based on three studies that lacked validity and precision to assess an association between MMR vaccine and encephalitis or encephalopathy.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

TABLE 4-1 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Encephalopathy or Encephalitis


Citation Operationally Defined Outcome Study Setting Defined Study Population Study Design Sample Size Primary Effect
Size Estimatea
(95% CI or
p value)
Heterogeneous
Subgroups at
Higher Riskb
Limitations
(Negligible or Serious )c

Makela et al.(2002) Encephalitis or encephalopathy identified in the nationwide hospital discharge register Finland from 11/1982 to 6/1986 Ages 1-7 years Retrospective cohort
Risk period: 0-3 months after MMR vaccination
Control period: Subsequent
3-month intervals
after the risk
period until 24
months was reached
535,544 children 199 children hospitalized for encephalitis Nine encephalitis events occurred within 3 months of MMR vaccination No increased risk of encephalitis within 3 months of MMR vaccination (p = .28) None described Serious
Ray et al. (2006) Hospitalization for a primary or secondary diagnosis of encephalopathy, encephalitis, or Reye syndrome Four HMOs participating in the VSD from 1/1/1981 through 12/31/1995 Ages 0-6 years Case-control Controls matched by age (within 7 days), sex, HMO location, and length of enrollment in the HMO 452 cases with encephalopathy One to three controls were matched to each case OR for unknown or suspected encephalopathy within 90 days of MMR vaccination: 1.23 (95% CI, 0.51-2.98; p = .647) None described Negligible
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
OR for encephalopathy among all cases and controls within 90 days of MMR vaccination: 0.98 (95% CI, 0.47-2.01; p = .951)
Ward et al. (2007) Diagnoses of severe neurologic disease (encephalitis or febrile seizures) obtained from monthly surveillance surveys to pediatricians United Kingdom or Ireland between 10/1998 and 9/2001 Ages 2-35 months Self-controlled case series Risk period: 6-11 days and 15-35 days after MMR vaccination Control period: all time observed outside the risk period 107 children (ages 12-35 months) with severe neurologic disease Six events occurred within 6-11 days of vaccination Five events occurred within 15-35 days of vaccination RR of severe neurologic disease within 6-11 days of MMR vaccination: 5.68 (95% CI, 2.31-13.97) RR of severe neurologic disease within 15-35 days of MMR vaccination: 1.34 (95% CI, 0.52-3.47) Four of the six children who had severe neurologic disease within 6-11 days of MMR vaccination reported complex febrile seizures combined with encephalopathy Negligible

a The committee assumed statistical significance below the conventional 0.05 level unless otherwise stated by the authors.

b The risk/effect estimate for the subgroup/alternate definition of exposure or outcome differs significantly (e.g., is heterogeneous with nonoverlapping 95% confidence intervals) compared with the risk/effect estimate reported for the primary group/definition.

c Studies designated as serious had more methodological limitations than those designated as negligible. Studies assessed as having very serious limitations were not considered in the weight of epidemiologic evidence.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Mechanistic Evidence Regarding Encephalitis

The committee identified 18 publications reporting encephalitis or meningoencephalitis after the administration of vaccines containing measles, mumps, and rubella alone or in combination. Mustafa et al. (1993) described one case of encephalitis developing after administration of a MMR vaccine; however, wild-type measles virus was demonstrated in the patient. Fourteen publications did not provide evidence beyond temporality (Ehrengut and Zastrow, 1989; Fescharek et al., 1990; Forster and Urbanek, 1982; Jagdis et al., 1975; Jorch et al., 1984; Kumar et al., 1982; Landrigan and Witte, 1973; Pollock and Morris, 1983; Ross and Yeager, 1977; Schneck, 1968; Schuil et al., 1998; Shuper, 2011; Wiersbitzky et al., 1992b, 1993a). In addition, five publications reported concomitant infections that could contribute to the development of symptoms (Ehrengut and Zastrow, 1989; Forster and Urbanek, 1982; Jorch et al., 1984; Wiersbitzky et al., 1992b, 1993a). These publications did not contribute to the weight of mechanistic evidence.

Described below are three publications reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Bakshi et al. (1996) described a 16-month-old boy presenting with a focal seizure on the right side and left hemipareses and a left gaze preference 5 months after receiving a measles, mumps, and rubella vaccine and 3 days after undergoing bone marrow transplantation. The patient was administered the vaccine prior to being diagnosed with sickle cell trait and a severe combined immunodeficiency. Serum and CSF were negative for bacteria and fungi. Mumps virus was demonstrated in the urine, serum, and CSF. The patient was diagnosed with meningoencephalitis and died 2 months after the onset of symptoms. Pathological examination of the leptomeninges showed chronic and focally prominent meningitis.

Lacroix et al. (1995) describe a 5-year-old acquired immune deficiency syndrome (AIDS) patient presenting with fever, generalized seizures, and the inability to stand or walk approximately 2 years after vaccination against measles. The patient died months after presenting with neurological symptoms. Retrospective serum analysis showed measles antibody prior to vaccination. Viral cultures of brain samples were negative for measles virus. Frozen sections of basal ganglia, frontal cortex, and white matter were stained with antibodies against measles virus indicating the presence of measles virus in the brain.

Valmari et al. (1987) described a 7-year-old girl presenting with vomiting, headache, twitching of upper extremities, followed by coma lasting for several hours 54 days after receiving a measles, mumps, and rubella vaccine containing the Moraten measles strain and 5.5 years after receiving a

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

measles vaccine containing the Schwarz measles strain. On the day the measles, mumps, and rubella vaccine was administered the patient complained of back pains leading to a diagnosis of acute lymphoblastic leukemia 23 days after vaccination. The patient presented with the symptoms described above 1 day after the fourth methotrexate treatment. Treatment with acyclovir was started and the patient seemed to improve. Measles virus was demonstrated in the CSF. The patient experienced a recrudescence of the neurological symptoms 58 days postvaccination and fever, photophobia, conjunctival inflammation, and a maculopapular rash 63 days postvaccination. Measles virus was demonstrated in the CSF again.

Weight of Mechanistic Evidence

Encephalitis is considered a complication of infection with wild-type measles, mumps, and rubella viruses (Gershon, 2010a,b; Litman and Baum, 2010). Encephalitis develops in 1:1,000 to 1:2,000 patients infected with measles virus (Gershon, 2010a). In addition many patients upon recovering suffer from neurologic sequelae (Gershon, 2010a). Encephalitis develops in 1:400 to 1:6,000 patients infected with mumps virus (Litman and Baum, 2010). In patients developing early-onset encephalitis upon infection with mumps virus, the damage to the neurons is by direct viral invasion (Litman and Baum, 2010). In patients infected with rubella virus, encephalitis develops in 1:5,000 patients (Gershon, 2010b). The committee considers the effects of natural infection one type of mechanistic evidence.

The three publications described above, when considered together, did not present evidence sufficient for the committee to conclude the vaccine may be a contributing cause of encephalitis after administration of a measles or MMR vaccine. The patients described in the cases above had demonstrated immunodeficiencies. The publications presented evidence of the detection of viral antigens on frozen sections or the isolation of mumps or measles virus from the patients. However, the authors did not identify the virus as vaccine strain.

The latency between vaccination and the development of encephalitis in the publications described above ranged from 5 months to 2 years, suggesting persistent viral infection as the mechanism. Direct viral infection and viral reactivation may contribute to encephalitis; however, the publications did not provide evidence linking these mechanisms to MMR vaccine.

The committee assesses the mechanistic evidence regarding an association between MMR vaccine and encephalitis as weak based on knowledge about the natural infection and three cases.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Causality Conclusion

Conclusion 4.2: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and encephalitis.

Mechanistic Evidence Regarding Encephalopathy

The committee identified 11 publications reporting encephalopathy after the administration of vaccines containing measles, mumps, and rubella alone or in combination. Nine publications did not provide evidence of causality beyond a temporal relationship between vaccination and the development of symptoms (Aydin et al., 2006; Ehrengut and Zastrow, 1989; Landrigan and Witte, 1973; Martinon-Torres, 1999; Shuper, 2011; Verity et al., 2010; Weibel et al., 1998; Wiersbitzky et al., 1991, 1993a). In addition, three publications reported concomitant infections that could contribute to the development of symptoms (Verity et al., 2010; Wiersbitzky et al., 1991, 1993a). Furthermore, the viral strains in the MMR vaccine administered to the patient described by Verity et al. (2010) are unknown. These publications did not contribute to the weight of mechanistic evidence.

Described below is one publication that merits greater discussion, although it does not contribute to the weight of mechanistic evidence.

Poling et al. (2006) reported the case of a 19-month-old girl who developed symptoms of encephalopathy and fever 48 hours after receiving a number of immunizations, one of which was a measles, mumps, and rubella vaccine. The only relationship reported for these symptoms is temporal, which the committee did not consider evidence of causality. The patient subsequently developed a number of neurologic and gastrointestinal symptoms, ultimately resulting in a diagnosis of autism. At approximately 2 years of age, the patient was also diagnosed with a mitochondrial disorder. The authors did not attribute the symptoms of encephalopathy to the vaccines.

Described below is one publication reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

As described in greater detail in the encephalitis section Valmari et al. (1987) reported the isolation of measles virus, on two occasions, from the CSF in a patient that developed symptoms of encephalopathy after administration of measles, mumps, and rubella vaccines.

Weight of Mechanistic Evidence

Neurological sequelae of encephalitis, including aphasia and psychomotor retardation, have been reported after infection with both wild-type measles virus and wild-type mumps virus (Gershon, 2010a; Litman and

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Baum, 2010). The committee considers the effects of natural infection one type of mechanistic evidence.

The publication described above did not present evidence sufficient for the committee to conclude the vaccine may be a contributing cause of encephalopathy after administration of MMR vaccine. Measles virus was demonstrated in the patient’s CSF on two occasions. However, the authors did not identify the virus as vaccine strain. In addition, the patient underwent immunosupressive therapy shortly after administration of the vaccine, which could have contributed to the development of symptoms.

The latency between vaccination and the development of encephalopathy in the publication described was 54 days suggesting persistent viral infection as the mechanism. Direct viral infection and viral reactivation may contribute to the symptoms of encephalopathy; however, the publications did not provide evidence linking these mechanisms to MMR vaccine.

The committee assesses the mechanistic evidence regarding an association between MMR vaccine and encephalopathy as weak based on knowledge about the natural infection and one case.

Causality Conclusion

Conclusion 4.3: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and encephalopathy.

FEBRILE SEIZURES

Epidemiologic Evidence

The committee reviewed 19 studies to evaluate the risk of febrile seizures after the administration of vaccines containing measles, mumps, and rubella alone or in combination. Nine studies (Al Awaidy et al., 2010; Bino et al., 2003; D’Souza et al., 2000; Fescharek et al., 1990; Landrigan and Witte, 1973; Miller, 1982; Patja et al., 2000; Stetler et al., 1985; Vahdani et al., 2005) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations. Two controlled studies (Menniti-Ippolito et al., 2007; Morley et al., 1964) had very serious methodological limitations that precluded their inclusion in this assessment. The study by Menniti-Ippolito et al. (2007) provided inadequate information on the selection of controls and did not validate vaccination information provided in self-report questionnaires from the study participants. Morley et al. (1964) conducted a double-blind, randomized controlled trial in children living in Nigeria, but the sample size was too small to adequately

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

assess the risk of seizures following administration of the Edmonston B strain measles vaccine.

The eight remaining controlled studies (Andrews et al., 2007; Barlow et al., 2001; Chen et al., 1997; Farrington et al., 1995; Griffin et al., 1991; Miller et al., 2007; Vestergaard et al., 2004; Ward et al., 2007) contributed to the weight of epidemiologic evidence and are described below.

Griffin et al. (1991) conducted a retrospective cohort study in 18,364 children (12 to 36 months of age) enrolled in the Tennessee Medicaid program from 1974 through 1984. The study reviewed county health department records to identify children who received immunizations at public health clinics; 82 percent of these records were linked to Tennessee birth certificates for children born from 1974 through 1984. The study cohort included children enrolled in the Tennessee Medicaid program within 90 days of birth who received at least one diphtheria, tetanus, and pertussis (DTP) vaccination (during 29 to 365 days of birth) and one MMR or measles-rubella (MR) vaccination (during 12 to 36 months of age). The investigators screened Medicaid inpatient and outpatient claims files for diagnoses of febrile seizures, afebrile seizures, and symptomatic seizures following administration of MMR or MR vaccine. The claims files were verified with hospital-based records; events not leading to hospitalization were excluded from the analysis. Of the 18,222 MMR and 363 MR vaccines administered to the study participants, 77 cases of febrile seizures were reported following vaccination. The risk period and control period were defined as 7 to 14 days and 30 or more days after vaccination, respectively. The age-adjusted relative risk of febrile seizures 7 to 14 days after MMR or MR vaccination was 2.1 (95% CI, 0.7–6.4). Thus, the authors found a nonsignificant increased risk of febrile seizures within 7 to 14 days of MMR or MR vaccination.

Farrington et al. (1995) conducted a case-crossover study in children (12 to 24 months of age) who were enrolled from computerized hospital records in five districts in the United Kingdom between October 1988 and February 1993. A total of 1,057 cases of febrile seizures were identified using hospital diagnosis codes. MMR vaccination information was obtained from computerized child health and general practice records for 75 percent of the participants. The vaccine batch number was available in 78 percent of these records and was used to determine the mumps strain (Jeryl Lynn or Urabe) administered during vaccination. The risk periods for febrile seizures were defined as 6–11 days and 15–35 days after MMR vaccination based on when the authors might expect to observe neurological events attributable to the measles and mumps components of the vaccine. The control period was defined as any time not included in the risk period. The relative risk of febrile seizures within 6–11 days of MMR vaccination including the Jeryl Lynn mumps strain was 3.77 (95% CI, 1.95–7.30) and

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

within 15–35 days was 1.04 (95% CI, 0.56–1.93). The authors found a significantly increased risk of febrile seizures within 6 to 11 days of MMR vaccination.

Chen et al. (1997) conducted a self-controlled case-series study in more than 500,000 children (0 to 6 years of age) enrolled in four HMOs participating in the VSD from 1991 through 1996. Vaccination information and diagnostic codes for seizures were obtained from the HMO data systems without chart review. Children who experienced any type of seizure were included in the analysis (the number of cases was not provided). The relative rates of seizures observed during the risk periods (1–3 days, 4–7 days, 8–14 days, and 15–30 days following vaccination) were compared with prevaccination and more distant postvaccination control periods. The relative risk of seizures within 8–14 days of MMR vaccination (adjusted for concomitant Haemophilus influenzae type B [HiB] vaccination) was 2.42 (95% CI, 1.8–3.2). The authors did not provide relative risk information for the other defined risk periods.

Barlow et al. (2001) collected additional data on children enrolled in the study by Chen et al. (1997), which is described above. The authors conducted a retrospective cohort study in 679,942 children enrolled in four HMOs participating in the VSD from January 1991 to September 1993. A total of 2,281 children with possible first seizures were identified in the HMO data systems using diagnostic codes for seizures, seizures in a newborn, epilepsy, and myoclonus. The diagnostic codes were primarily limited to hospitalizations and emergency department visits. The investigators reviewed the medical records of 1,094 randomly selected children in order to validate and classify the events. Of the 716 validated diagnoses of first seizure, 487 were febrile seizures, 137 were afebrile seizures, 36 were infantile spasms, and 56 were from other causes. MMR immunization information was obtained from the HMO data systems but was not validated with medical record review. The risk intervals for febrile seizures were defined as 1–7 days, 8–14 days, and 15–30 days following MMR vaccination. The children in the exposed group were matched to the reference group on calendar time, age (within 1 day), and HMO. The reference group had not received an MMR vaccination within the preceding 30 days of the index date. The analysis was adjusted for age, sex, HMO, calendar time, and DTP administration. The adjusted relative risk of febrile seizures within 1–7 days of MMR vaccination was 1.73 (95% CI, 0.72–4.15), within 8–14 days was 2.83 (95% CI, 1.44–5.55), and within 15–30 days was 0.97 (95% CI, 0.49–1.95). The authors confirmed a significantly increased risk of febrile seizures within 8 to 14 days of MMR vaccination in a more detailed analysis of the population first reported in Chen et al. (1997).

Vestergaard et al. (2004) conducted a retrospective cohort study in children born in Denmark from January 1991 through December 1998. The

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

children were enrolled from the Danish Civil Registration System, which maintains personal identification information for all residents. These data were linked to records from other national registries. Diagnoses of febrile seizures were derived from diagnostic codes in the National Hospital Registry and MMR vaccination data were obtained from the National Board of Health. The MMR vaccine in use during the study period contained the same measles, mumps, and rubella strains as the U.S. vaccine. Children were classified as having a febrile seizure if they were 3 to 60 months of age at the time of hospital discharge and did not have a record of afebrile seizures or other exclusionary conditions (cerebral palsy, severe head trauma, intracranial tumors, meningitis, or encephalitis). Follow-up began at 3 months of age and continued until December 31, 1999, or the date of first diagnosis of febrile seizure, diagnosis of an exclusionary condition, 5 years of age, emigration, or death. A total of 537,171 children were followed for an average of 3.5 years; 17,986 children had at least one diagnosis of febrile seizures, of which 973 experienced the seizure within 2 weeks of MMR vaccination. Relative risks were calculated and adjusted for age (3-month categories) and calendar year. The adjusted relative risk of febrile seizures during the first week following MMR vaccination was 2.46 (95% CI, 2.22–2.73), during the second week following MMR vaccination was 3.17 (95% CI, 2.89–3.49), and within the combined 2 weeks following MMR vaccination was 2.75 (95% CI, 2.32–3.26). The authors concluded that MMR vaccination is associated with a significantly increased risk of febrile seizures within 2 weeks of vaccine administration.

Andrews et al. (2007) conducted a self-controlled case-series study in children (28 days to 17 years of age) diagnosed with seizures from November 1999 through September 2003 in the United Kingdom. MMR vaccines with the Jeryl Lynn or RIT 4385 mumps component (which is derived from the Jeryl Lynn strain), and Moraten or Schwarz measles component were in use during the study period. The cases were identified using diagnostic codes for seizures located in the hospital episode data from the London and South East regions. The hospital episode data was linked to vaccination information in the child-health databases from the same regions. The study participants were divided into three age groups: 28–365 days (infants), 1 year of age (toddlers), and 2–17 years of age (children). Cases were excluded from the analysis if they received a vaccination outside the recommended age range; MMR vaccine was not recommended in infants and these cases were excluded. Two risk periods were defined as 6–11 days and 15–35 days after MMR vaccination, and were compared to the background risk of seizures among the study participants (excluding the 7-day period before vaccination). A total of 342 participants from the 1-year age group reported 367 seizures (326 febrile seizures and 41 other or unspecified seizures) and 788 participants from the 2- to 17-year age group reported 863

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

seizures (500 febrile seizures and 363 other or unspecified seizures). The relative risk of seizures in the 1-year age group within 6–11 days of MMR vaccination was 2.07 (95% CI, 1.00–4.27) and within 15–35 days of MMR vaccination was 0.65 (95% CI, 0.36–1.19). The relative risk of seizures in the 2- to 17-year age group within 6–11 days of MMR vaccination was 1.74 (95% CI, 0.49–6.14) and within 15–35 days of MMR vaccination was 1.39 (95% CI, 0.71–2.74). The analyses were not separated by type of seizure. The authors found a significant increased risk of seizures in the 1-year age group within 6 to 11 days of MMR vaccination. However, the study included two vaccine formulations, one of which is not available in the United States, and the association of these vaccines with febrile seizures was not analyzed separately.

Miller et al. (2007) conducted a self-controlled case-series study in children (12 to 23 months of age) diagnosed with seizures from January 1998 through June 2002 in the United Kingdom. MMR vaccines with the Jeryl Lynn or RIT 4385 mumps component, and Moraten or Schwarz measles component were in use during the study period. The cases were identified using computerized hospital records listing admissions to the National Health Service hospitals, which were linked to MMR vaccination data from computerized immunization records in the North and South Thames regions. Cases with a diagnosis code for febrile seizures or unspecified seizures were included in the study. Two risk periods were defined as 6–11 days and 15–35 days after MMR vaccination, and were compared to the background risk of seizures among the participants (excluding the 2 weeks before vaccination). A total of 894 children were hospitalized with 988 seizure episodes during the study period and were included in the analysis; 73 received meningococcal C conjugate vaccine concurrently with MMR vaccine. The relative risk of febrile seizures within 6–11 days of MMR vaccination was 4.27 (95% CI, 3.17–5.76) and within 15–35 days of vaccination was 1.33 (95% CI, 1.00–1.77). The authors concluded that administration of MMR vaccine increases the risk of febrile seizures during the 6–11 days following vaccination. However, the study included two vaccine formulations, one of which is not available in the United States, and the association of these vaccines with febrile seizures was not analyzed separately.

The study by Ward et al. (2007) was described in detail in the section on encephalitis and encephalopathy. This self-controlled case-series study included 107 children (12 to 35 months of age) with confirmed severe neurologic disease, residing in the United Kingdom or Ireland between October 1998 and September 2001. The relative risk of severe neurologic disease within 6–11 days after MMR vaccination was 5.68 (95% CI, 2.31–13.97) and within 15–35 days after MMR vaccination was 1.34 (95% CI, 0.52– 3.47). While a significant increased risk of disease was observed during the 6- to 11-day postvaccination period, three of the six cases received MMR

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

and meningococcal C conjugate vaccine on the same day, and four of the six cases reported complex febrile seizures combined with encephalopathy. The authors concluded that administration of MMR vaccine is associated with an increased risk of severe neurologic disease within 6 to 11 days of vaccination, and attributed the risk to the inclusion of cases with complex febrile seizures. Furthermore, the study included two vaccine formulations, one of which is not available in the United States, and the association of these vaccines with febrile seizures was not analyzed separately.

Weight of Epidemiologic Evidence

Eight analyses of seven study groups contributed to the weight of evidence; Barlow et al. (2001) and Chen et al. (1997) examined the same population. Five studies assessed the risk of seizures using MMR formulations currently administered in the United States (Barlow et al., 2001; Chen et al., 1997; Farrington et al., 1995; Griffin et al., 1991; Vestergaard et al., 2004), while three studies combined assessments for two vaccine formulations, one of which is not available in the United States (Andrews et al., 2007; Miller et al., 2007; Ward et al., 2007). All found an increase in seizures within 7 to 14 days following MMR vaccination. Six of the studies noted these were febrile seizures; two studies (Andrews et al., 2007; Chen et al., 1997) did not mention whether the seizures were febrile or afebrile. In six studies the association was statistically significant. See Table 4-2 for a summary of the studies that contributed to the weight of epidemiologic evidence.

The committee has a high degree of confidence in the epidemiologic evidence based on seven studies with validity and precision to assess an association between MMR vaccine and febrile seizures; these studies consistently report an increased risk.

Mechanistic Evidence

The committee identified 15 publications reporting febrile seizures developing after the administration of vaccines containing measles, mumps, and rubella alone or in combination. One publication described multiple cases; some did not provide evidence beyond temporality (Ehrengut and Zastrow, 1989). These cases did not contribute to the weight of mechanistic evidence. Eleven publications did not provide evidence beyond temporality (Forster and Urbanek, 1982; Hilleman et al., 1968; Konkel et al., 1993; Landrigan and Witte, 1973; Maspero et al., 1984; Miller, 1982; Miyake et al., 2001; Nader and Warren, 1968; Wiersbitzky et al., 1991, 1993b, 1995). In addition, five publications reported concomitant infections that could contribute to the development of symptoms (Forster and Urbanek,

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

TABLE 4-2 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Febrile Seizures


Citation Operationally Defined Outcome Study Setting Defined Study Population Study Design Sample Size Primary Effect Size Estimatea (95% CI or p value) Heterogeneous Subgroups at Higher Riskb Limitations (Negligible or Serious)c

Griffin et al. (1991) Inpatient and outpatient diagnoses of febrile seizures Tennessee Medicaid program from 1974-1984 Ages 12-36 months born from 1974 through 1984 and enrolled in the Tennessee Medicaid program within 90 days of birth Retrospective cohort Risk periods: 7-14 days after vaccination Control period: 30 or more days after vaccination 18,364 children received a MMR or MR vaccination Four children had febrile seizures 7-14 days after MMR or MR vaccination Age-adjusted RR of febrile seizures 7-14 days after MMR or MR vaccination: 2.1 (95% CI, 0.7-6.4) None described Serious
Farrington et al. (1995) Hospital diagnosis for febrile seizures in the computerized hospital records Hospitals in five districts in the United Kingdom between 10/1988 and 2/1993 Ages 12-24 months who were hospitalized for febrile seizures Case-crossover Risk periods: 6-11 days and 15-35 days after MMR vaccination Control period: all time not included in the risk period 1,057 cases of febrile seizures RR of febrile seizures within 6-11 days of MMR vaccination: 3.77 (95% CI, 1.95-7.30) RR of febrile seizures within 15-35 days of MMR vaccination: 1.04 (95% CI, 0.56-1.93) None described Serious
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Citation Operationally Defined Outcome Study Setting Defined Study Population Study Design Sample Size Primary Effect Size Estimatea (95% CI or p value) Heterogeneous Subgroups at Higher Riskb Limitations (Negligible or Serious)c

Chen et al. (1997) Diagnostic codes for seizures obtained from the HMO data systems Four HMOs participating in the VSD from 1991-1996 Ages 0-6 years Retrospective cohort Risk periods: 1-3 days, 4-7 days, 8-14 days, and 15-30 days after MMR vaccination 500,000 children RR of seizures within 8-14 days of MMR vaccination: 2.42 (95% CI, 1.8-3.2) None described Serious
Barlow et al. (2001) Validated diagnoses of febrile seizures from medical records obtained in the HMO data systems Four HMOs participating in the VSD from 1991-1993 Ages 0-6 years Retrospective cohort Risk periods: 1-7 days, 8-14 days, and 15-30 days after MMR vaccination 487 children with febrile seizures 32 febrile seizures occurred within 30 days of MMR vaccination Adjusted RR of febrile seizures within 1-7 days of MMR vaccination: 1.73 (95% CI, 0.72-4.15) Adjusted RR of febrile seizures within 8-14 days of MMR vaccination: 2.83 (95% CI, 1.44-5.55) Adjusted RR of febrile seizures within 15-30 days of MMR vaccination: 0.97 (95% CI, 0.49-1.95) None described Serious
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Vestergaard et al. (2004) Diagnoses of febrile seizures derived from diagnostic codes in the National Hospital Registry Danish Civil Registration System and four other national registries Children born in Denmark from 1/1/1991 through 12/31/1998 Retrospective cohort 537,171 children 17,986 had at least one diagnosis of febrile seizures 973 had febrile seizures within 2 weeks of MMR vaccination Adjusted RR of febrile seizures during the first week following MMR vaccination: 2.46 (95% CI, 2.22-2.73) Adjusted RR of febrile seizures during the second week following MMR vaccination: 3.17 (95% CI, 2.89-3.49) Adjusted RR of febrile seizures within the combined 2 weeks following MMR vaccination: 2.75 (95% CI, 2.32-3.26) None described Serious
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Citation Operationally Defined Outcome Study Setting Defined Study Population Study Design Sample Size Primary Effect Size Estimatea (95% CI or p value) Heterogeneous Subgroups at Higher Riskb Limitations (Negligible or Serious)c

Andrews et al. (2007) Hospital admission for seizures Hospitals from the London and South East region of the United Kingdom Ages 28 days to 17 years diagnosed with seizures from 11/1/1999 through 9/30/2003 Self-controlled case series Risk periods: 6-11 days and 15-35 days after MMR vaccination Control period: all time not included in the risk period, excluding the 7 days before vaccination 342 children in 1-year age group experienced a total of 367 seizures (326 febrile seizures and 41 other or unspecified seizures) 788 children in 2- to 17-year age group experienced a total of 863 seizures (500 febrile seizures and 363 other or unspecified seizures) RR of seizures in the 1-year age group within 6-11 days of MMR vaccination: 2.07 (95% CI, 1.00-4.27) RR of seizures in the 1-year age group within 15-35 days of MMR vaccination: 0.65 (95% CI, 0.36-1.19) RR of seizures in the 2- to 17-year age group within 6-11 days of MMR vaccination: 1.74 (95% CI, 0.49-6.14) RR of seizures in the 2- to 17-year age group within 15-35 days of MMR vaccination: 1.39 (95% CI, 0.71-2.74) 1-year age group within 6 to 11 days of MMR vaccination Serious
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Miller et al. (2007) Hospital admissions for febrile convulsions (includes all National Health Service hospitals) North and South Thames region of the United Kingdom Ages 12-23 months diagnosed with seizures from 1/1/1998 through 6/30/2002 Self-controlled case series Risk periods: 6-11 days and 15-35 days after MMR vaccination Control period: all time not included in the risk period, excluding the 2 weeks before vaccination 894 children were hospitalized with 988 seizure episodes 52 febrile seizures occurred within 6-11 days of MMR vaccination 57 febrile seizures occurred within 15-35 days of MMR vaccination RR of febrile seizures within 6-11 days of MMR vaccination: 4.27 (95% CI, 3.17-5.76) RR of febrile seizures within 15-35 days of MMR vaccination: 1.33 (95% CI, 1.00-1.77) None described Serious
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Citation Operationally Defined Outcome Study Setting Defined Study Population Study Design Sample Size Primary Effect Size Estimatea (95% CI or p value) Heterogeneous Subgroups at Higher Riskb Limitations (Negligible or Serious)c

Ward et al. (2007) Cases of severe neurologic disease (encephalitis or febrile seizures) obtained from monthly pediatrician surveillance surveys United Kingdom or Ireland Ages 2-35 months residing in United Kingdom or Ireland between 10/1998 and 9/2001 Self-controlled case series Risk periods: 6-11 days and 15-35 days after MMR vaccination 107 children (ages 12-35 months) with severe neurologic disease RR of severe neurologic disease within 6-11 days after MMR vaccination: 5.68 (95% CI, 2.31-13.97) RR of severe neurologic disease within 15-35 days after MMR vaccination: 1.34 (95% CI, 0.52-3.47) None described Serious

a The committee assumed statistical significance below the conventional 0.05 level unless otherwise stated by the authors.

bThe risk/effect estimate for the subgroup/alternate definition of exposure or outcome differs significantly (e.g., is heterogeneous with nonoverlapping 95% confidence intervals) compared with the risk/effect estimate reported for the primary group/definition.

cStudies designated as serious had more methodological limitations than those designated as negligible. Studies assessed as having very serious limitations were not considered in the weight of epidemiologic evidence.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

1982; Konkel et al., 1993; Wiersbitzky et al., 1991, 1993b, 1995). These publications did not contribute to the weight of mechanistic evidence.

Described below are four publications reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Abe et al. (1985) described a 19-month-old boy presenting with fever and a generalized tonic-clonic seizure lasting 30 minutes 11 days after receiving a measles vaccine containing the Schwarz measles strain. The following day a morbilliform eruption and Koplik spots appeared. The patient experienced febrile seizures on three additional occasions 2 weeks, 5 weeks, and 7 months after the first seizure.

Ehrengut and Zastrow (1989) reported 14 cases of febrile seizures developing after administration of a vaccine containing measles, mumps, and rubella alone or in combination. Case 1 (number 1 in the report) presented with a tonic-clonic seizure lasting 10 minutes while febrile and eye rolling to the right 8 days after administration of a measles, mumps, and rubella vaccine. Case 2 (number 4 in the report) presented with a tonic-clonic seizure lasting 5 minutes while febrile and meningismus 8 days after receiving a measles and mumps vaccine. Case 3 (number 7 in the report) presented with a febrile seizure and hemiplegia 14 days after administration of a measles and mumps vaccine. Case 4 (number 18 in the report) presented with a febrile seizure and exanthem 7 days after administration of a measles and mumps vaccine. Case 5 (number 25 in the report) presented with a maculopapular exanthema and febrile seizure 3 days and 9 days, respectively, after administration of a measles and mumps vaccine.

Fescharek et al. (1990) reported 6 of 34 cases of febrile seizures developing after vaccination against measles, mumps, and rubella alone or in combination in detail. One case (number 11 in the report) was previously published by Forster and Urbanek (1982). Case 1 (number 7 in the report) presented with a clonic seizure while febrile, ataxia, and general retardation 13 days after receiving a measles and mumps vaccine. Case 2 (number 10 in the report) presented with a tonic-clonic seizure with fever, hemiparesis, and nystagmus 9 days after administration of a measles and mumps vaccine. Case 3 (number 14 in the report) presented with a tonic-clonic seizure lasting 10 minutes with fever, exanthem, meningismus, and pharyngitis 10 days after receiving a measles and mumps vaccine. Case 4 (number 19 in the report) presented with a febrile tonic-clonic seizure lasting 10 minutes while febrile and right side hemiparesis with hyperreflexia 9 days after administration of a measles, mumps, and rubella vaccine. Case 5 (number 21 in the report) presented with a febrile seizure, exanthem, meningismus, and right side hemiparesis 10 days after receiving a measles, mumps, and rubella vaccine.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Parisi et al. (1991) described a 9-month-old patient (case 3 in the report) presenting with an exanthematic febrile reaction 11 days after administration of a measles vaccine. Physical examination showed hyperemic pharynx, rhinitis, conjunctivitis, and a maculopapular exanthem over the entire body. The symptoms disappeared after 4 to 5 days.

Weight of Mechanistic Evidence

Fever is a prodromal symptom beginning after the 10- to 14-day incubation phase for wild-type measles virus and the 16- to 18-day incubation period for wild-type mumps virus (Gershon, 2010a; Litman and Baum, 2010). In addition, acute measles encephalitis is associated with fever and seizures (Gershon, 2010a). The committee considers the effects of natural infection one type of mechanistic evidence.

In addition, the four publications described above presented clinical evidence sufficient for the committee to conclude the vaccine may be a contributing cause of febrile seizures after administration of MMR vaccine. The publications presented a symptomology of fever with seizure developing within the incubation phases for measles and mumps viruses. In addition, some of the cases presented with exanthems and other neurologic symptoms consistent with measles infection. The failure to demonstrate vaccine-strain virus in the cases described above detracted from the weight of evidence.

The latency between vaccination and the development of the symptomology described above ranged from hours to 28 days after administration of a vaccine containing measles, mumps, and rubella alone or in combination; however, most of the cases discussed above presented between 7 and 14 days after vaccination. Fever, in some instances, may contribute to the development of seizures.

The committee assesses the mechanistic evidence regarding an association between MMR vaccine and febrile seizures as intermediate based on 12 cases presenting clinical evidence.

Causality Conclusion

Conclusion 4.4: The evidence convincingly supports a causal relationship between MMR vaccine and febrile seizures.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

AFEBRILE SEIZURES

Epidemiologic Evidence

The committee reviewed 11 studies to evaluate the risk of afebrile seizures after the administration of vaccines containing measles, mumps, and rubella alone or in combination. Seven studies (Al Awaidy et al., 2010; Bino et al., 2003; D’Souza et al., 2000; Fescharek et al., 1990; Patja et al., 2000; Stetler et al., 1985; Vahdani et al., 2005) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations. Two controlled studies (Griffin et al., 1991; Menniti-Ippolito et al., 2007) had very serious methodological limitations that precluded their inclusion in this assessment. The study by Menniti-Ippolito et al. (2007) used a self-report questionnaire but did not validate vaccination histories and provided inadequate information for the selection of controls. A study by Griffin et al. (1991) was described in detail in the section on febrile seizures following MMR vaccination. This retrospective cohort study did not observe an adequate number of children with afebrile seizures to estimate a relative risk; the authors only report that one child had afebrile seizures 1 and 3 days after vaccination.

The two remaining controlled studies (Barlow et al., 2001; Davis et al., 1997) contributed to the weight of epidemiologic evidence and are described below.

Davis et al. (1997) conducted a retrospective cohort study in children enrolled in the Group Health Cooperative (GHC) of Puget Sound and Northern California Kaiser (NCK) HMOs. The study included children who received MMR immunizations from March 1991 through December 1994, and were enrolled in the HMO at least 3 months before and 3 months after vaccination. Children in two age groups were examined: 4 to 6 years and 10 to 12 years. Based on routine practice in the GHC and NCK the authors assumed that an MMR immunization received in either of these two age groups was a second dose. History of a previous MMR vaccination was not validated. Other immunizations were given concurrently in some children: hepatitis B vaccine was most common in the 10- to 12-year age group, and DTaP (or DT or Td) and oral polio virus vaccines were mainly seen in the 4- to 6-year age group. The risk period began the day after immunization and continued for 30 days; the control period began 3 months before immunization and continued for 30 days, ending 2 months before immunization. A total of 18,036 children aged 10 to 12 years and 8,514 children aged 4 to 6 years were included in the analysis. Clinic, emergency department, and hospital visits for seizures were obtained from the medical records, and chart validation was performed to confirm the event. The

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

4- to 6-year-olds reported no chart-confirmed visits for seizure diagnoses during the risk period. The 10- to 12-year-olds reported more seizure diagnoses during the risk period (three cases) compared to the control period (no cases). The three seizures were described as one grand mal seizure, one syncopal seizure, and one partial complex seizure. Two of the children had similar seizure episodes that occurred before MMR vaccination and one was evaluated for a tic disorder prior to vaccination.

The study by Barlow et al. (2001) was described in detail in the section on febrile seizures following MMR vaccination. This retrospective cohort study assessed the risk of afebrile seizures within 0–7 days, 8–14 days, and 15–30 days of MMR vaccination. Of the 716 validated diagnoses of first seizure, 137 were afebrile seizures; seizures among children with diagnoses of epilepsy or residual seizure disorder were also classified as afebrile seizures. The relative risk of afebrile seizures within 8–14 days of MMR vaccination was 1.11 (95% CI, 0.11–11.28) and within 15–30 days was 0.48 (95% CI, 0.05–4.64); a relative risk was not calculated for afebrile seizures within 0–7 days of MMR vaccination. The authors found that MMR vaccination is not associated with an increased risk of afebrile seizures, but the confidence intervals were very wide.

Weight of Epidemiologic Evidence

Two large studies (Barlow et al., 2001; Davis et al., 1997) failed to identify enough cases to adequately address whether MMR vaccination is associated with an increased risk of afebrile seizures. See Table 4-3 for a summary of the studies that contributed to the weight of epidemiologic evidence.

The committee has limited confidence in the epidemiologic evidence, based on two studies that lacked validity and precision to assess an association between MMR vaccine and afebrile seizures.

Mechanistic Evidence

The committee identified 10 publications reporting afebrile seizures developing after the administration of measles, mumps, and rubella alone or in combination. Popovic-Miocinovic et al. (1994) did not observe exacerbation of epilepsy after vaccination against measles in patients undergoing anticonvulsant therapy. One publication identified the development of status epilepticus in one patient after administration of a measles vaccine, but details including the time frame between vaccination and the development of symptoms were not provided (Scholtes et al., 1996). Eight publications did not provide evidence beyond temporality, some too short based on the

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

TABLE 4-3 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Afebrile Seizures


Citation Operationally Defined Outcome Study Setting Defined Study Population Study Design Sample Size Primary Effect Size Estimatea (95% CI or p value) Heterogeneous Subgroups at Higher Riskb Limitations (Negligible or Serious)c

Davis et al. (1997) Chart-confirmed clinic, emergency department, and hospital visits for seizures and NCK HMOs from 3/1991 through 12/1994 Ages 4-6 years and 10-12 years Retrospective cohort 18,036 children ages 10-12 years 4- to 6-year-olds: No chart-confirmed visits for seizure diagnoses None described Serious
Risk period: 1 month after MMR vaccination 8,514 children ages 4-6 years 10- to 12-year-olds: Three seizures diagnoses during the risk period compared to none during the control period
Control period: Began 3 months before MMR vaccination and ended 2 months before vaccination
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Citation Operationally Defined Outcome Study Setting Defined Study Population Study Design Sample Size Primary Effect Size Estimatea (95% CI or p value) Heterogeneous Subgroups at Higher Riskb Limitations (Negligible or Serious)c

Barlow et al. (2001) Validated diagnoses of afebrile seizures from medical records obtained in the HMO data systems Four HMOs participating in the VSD from 1991-1993 Ages 0-6 years Retrospective cohort 137 children with afebrile seizures Adjusted RR of afebrile seizures within 8-14 days of MMR vaccination: 1.11 (95% CI, 0.11-11.28) None described Serious
Seizures among children with diagnoses of epilepsy or residual seizure disorder were also classified as afebrile seizures Risk periods: 0-7 days, 8-14 days, and 15-30 days after MMR vaccination Three afebrile seizures occurred within 30 days of MMR vaccination Adjusted RR of afebrile seizures within 15-30 days of MMR vaccination: 0.48 (95% CI, 0.05-4.64)
RR was not calculated for afebrile seizures within 0-7 days of MMR vaccination

a The committee assumed statistical significance below the conventional 0.05 level unless otherwise stated by the authors.
b The risk/effect estimate for the subgroup/alternate definition of exposure or outcome differs significantly (e.g., is heterogeneous with nonoverlapping 95% confidence intervals) compared with the risk/effect estimate reported for the primary group/definition.
c Studies designated as serious had more methodological limitations than those designated as negligible. Studies assessed as having very serious limitations were not considered in the weight of epidemiologic evidence.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

possible mechanisms involved (Ehrengut and Zastrow, 1989; Fescharek et al., 1990; Konkel et al., 1993; Kumar et al., 1982; Nader and Warren, 1968; Schneck, 1968; Wiersbitzky et al., 1993b, 1995). The publications did not contribute to the weight of mechanistic evidence.

Weight of Mechanistic Evidence

The committee assesses the mechanistic evidence regarding an association between MMR vaccine and afebrile seizures as lacking.

Causality Conclusion

Conclusion 4.5: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and afebrile seizures.

MENINGITIS

Epidemiologic Evidence

The committee reviewed nine studies to evaluate the risk of meningitis after the administration of MMR vaccine. Three studies (Fescharek et al., 1990; Miller et al., 1993; Schlipköter et al., 2002) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations. Three controlled studies (Davis et al., 1997; dos Santos et al., 2002; Miller et al., 2007) had very serious methodological limitations that precluded their inclusion in this assessment. The studies by Davis et al. (1997) and dos Santos et al. (2002) were unable to find any cases of meningitis following MMR immunization, so no conclusions could be drawn from these analyses. Miller et al. (2007) conducted a retrospective cohort study comparing the risk of meningitis after MMR vaccination with an RIT 4385 mumps component (derived from the Jeryl Lynn strain) to a historical control population. The historical comparison group also received MMR vaccine (Urabe mumps component) and was inadequate for assessing the risk of meningitis following the administration of RIT 4385 mumps component MMR vaccine.

The three remaining controlled studies (Black et al., 1997; Ki et al., 2003; Makela et al., 2002) contributed to the weight of epidemiologic evidence and are described below.

Black et al. (1997) conducted a case-control study in children (12 to 23 months of age) with meningitis enrolled at four HMOs participating in the VSD from 1984 to 1993. The cases were identified in the HMO hospitaliza-

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

tion records. The medical record of each case was reviewed to validate the meningitis diagnosis and ensure the absence of a prior underlying disease; the controls also had no evidence of underlying illness. Two controls were matched to each case on age (within 1 month), sex, HMO, and HMO membership status. A total of 59 cases and 118 matched controls were included in the analysis. The odds ratio for developing meningitis after the administration of MMR vaccine in combination with other vaccines was reported for three time intervals: within 14 days, 0.50 (95% CI, 0.1–4.5); within 30 days, 0.84 (95% CI, 0.2–3.5); and within 8 to 14 days, 1.00 (95% CI, 0.1–9.2). The authors concluded that MMR vaccination does not appear to increase the risk of hospitalization for aseptic meningitis in children, but the confidence intervals were very wide.

The study by Makela et al. (2002) was described in detail in the section on encephalitis and encephalopathy. This retrospective cohort study investigated the occurrence of aseptic meningitis following MMR vaccination in children (1 to 7 years of age) in Finland. Cases of aseptic meningitis identified in the nationwide hospital discharge register that occurred within 3 months of vaccination were validated with information from the patients’ medical records, and the exact dates of vaccination were verified. The risk period was defined as 3 months after vaccination; the control period was defined as subsequent 3-month postvaccination intervals until 24 months was reached. A total of 161 children were hospitalized for aseptic meningitis during the study period, of which 10 occurred within 3 months of MMR vaccination, 54 occurred in the subsequent 21 months, and 41 occurred before MMR vaccination. The analysis did not find an increase of aseptic meningitis hospitalizations within 3 months of vaccination (p = .57). The authors concluded that MMR vaccination does not appear to increase the risk of aseptic meningitis in children.

Ki et al. (2003) conducted a case-crossover study in children (8 to 36 months of age) with aseptic meningitis residing in Korea during 1998. The cases were identified using insurance claims data and included if they were hospitalized at the time of their diagnosis. A parental telephone survey was used to collect information on prior vaccinations; only patients that provided the vaccination date and place of vaccination from a vaccine record were included. Since information on the mumps strain used was not available, the authors assumed the MMR vaccines administered at public health centers would contain Urabe or Hoshino strains, and those administered at private clinics or hospitals would contain Jeryl Lynn or Rubini strains. A total of 67 children who received MMR vaccine within 1 year of aseptic meningitis onset were included in the analysis, of which 29 received Urabe or Hoshino mumps strain and 38 received Jeryl Lynn or Rubini mumps strain. Since neither Urabe nor Hoshino strain were used in the United States, the committee only looked at the results of the subset of patients

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

who received either Jeryl Lynn (U.S. mumps vaccine strain) or Rubini strain. The risk period was defined as 42 days before disease onset and the control period extended to 1 year before onset excluding the risk period (cases were self-matched). In the Jeryl Lynn or Rubini group (n = 38), the relative risk of aseptic meningitis within 42 days of MMR vaccination was 0.6 (95% CI, 0.18–1.97). The authors concluded that MMR vaccination with Jeryl Lynn or Rubini mumps strain does not appear to be associated with an increased risk of aseptic meningitis in children.

Weight of Epidemiologic Evidence

Three studies evaluating the risk of aseptic meningitis after MMR vaccination were included in the committee’s review of the epidemiologic evidence (Black et al., 1997; Ki et al., 2003; Makela et al., 2002). None of these studies found a significant increased risk of aseptic meningitis after MMR vaccination with strains used in the United States. Although power was limited in all the studies, they were generally well done and results were consistent, supporting the committee’s conclusion that the evidence overall reached a moderate level of confidence for a null association. See Table 4-4 for a summary of the studies that contributed to the weight of epidemiologic evidence.

The committee has a moderate degree of confidence in the epide-miologic evidence based on three studies with sufficient validity and precision to assess an association between MMR vaccine and meningitis; these studies consistently report a null association.

Mechanistic Evidence

The committee identified eight publications reporting meningitis after the administration of vaccines containing measles, mumps, and rubella alone or in combination. Usonis et al. (1999) reported one case of suspected meningitis or febrile seizure after MMR vaccination but did not provide clinical, diagnostic, or experimental evidence, including the time frame between vaccine administration and development of symptoms. Two publications described multiple cases, some of which did not provide evidence beyond temporality or attributed the symptoms to another etiology (Ehrengut and Zastrow, 1989; Fescharek et al., 1990). These cases did not contribute to the weight of mechanistic evidence. Four publications did not provide evidence of causality beyond a temporal relationship between vaccination and the development of symptoms (Jorch et al., 1984; Riordan et al., 1995; Wiersbitzky et al., 1992a,b). In addition, two publications attributed the development of meningitis postvaccination to concomitant

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

TABLE 4-4 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Meningitis


Citation Operationally Defined Outcome Study Setting Defined Study Population Study Design Sample Size Primary Effect Size Estimatea (95% CI or p value) Heterogeneous Subgroups at Higher Riskb Limitations (Negligible or Serious)c

Black ct al. (1997) Meningitis diagnosis identified in the medical record Four HMOs participating in the VSD from 1984-1993 Ages 12-23 months Case-control 59 children with meningitis OR for meningitis diagnosis within 14 days of MMR vaccination: 0.50 (95% CI 0.1-4.5) None described Negligible
Controls matched by age (within 1 month), sex, HMO, and HMO membership status 118 matched controls OR for meningitis diagnosis within 30 days of MMR vaccination: 0.84 (95% CI 0.2-3.5)
OR for meningitis diagnosis within 8-14 days of MMR vaccination: 1.00 (95% CI 0.1-9.2)
Makela et al. (2002) Aseptic meningitis identified in the nationwide hospital Finland from 11/1982 to 6/1986 Ages 1-7 years Retrospective cohort
Risk period: 0-3 months after MMR vaccination
535,544 children
161 children hospitalized for meningitis
No significant increase in aseptic meningitis within 3 months of MMR vaccination None described Serious
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
discharge register Control period: Subsequent 3-month intervals after the risk period until 24 months was reached 10 meningitis events occurred within 3 months of MMR vaccination (p = .57)
Ki et al. (2003) Aseptic meningitis identified in insurance claims data Korea during 1998 Ages 8-36 months Case-crossover
Risk period: 42 days before the onset of meningitis
38 children received MMR vaccines with Jeryl Lynn or Rubini mumps strains Aseptic meningitis within 42 days of MMR vaccination (Jeryl Lynn or Rubini mumps strain): 0.6 (95% CI, 0.18-1.97) None described Serious
Control period; 1 year before the onset of meningitis excluding the risk period Three children had aseptic memnpitis within 42 days of vaccination

a The committee assumed statistical significance below the conventional 0.05 level unless otherwise stated by the authors.
b The risk/effect estimate for the subgroup/alternate definition of exposure or outcome differs significantly (e.g., is heterogeneous with nonoverlapping 95% confidence intervals) compared with the risk/effect estimate reported for the primary group/definition.
c Studies designated as serious had more methodological limitations than those designated as negligible. Studies assessed as having very serious limitations were not considered in the weight of epidemiologic evidence.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

infections (Jorch et al., 1984; Riordan et al., 1995). These cases did not contribute to the weight of mechanistic evidence.

Described below are three publications describing clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

The case reported by Bakshi et al. (1996) was described in detail in the section on encephalitis. The authors reported the isolation of mumps virus from the urine, serum, and CSF in a patient that developed symptoms of meningoencephalitis after administration of a MMR vaccine.

Ehrengut and Zastrow (1989) reported five cases of meningitis after vaccination against either mumps or measles and mumps. Case 3 described a 6-year-old boy presenting with vomiting, dizziness, and fever 21 days after receiving a mumps vaccine containing the Jeryl Lynn mumps strain. Mumps virus was demonstrated in pharyngeal smears. Cell culture examination showed that the isolated virus produced fewer syncytia, smaller inclusion bodies, and induced less cell damage to monkey kidney cells than wild-type mumps virus, suggesting vaccine-strain virus.

Fescharek et al. (1990) reported 14 cases of meningitis after vaccination against either mumps, measles and mumps, or measles, mumps, and rubella. Case 8 describes a 6-year-old boy presenting with diarrhea and vomiting 1 day after, and headache, fever, abdominal pain, and meningism 9 days after receiving a measles and mumps vaccine. Mumps virus was demonstrated in pharyngeal fluid. Case 12 describes an 8-year-old boy (whose friend’s sister was suffering from mumps) presenting with fatigue, and malaise 9 days after, and vomiting and fever 12 days after receiving a mumps vaccine. ECHO virus type II was demonstrated in the stool, and mumps virus was demonstrated in the CSF.

Weight of Mechanistic Evidence

Meningitis develops in 1–10 percent of persons infected with wild-type mumps virus (Litman and Baum, 2010). Furthermore, mumps meningitis can present before, during, or after parotitis (Litman and Baum, 2010). The committee considers the effects of natural infection one type of mechanistic evidence.

The three publications described above did not present evidence sufficient for the committee to conclude the vaccine may be a contributing cause of meningitis after administration of a vaccine containing measles, mumps, and rubella alone or in combination. The publications reported the isolation of mumps virus from urine, blood, pharyngeal fluid and smears, and CSF, but while one publication reported the isolation of a mumps virus that acted similarly to vaccine strain mumps virus in cell culture studies, no publications definitively reported the isolation of vaccine strain mumps virus.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

The latency between vaccination and the development of meningitis in the publications described above ranged from 9 days to 9 months, suggesting direct viral infection or persistent viral infection as the mechanism.

The committee assesses the mechanistic evidence regarding an association between mumps vaccine and meningitis as weak based on knowledge about the natural infection and four cases.

The committee assesses the mechanistic evidence regarding an association between measles or rubella vaccine and meningitis as lacking.

Causality Conclusion

Conclusion 4.6: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and meningitis.

ATAXIA

Epidemiologic Evidence

The committee reviewed four studies to evaluate the risk of ataxia after the administration of vaccines containing measles, mumps, and rubella alone or in combination. These four studies (Fescharek et al., 1990; Geier and Geier, 2003; Landrigan and Witte, 1973; Plesner et al., 2000) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between MMR vaccine and ataxia.

Mechanistic Evidence

The committee identified eight publications reporting ataxia after the administration of vaccines containing measles, mumps, and rubella alone or in combination. Seven publications did not provide evidence beyond temporality (Ehrengut and Zastrow, 1989; Fescharek et al., 1990; Martinon-Torres, 1999; Nader and Warren, 1968; Peltola et al., 1998; Plesner et al., 2000; Trump and White, 1967). It was unclear what viral strains were

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

administered to the patient described by Martinon-Torres (1999). These publications did not contribute to the weight of mechanistic evidence.

Described below is one publication reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Landrigan and Witte (1973) retrospectively analyzed cases of neurological disorders developing within 1 month after administration of a measles vaccine from 1963 to 1971 reported to the Immunization Branch of the Center for Disease Control. The authors report three cases of ataxia developing after vaccination. Measles virus was demonstrated in the CSF of one patient that developed choreoathetosis and ataxia 7 days after vaccination. Laboratory analysis including infectivity titer, plaquing, and tissue culture sensitivity suggest the isolated virus to be vaccine-like.

Weight of Mechanistic Evidence

While rare, infection with wild-type mumps is associated with cerebellar ataxia (Litman and Baum, 2010). In addition, invasion of the central nervous system by wild-type measles virus is common (Gershon, 2010a). The committee considers the effects of natural infection one type of mechanistic evidence.

The publication described above did not present evidence sufficient for the committee to conclude the vaccine may be a contributing cause of ataxia. The publication reported the demonstration of measles virus in the CSF and that the isolated virus acted similarly to vaccine-strain measles virus in cell culture studies. However, the publication did not definitively report the isolation of vaccine strain measles virus.

The latency between vaccination and the development of ataxia in the publication described above was 7 days, suggesting direct viral infection as the mechanism.

The committee assesses the mechanistic evidence regarding an association between measles or mumps vaccine and ataxia as weak based on knowledge about the natural infection and one case.

The committee assesses the mechanistic evidence regarding an association between rubella vaccine and ataxia as lacking.

Causality Conclusion

Conclusion 4.7: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and ataxia.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

AUTISM

Epidemiologic Evidence

The committee reviewed 22 studies to evaluate the risk of autism after the administration of MMR vaccine. Twelve studies (Chen et al., 2004; Dales et al., 2001; Fombonne and Chakrabarti, 2001; Fombonne et al., 2006; Geier and Geier, 2004; Honda et al., 2005; Kaye et al., 2001; Makela et al., 2002; Mrozek-Budzyn and Kieltyka, 2008; Steffenburg et al., 2003; Takahashi et al., 2001, 2003) were not considered in the weight of epidemiologic evidence because they provided data from a passive surveillance system lacking an unvaccinated comparison population or an ecological comparison study lacking individual-level data. Five controlled studies (DeStefano et al., 2004; Richler et al., 2006; Schultz et al., 2008; Taylor et al., 2002; Uchiyama et al., 2007) had very serious methodological limitations that precluded their inclusion in this assessment. Taylor et al. (2002) inadequately described the data analysis used to compare autism compounded by serious bowel problems or regression (cases) with autism free of such problems (controls). DeStefano et al. (2004) and Uchiyama et al. (2007) did not provide sufficient data on whether autism onset or diagnosis preceded or followed MMR vaccination. The study by Richler et al. (2006) had the potential for recall bias since the age at autism onset was determined using parental interviews, and their data analysis appeared to ignore pair-matching of cases and controls, which could have biased their findings toward the null. Schultz et al. (2008) conducted an Internet-based case-control study and excluded many participants due to missing survey data, which increased the potential for selection and information bias.

The five remaining controlled studies (Farrington et al., 2001; Madsen et al., 2002; Mrozek-Budzyn et al., 2010; Smeeth et al., 2004; Taylor et al., 1999) contributed to the weight of epidemiologic evidence and are described below.

Taylor et al. (1999) conducted a self-controlled case-series study in children with autistic disorders residing in the North East Thames region of the United Kingdom. The children were identified from computerized special needs or disability registers. A total of 498 children who were born from 1979 through 1998 and had an autism diagnosis before 16 years of age were included in the analysis. After reviewing the clinical records, the investigators confirmed that the autism diagnoses met the criteria of the International Classification of Diseases, 10th revision (ICD-10) in 82 percent of typical autism cases and 31 percent of atypical autism cases (the authors used the term core to describe typical autism, as noted in the methods). The self-controlled analysis investigated the risk of typical or atypical autism diagnosis among 357 cases during two postvaccination periods (12 or 24

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

months after vaccination). The reference period consisted of time from birth through August 1998, not including the postvaccination risk periods. The relative risk of autism diagnosis within 12 months of MMR vaccination was 0.94 (95% CI, 0.60–1.47) and within 24 months of MMR vaccination was 1.09 (95% CI, 0.79–1.52). The relative risk of autism diagnosis within 12 months and 24 months of vaccination with MMR or single-antigen measles with mumps and rubella was 0.80 (95% CI, 0.53–1.22) and 1.05 (95% CI, 0.76–1.44), respectively. The authors noted the results were similar when the analyses were restricted to confirmed cases of typical or atypical autism. The authors concluded that MMR vaccination is not associated with autism.

Farrington et al. (2001) conducted a reanalysis of the study by Taylor et al. (1999). The two risk periods were changed to autism diagnosis within 59 months and any time after vaccination, and compared to a reference period that consisted of time from birth through 191 months of age or August 1998, whichever occurred first. The analysis was adjusted for both calendar year and age. The relative risk of autism diagnosis within 59 months of vaccination with MMR was 1.24 (95% CI, 0.67–2.27), and with MMR and any measles-containing vaccines was 0.96 (95% CI, 0.52–1.77). The relative risk of autism diagnosis any time after vaccination with MMR was 1.06 (95% CI, 0.49–2.30), and with MMR and any measles-containing vaccines was 2.03 (95% CI, 0.80–5.18). The authors concluded that there is no association between MMR or measles-containing vaccines and autism diagnosis any time after vaccination.

Madsen et al. (2002)2 conducted a retrospective cohort study in children born in Denmark from January 1991 through December 1998. The children were enrolled from the Danish Civil Registration System, which stores personal identification information for all residents, and linked records to five other national registries. MMR vaccination data were obtained from the National Board of Health; autism diagnosis was derived from the Danish Psychiatric Central Register. The National Hospital Registry and Danish Medical Birth Registry provided birth weight and gestational age information, and data on socioeconomic status and mother’s education came from Statistics Denmark. Autism diagnoses were based on criteria from the ICD-10; the diagnostic codes were separated into cases of autistic disorder or other autistic-spectrum disorders. Children with congenital rubella or an inherited genetic condition (fragile X syndrome, Angelman’s syndrome, or tuberous sclerosis) were excluded from the analysis. A total of 537,303 children were included in the cohort, of which 316 had an autistic disorder diagnosis and 422 had an autistic-spectrum disorder diagnosis. Follow-up

___________

2 One of the authors of this article, P. Thorsen, was indicted for embezzlement on April 13, 2011. The implications for the integrity of the study are unknown at this time.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

began at 1 year of age and continued through December 31, 1999, or the date of autism diagnosis, diagnosis of other associated conditions, emigration, or death. Children who were vaccinated with MMR contributed 1,647,504 person-years of follow-up, and those not vaccinated contributed 482,360 person-years. Relative risks were calculated and adjusted for age, calendar period, sex, birth weight, gestation age, mother’s education, and socioeconomic status. The adjusted relative risk of autism diagnosis after MMR vaccination was 0.92 (95% CI, 0.68–1.24) and of other autistic spectrum disorders after MMR vaccination was 0.83 (95% CI, 0.65–1.07). The authors concluded that MMR vaccination is not associated with an increased risk of autistic disorder or other autistic-spectrum disorders.

Smeeth et al. (2004) conducted a case-control study in children (born between 1973 and 1999) enrolled in the General Practice Research Database (GPRD) from June 1987 through December 2001. The study included 991 cases with a recorded diagnosis of autism and 303 cases with other pervasive developmental disorder diagnosis. A total of 4,469 controls were individually matched to cases on year of birth (within 1 year), sex, and general practice. The study excluded cases and controls that were not enrolled in the database for at least 12 months before the diagnosis or index date (date that control was same age as matched case at time of diagnosis). MMR vaccination data were abstracted from the GPRD records, and the case or control status was concealed during the assessment. The unadjusted odds ratio for autism diagnosis after MMR vaccination was 0.77 (95% CI, 0.60–0.98). After adjustment for the age at which participants joined the GPRD, the odds ratio was 0.88 (95% CI, 0.67–1.15). The authors concluded that MMR vaccination is not associated with an increased risk of autism.

Mrozek-Budzyn et al. (2010) conducted a case-control study in children identified in the general practitioner records in the Malopolska Province of Poland. The study included 96 cases and 192 matched controls. The cases were diagnosed with childhood or atypical autism by a child psychiatrist according to the ICD-10 criteria. Two controls were matched to each case on year of birth, gender, and physician’s practice. Vaccination histories and the date of autism diagnosis were extracted from the physician’s records. Date of onset of symptoms was derived from parental interview. If MMR or single-antigen measles vaccination preceded the onset of symptoms, cases were classified as vaccinated. Controls were considered vaccinated if they received an MMR or single-antigen measles vaccine before the age of symptom onset observed in the matched case. The analysis adjusted for mother’s age, medication during pregnancy, gestation time, perinatal injury, and 5-minute Apgar scale score. The adjusted odds ratio for autism diagnosis after MMR vaccination was 0.17 (95% CI, 0.06–0.52). The adjusted odds ratio for autism diagnosis after single-antigen measles or MMR vaccination

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

was 0.28 (95% CI, 0.10–0.76). The authors concluded that administration of MMR or single-antigen measles vaccine is not associated with an increased risk of autism in children.

Weight of Epidemiologic Evidence

Three unique studies (Madsen et al., 2002; Smeeth et al., 2004; Taylor et al., 1999) were judged to have negligible limitations; all reported null associations (on average) between MMR vaccination and subsequent autism diagnosis (or onset) and the overall precision was high. A separate report (Farrington et al., 2001) using the same population and methods as Taylor et al. (1999) reported a null association (moderate precision) between MMR vaccination and subsequent onset or diagnosis of the regressive subtype of autism. The fifth study (Mrozek-Budzyn et al., 2010) also found no association between measles or MMR immunization using a hospital-based case-control design with appropriate methods for matching and analysis. This study was rated as having serious limitations because it did not provide information on medical conditions among the controls and relied on medical record abstraction for immunization dates and autism diagnosis dates. Overall, the studies were reasonably valid, and provided consistent and precise evidence supporting no increased risk. See Table 4-5 for a summary of the studies that contributed to the weight of epidemiologic evidence.

The committee has a high degree of confidence in the epidemiologic evidence based on four studies with validity and precision to assess an association between MMR vaccine and autism; these studies consistently report a null association.

Mechanistic Evidence

The committee identified four publications reporting autism developing after the administration of MMR vaccine. Three publications did not provide evidence beyond temporality, some too long (Frenkel et al., 1996; Spitzer et al., 2001; Wakefield et al., 1998).3 Long latencies between vaccine administration and development of behavioral symptoms make it impossible to rule out other possible causes. In addition, the committee identified an editorial by Sharrard (2010) in which a temporal relationship between administration of a measles, mumps, and rubella vaccine and the development of autism was attributed to one patient reported in Verity et al. (2010). However, as reported in the original article and affirmed in a subsequent letter to the editor (Verity et al., 2011) the vaccinee did not

___________

3 During the committee’s review the publisher issued a retraction of Wakefield et al. (1998).

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

TABLE 4-5 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Autism


Citation Operationally Defined Outcome Study Setting Defined Study Population Study Design Sample Size Primary Effect Size Estimatea (95% CI or p value) Heterogeneous Subgroups at Higher Riskb Limitations (Negligible or Serious)c

Taylor et al. (1999) Autism diagnosis obtained from computerized special needs or disability registers North East Thames Region of United Kingdom Children born from 1979-1998, with autism diagnosis before age 16 Self-controlled case series 357 children with autism diagnosis RR of autism diagnosis within 12 months of MMR vaccination: 0.94 (95% CI, 0.60-1.47) RR of parental concern within 6 months of MMR vaccination: 1.48 (95% CI, 1.04-2.12) Negligible
82 percent of typical autism cases and 31 percent of atypical autism cases met ICD-10 criteria Risk periods: 12 and 24 months after vaccination RR of autism diagnosis within 24 months of MMR vaccination: 1.09 (95% CI, 0.79-1.52)
Control period: time from birth through August 1998, not including the post-vaccination risk period
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Citation Operationally Defined Outcome Study Setting Defined Study Population Study Design Sample Size Primary Effect Size Estimatea (95% CI or p value) Heterogeneous Subgroups at Higher Riskb Limitations (Negligible or Serious)c

Farrington et al. (2001) Autism diagnosis obtained from computerized special needs or disability registers North East Thames Region of United Kingdom Children born from 1979-1998, with autism diagnosis before age 16 Self-controlled case series 357 children with autism diagnosis RR of autism diagnosis within 59 months of MMR vaccination: 1.24 (95% CI, 0.67-2.27) None described Negligible
Reanalysis of Taylor et al. (1999) 82% of typical autism cases and 31% of atypical autism cases met ICD-10 criteria Risk periods: 59 months and anytime after vaccination RR of autism diagnosis anytime after MMR vaccination: 1.06 (95% CI, 0.49-2.30)
Control period: time from birth to 191 months of age or August 1998, not including post-vaccination risk period
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Madsen et al. (2002) Autism diagnosis met the ICD-10 criteria and was obtained from Danish Psychiatric Central Register Danish Civil Registration System and five other national registries Children born in Denmark from 1/1/1991 through 12/31/1998 Retrospective cohort 537,303 children Adjusted RR of autism diagnosis after MMR vaccination: 0.92 (95% CI, 0.68-1.24) None described Negligible
316 children with autism diagnosis Adjusted RR of diagnosis of other autistic spectrum disorders following MMR vaccination: 0.83 (95% CI, 0.65-1.07)
1,647,504 person-years of follow-up for exposed group
482,360 person-years of follow-up for unexposed group
Smeeth et al. (2004) Autism diagnosis obtained from medical records GPRD Children born from 1973-1999 and enrolled in the GPRD from 6/1/1987 through 12/31/2001 Case-control 991 children with autism diagnosis Unadjusted OR for autism diagnosis after MMR vaccination: 0.77 (95% CI, 0.60-0.98) None described Negligible
4,469 controls Adjusted OR for autism diagnosis after MMR vaccination: 0.88 (95% CI, 0.6-1.15; p = .35
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Citation Operationally Defined Outcome Study Setting Defined Study Population Study Design Sample Size Primary Effect Size Estimatea (95% CI or p value) Heterogeneous Subgroups at Higher Riskb Limitations (Negligible or Serious)c

Mrozek-Budzyn et al. (2010) Autism diagnosis met the ICD-10 criteria and was obtained from general practitioner records Malopolska Province of Poland Children ages 2-15 years with general practice records Case-control 96 children with autism diagnosis Adjusted OR for autism diagnosis after MMR vaccination: 0.17 (95% CI, 0.06-0.52) None described Serious
Controls matched by age, gender, and physician's practice 192 controls Adjusted OR for autism diagnosis after single-antigen measles or MMR vaccination: 0.28 (95% CI, 0.10-0.76)

a The committee assumed statistical significance below the conventional 0.05 level unless otherwise stated by the authors.
b The risk/effect estimate for the subgroup/alternate definition of exposure or outcome differs significantly (e.g., is heterogeneous with nonoverlapping 95% confidence intervals) compared with the risk/effect estimate reported for the primary group/definition.
c Studies designated as serious had more methodological limitations than those designated as negligible. Studies assessed as having very serious limitations were not considered in the weight of epidemiologic evidence.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

develop autism, a fact that was misreported in the editorial by Sharrard. Two publications studied the association between MMR vaccination and autism with enteropathy (Hornig et al., 2008; Peltola et al., 1998). The authors reported a temporal relationship between vaccine administration and development of gastrointestinal disturbances but did not report autism after vaccination. The publications did not contribute to the weight of mechanistic evidence.4

Weight of Mechanistic Evidence

The committee assesses the mechanistic evidence regarding an association between MMR vaccine and autism as lacking.

Causality Conclusion

Conclusion 4.8: The evidence favors rejection of a causal relationship between MMR vaccine and autism.

ACUTE DISSEMINATED ENCEPHALOMYELITIS

Epidemiologic Evidence

The committee reviewed one study to evaluate the risk of acute disseminated encephalomyelitis (ADEM) after the administration of measles vaccine. This one study (Landrigan and Witte, 1973) was not considered in the weight of epidemiologic evidence because it provided data from a passive surveillance system and lacked an unvaccinated comparison population.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between MMR vaccine and ADEM.

Mechanistic Evidence

The committee identified three publications reporting the development of ADEM after the administration of vaccines containing measles, mumps, and rubella alone or in combination. The publications did not provide evidence beyond temporality (Gomez Sanchez et al., 2005; Landrigan and

___________

4 The case report authored by Poling et al. (2006) is described in the section under encephalopathy.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Witte, 1973; Tenembaum et al., 2002). The publications did not contribute to the weight of mechanistic evidence.

Weight of Mechanistic Evidence

While rare, wild-type measles, mumps, or rubella infections have been associated with the development of ADEM (Davis, 2008). The committee considers the effects of natural infection one type of mechanistic evidence.

The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of ADEM. Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms of ADEM; however, the publications did not provide evidence linking these mechanisms to MMR vaccine.

The committee assesses the mechanistic evidence regarding an association between MMR vaccine and ADEM as weak based on knowledge about the natural infection.

Causality Conclusion

Conclusion 4.9: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and ADEM.

TRANSVERSE MYELITIS

Epidemiologic Evidence

The committee reviewed one study to evaluate the risk of transverse myelitis after the administration of measles vaccine. This one study (Landrigan and Witte, 1973) was not considered in the weight of epidemiologic evidence because it provided data from a passive surveillance system and lacked an unvaccinated comparison population.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between MMR vaccine and transverse myelitis.

Mechanistic Evidence

The committee identified five publications reporting the development of transverse myelitis after the administration of vaccines containing measles, mumps, and rubella alone or in combination. Two publications did not provide evidence beyond temporality (Cizman et al., 2005; Landrigan and

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Witte, 1973). In addition, Cizman et al. (2005) reported the concomitant administration of vaccines, making it difficult to determine which, if any, vaccine could have been the precipitating event. Furthermore, Cizman et al. (2005) reported serologic testing that showed an acute infection with Epstein-Barr virus that could have contributed to the development of transverse myelitis. This publication did not contribute to the weight of mechanistic evidence.

Described below are three publications describing clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Holt et al. (1976) described a 17-year-old girl presenting with sensory and motor impairment in the legs and transient paraesthesiae in the left arm 2 weeks after administration of a rubella vaccine containing the RA 27/3 strain. The vaccine was administered 1 week postpartum. Over the ensuing 3 days the patient developed anaesthesia below D4 dermatomal level, flaccid paraplegia with retention of urine, and fecal incontinence. The serum rubella haemagglutination inhibition titers increased from 1:20 prevaccination to 1:128 19 days postvaccination.

Lim et al. (2004) described a 9-year-old girl presenting with urinary incontinence 16 days after administration of a measles and rubella vaccine containing the Edmonston-Zagreb measles strain and RA 27/3 rubella strains. Lower limb weakness and back pain developed 4 days later. Serological testing was negative for Mycoplasma, herpes simplex virus, varicella zoster virus, and cytomegalovirus.

Joyce and Rees (1995) described a 20-year-old man presenting with malaise, fever, sore throat, and a transient rash over the upper torso 5 days after administration of a measles, mumps, and rubella vaccine. The symptoms fluctuated over the ensuing 2 weeks after which the patient developed urinary retention and ascending paraesthesia. Serologic testing showed a significant rise in titers of rubella antibodies postvaccination.

Weight of Mechanistic Evidence

While rare, infection with wild-type mumps virus has been associated with the development of transverse myelitis (Litman and Baum, 2010). In addition, infection with wild-type measles and rubella viruses have been associated with the development of myelitis (Davis, 2008). The committee considers the effects of natural infection one type of mechanistic evidence.

The publications described above, when considered together, did not present evidence sufficient for the committee to conclude the vaccine may be a contributing cause of transverse myelitis. Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms of transverse myelitis; however, the publications did not provide evidence linking these mechanisms to MMR vaccine.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

The committee assesses the mechanistic evidence regarding an association between MMR vaccine and transverse myelitis as weak based on knowledge about the natural infection and three cases.

Causality Conclusion

Conclusion 4.10: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and transverse myelitis.

OPTIC NEURITIS

Epidemiologic Evidence

The committee reviewed one study to evaluate the risk of optic neuritis after the administration of MMR vaccine. This one controlled study (DeStefano et al., 2003) was included in the weight of epidemiologic evidence and is described below.

DeStefano et al. (2003) conducted a case-control study to evaluate the association between MMR vaccination and optic neuritis using data from three HMOs participating in the VSD. The optic neuritis analysis included 108 cases and 228 controls. The cases had a documented physician’s diagnosis from January 1995 through December 1999, and were matched to controls from the HMO on date of birth (within 1 year) and sex. The authors evaluated the date of disease onset using data described in the medical record or reported in the telephone interview. The immunization status was obtained from vaccination records, medical records, and telephone interviews. The study had high rates of self-reported vaccinations from outside the HMO system (64 percent of cases and 65 percent of controls) that could not be verified, which may have biased the results. The odds ratio for ever vaccinated with MMR before optic neuritis diagnosis was 0.8 (95% CI, 0.3–2.2). The authors concluded that MMR vaccination does not appear to be associated with an increased risk of optic neuritis in adults.

Weight of Epidemiologic Evidence

The committee has limited confidence in the epidemiologic evidence, based on one study that lacked validity and precision to assess an association between MMR vaccine and optic neuritis.

Mechanistic Evidence

The committee identified three publications reporting optic neuritis developing after the administration of vaccines containing measles, mumps,

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

and rubella alone or in combination. Kazarian and Gager (1978) did not provide evidence beyond temporality. This publication did not contribute to the weight of mechanistic evidence.

Described below are two publications reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Stevenson et al. (1996) described two cases of optic neuritis developing after vaccination. Case one did not provide evidence of causality beyond a temporal relationship of 3 weeks between administration of a measles and rubella vaccine and development of symptoms after vaccination. Case two described a 13-year-old girl presenting with blurred vision and pain upon movement of the left eye 18 days after receiving a measles and rubella vaccine. Laboratory examination of the CSF revealed oligoclonal bands.

Riikonen (1995) described a 13-year-old girl presenting with acute pain and decreased visual acuity in the left eye 3 months after receiving a rubella vaccine. Laboratory examination of the CSF revealed oligoclonal antibodies and intrathecal antibody production against rubella 2 months after the onset of optic neuritis. Four months later antirubella antibody titers in the CSF were increased.

Weight of Mechanistic Evidence

While rare, infection with wild-type measles, mumps, or rubella viruses have been associated with optic neuritis (Davis, 2008). The committee considers the effects of natural infection one type of mechanistic evidence.

The publications described above, when considered together, did not present evidence sufficient for the committee to conclude the vaccine may be a contributing cause of optic neuritis after administration of rubella vaccine. Laboratory analysis of the CSF from both publications revealed oligoclonal antibodies, which are present in chronic rubella infections of the central nervous system. In addition, analysis of the CSF from one publication revealed intrathecal antirubella antibody production suggesting infection of the central nervous system. However, vaccine-strain rubella virus was not isolated.

Autoantibodies, T cells, immune complexes, direct viral infection, persistent viral infection, and molecular mimicry may contribute to the symptoms of optic neuritis; however, the publications did not provide evidence linking these mechanisms to MMR vaccine.

The committee assesses the mechanistic evidence regarding an association between MMR vaccine and optic neuritis as weak based on knowledge about the natural infection and two cases.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Causality Conclusion

Conclusion 4.11: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and optic neuritis.

NEUROMYELITIS OPTICA

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of neuromyelitis optica (NMO) after the administration of MMR vaccine.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between MMR vaccine and NMO.

Mechanistic Evidence

The committee identified one publication reporting the development of NMO after the administration of rubella vaccine. Kline et al. (1982) described a 31-year-old woman presenting with left periorbital pain and a headache on the left side 5 days after vaccination. Over the next several days the patient reported pain upon left eye movement and a drop in visual acuity in the left eye. The patient developed soreness in the neck, shoulders, and lower part of the back; intermittent fever; lower extremity weakness; and sensory loss below the T-10 level. The patient’s bladder function, visual acuity, and lower extremity weakness improved upon administration of prednisone. Two weeks after cessation of prednisone therapy the patient reported a burning sensation in both arms and legs, neck pain, generalized weakness, and bilateral deterioration of visual acuity. Laboratory examination of the CSF showed immune complexes, increased levels of myelin basic protein, and rubella antibodies (detected by enzyme-linked immunoabsorbent assay).

Weight of Mechanistic Evidence

While rare, infection with wild-type rubella virus has been associated with both optic neuritis and myelitis (Davis, 2008). Patients with neuromyelitis optica develop optic neuritis and transverse myelitis. The committee considers the effects of natural infection one type of mechanistic evidence.

The publication described above did not present evidence sufficient for the committee to conclude the vaccine may be a contributing cause of

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

NMO after administration of a rubella vaccine. The isolation of immune complexes and antirubella antibodies from the CSF are suggestive of their role in development of NMO after vaccination. However, the antigen and antibodies composing the immune complexes were not identified. Autoantibodies, T cells, complement activation, direct viral infection, and molecular mimicry may also contribute to the symptoms of NMO; however, the publication did not provide evidence linking these mechanisms to MMR vaccine.

The committee assesses the mechanistic evidence regarding an association between rubella vaccine and neuromyelitis optica as weak based on knowledge about the natural infection and one case.

The committee assesses the mechanistic evidence regarding an association between measles or mumps vaccine and NMO as lacking.

Causality Conclusion

Conclusion 4.12: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and neuromyelitis optica.

MULTIPLE SCLEROSIS ONSET IN ADULTS

Epidemiologic Evidence

The committee reviewed six studies to evaluate the risk of onset (date of first symptom) of multiple sclerosis (MS) in adults after the administration of measles or MMR vaccine. One study (Ahlgren et al., 2009a) was not considered in the weight of epidemiologic evidence because it lacked an unvaccinated comparison population. Three controlled studies (Pekmezovic et al., 2004; Ramagopalan et al., 2009; Zorzon et al., 2003) had very serious methodological limitations that precluded their inclusion in this assessment. The case-control study from Pekmezovic et al. (2004) used an inadequate control group that included patients diagnosed with other various neurological disorders. Ramagopalan et al. (2009) did not attempt to validate self-reported vaccination data or confirm the timing of vaccination, and the choice of spousal controls could have introduced selection bias. Zorzon et al. (2003) conducted a case-control study among MS patients and blood donor controls that could have introduced recall or selection bias. The study did not mention if the onset of MS was verified and did not adequately describe if vaccination occurred before disease onset.

The two remaining controlled studies (Ahlgren et al., 2009b; DeStefano et al., 2003) were included in the weight of epidemiologic evidence and are described below.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

The study by DeStefano et al. (2003) was described in detail in the section on optic neuritis. This case-control study evaluated the association between MMR vaccination and MS or optic neuritis onset using data from three HMOs participating in the VSD. The MS analysis included 332 cases and 722 controls. Although there are a large number of cases and controls, the study had high rates of self-reported vaccinations from outside the HMO system (64 percent of cases and 65 percent of controls) that could not be verified, which may have biased the results. The odds ratio for ever vaccinated with MMR before MS onset was 0.9 (95% CI, 0.4–1.8). The authors concluded that MMR vaccination does not appear to be associated with an increased risk of MS onset in adults.

Ahlgren et al. (2009b) conducted a case-control study in children born in Gothenburg, Sweden, from 1959 through 1986. The MS cases were identified from administrative diagnosis registries at Sahlgrenska University Hospital and the National Patient Register of the National Board of Health and Welfare. The authors reviewed the records and confirmed the MS diagnosis, and enrolled patients who had disease onset at 10 years of age or older. The controls were randomly selected from the Gothenburg general population register and were born during the same years as the MS patients. The study included 206 cases and 888 controls. The immunization histories of the study participants were obtained from child health and school health records; the authors recorded monovalent and combined measles, mumps, and rubella vaccinations. The immunization was classified as “early” if the vaccine was given at or before 10 years of age and “late” if the vaccine was given after 10 years of age; however, the authors do not state the timing of MS onset relative to the vaccination. The odds ratio for MS onset with MMR vaccination compared to no MMR vaccination was 1.13 (95% CI, 0.62–2.05). The odds ratio for MS onset with “early” MMR vaccination compared to MMR vaccinations given at other ages was 4.92 (95% CI, 1.97–12.20). The odds ratio for MS onset with monovalent or combined measles, mumps, and rubella vaccinations compared to no vaccination was 1.22 (95% CI, 0.77–1.92). This final analysis included U.S. vaccine strains, as well as Schwarz measles strain found in the monovalent vaccine. The authors concluded that measles, mumps, and rubella vaccinations are not associated with MS onset, and noted that the increased odds ratio observed with early MMR vaccination relative to MMR vaccination given at other ages is considered weak evidence owing to the small number of subjects (only eight subjects in early vaccination group). A further weakness of this study is that the analysis was done combining all age groups, which makes it difficult to assess the true association of MMR vaccine and the onset of MS in adults.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Weight of Epidemiologic Evidence

Neither of the two case-control studies considered in the assessment of the epidemiologic evidence found an association between MMR vaccine and onset of MS in adults. However, there are some concerns about the study designs and analyses. DeStefano et al. (2003) did not define a specific exposure time and had no short-term assessment in their primary analysis. The authors performed secondary analyses considering the timing of the MMR vaccination (< 1 year, 1–5 years, and > 5 years) relative to the MS onset, which showed no significant association, but they did not state how they handled the timing of vaccination for those who had more than one MMR vaccine before the onset of MS or when MMR was given in combination with other vaccines. Ahlgren et al. (2009b) performed the analysis combining all age groups, which makes it difficult to assess the true association of MMR vaccine and the onset of MS in adults. Given these study limitations and the small number of studies, the committee has limited confidence in the overall evidence. See Table 4-6 for a summary of the studies that contributed to the weight of epidemiologic evidence.

The committee has limited confidence in the epidemiologic evidence, based on two studies that lacked validity and precision to assess an association between MMR vaccine and onset of MS in adults.

Mechanistic Evidence

The committee identified one publication reporting the onset of MS in adults after the administration of rubella vaccine. Behan (1977) did not provide evidence beyond temporality. The publication did not contribute to the weight of mechanistic evidence.

Weight of Mechanistic Evidence

The symptoms described in the publication referenced above are consistent with MS. Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms of MS; however, the publication did not provide evidence linking these mechanisms to MMR vaccine.

The committee assesses the mechanistic evidence regarding an association between MMR vaccine and onset of MS in adults as lacking.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

TABLE 4-6 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and MS Onset in Adults


Citation Operationally Defined Outcome Study Setting Defined Study Population Study Design Sample Size Primary Effect Size Estimatec (95% CI or p value) Heterogeneous Subgroups at Higher Riskb Limitations (Negligible or Serious)c

DeStefano Date of MS Three HMOs Ages 18-49 Case-control 332 Adjusted OR of MS None Serious
et al. onset from participating years at MS Controls matched by date of birth (within 1 year) patients onset anytime after described
(2003) medical records or telephone interviews in the VSD diagnosis date Cases had MS with MS 722 matched controls MMR vaccination: 0.9 (95% CI, 0.4-1.8)
diagnosed
by a
physician
from
1/1/1995
through
12/31/1999
Ahlgren Date of MS Administrative Born in Case-control 208 OR of MS onset None Serious
et al. onset from registries from Gothenburg, patients with MMR described
(2009b) medical Sahlgrenska Sweden, with MS vaccination
records and University from 888 controls compared to no
confirmed by authors Hospital and the National Patient Register of Sweden 1959-1986 Cases had MS onset at 10 years of age or older MMR vaccination: 1.13(95% CI, 0.62-2.05; p = .6849) OR of MS onset with monovalent or
combined measles,
mumps, and
rubella vaccination
compared to no
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
vaccination: 1.22 (95% CI, 0.77- 1.92; p = .4101) OR of MS onset with “early” MMR vaccination compared to MMR vaccinations given at other ages: 4.92 (95% CI, 1.97-12.20; p = .0006)

a The committee assumed statistical significance below the conventional 0.05 level unless otherwise stated by the authors.
b The risk/effect estimate for the subgroup/alternate definition of exposure or outcome differs significantly (e.g., is heterogeneous with nonoverla pping 95% confidence intervals) compared with the risk/effect estimate reported for the primary group/definition.
c Studies designated as serious had more methodological limitations than those designated as negligible. Studies assessed as having very serious limitations were not considered in the weight of epidemiologic evidence.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Causality Conclusion

Conclusion 4.13: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and the onset of MS in adults.

MULTIPLE SCLEROSIS ONSET IN CHILDREN

Epidemiologic Evidence

The committee reviewed two studies to evaluate the risk of onset of MS in children after the administration of MMR vaccine. One study (Ahlgren et al., 2009a) was not considered in the weight of epidemiologic evidence because it lacked an unvaccinated comparison population.

The one remaining controlled study (Ahlgren et al., 2009b) was included in the weight of epidemiologic evidence and is described below.

The study by Ahlgren et al. (2009b) was described in detail in the section on onset of MS in adults following MMR vaccination. This case-control study performed multiple analyses for monovalent and combined measles, mumps, and rubella vaccinations. The odds ratio for MS onset with MMR vaccination compared to no MMR vaccination was 1.13 (95% CI, 0.62–2.05). The odds ratio for MS onset with “early” MMR vaccination compared to MMR vaccinations given at other ages was 4.92 (95% CI, 1.97–12.20). The odds ratio for MS onset with monovalent or combined measles, mumps, and rubella vaccinations compared to no vaccination was 1.22 (95% CI, 0.77–1.92). This final analysis included U.S. vaccine strains, as well as Schwarz measles strain found in the monovalent vaccine. The authors concluded that measles, mumps, and rubella vaccinations are not associated with MS onset, and noted that the increased odds ratio observed with early MMR vaccination relative to MMR vaccination given at other ages is considered weak evidence owing to the small number of subjects (only eight subjects in early vaccination group). A further weakness of this study is that the analysis was done combining all age groups, which makes it difficult to assess the true association of MMR vaccine and the onset of MS in children.

Weight of Epidemiologic Evidence

The committee has limited confidence in the epidemiologic evidence, based on one study that lacked validity and precision to assess an association between MMR vaccine and onset of MS in children.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Mechanistic Evidence

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of the onset of MS in children after the administration of MMR vaccine.

Weight of Mechanistic Evidence

Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms of MS; however, the committee did not identify literature reporting evidence of these mechanisms after administration of MMR vaccine.

The committee assesses the mechanistic evidence regarding an association between MMR vaccine and onset of MS in children as lacking.

Causality Conclusion

Conclusion 4.14: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and onset of MS in children.

GUILLAIN-BARRÉ SYNDROME

Epidemiologic Evidence

The committee reviewed five studies to evaluate the risk of GBS after the administration of measles or MMR vaccine. These five studies (Bino et al., 2003; Esteghamati et al., 2008; Patja et al., 2000, 2001b; Souayah et al., 2009) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between MMR vaccine and GBS.

Mechanistic Evidence

The committee identified seven publications reporting the development of GBS after the administration of vaccines containing measles, mumps, and rubella alone or in combination. Patja et al. (2001b) did not report

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

the development of GBS within 6 weeks after administration of MMR vaccine. Pritchard et al. (2002) did not report relapse in GBS patients after administration of measles, mumps, or rubella vaccines. Tonelli et al. (2005) reported the development of GBS after administration of a measles vaccine but did not provide clinical, diagnostic, or experimental evidence, including the time frame between vaccination and symptom development. Four publications did not provide evidence beyond temporality, some too short based on the possible mechanisms involved (Grose and Spigland, 1976; Koturoglu et al., 2008; Patja et al., 2000; Schessl et al., 2006). One publication also reported the concomitant administration of vaccines making it difficult to determine which, if any, vaccine could have been the precipitating event (Grose and Spigland, 1976). Furthermore, Schessl et al. (2006) reported serologic testing suggesting concomitant infections that could contribute to the development of GBS. The publications did not contribute to the weight of mechanistic evidence.

Weight of Mechanistic Evidence

While rare, infection with wild-type measles, mumps, or rubella viruses has been associated with the development of GBS (Davis, 2008). The committee considers the effects of natural infection one type of mechanistic evidence.

The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of GBS. Autoantibodies, complement activation, immune complexes, T cells, and molecular mimicry may contribute to the symptoms of GBS; however, the publications did not provide evidence linking these mechanisms to MMR vaccine.

The committee assesses the mechanistic evidence regarding an association between MMR vaccine and GBS as weak based on knowledge about the natural infection.

Causality Conclusion

Conclusion 4.15: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and GBS.

CHRONIC INFLAMMATORY DISSEMINATED POLYNEUROPATHY

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of chronic inflammatory disseminated polyneuropathy (CIDP) after the administration of MMR vaccine.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between MMR vaccine and CIDP.

Mechanistic Evidence

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of CIDP after the administration of MMR vaccine.

Weight of Mechanistic Evidence

Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms of CIDP; however, the committee did not identify literature reporting evidence of these mechanisms after administration of MMR vaccine.

The committee assesses the mechanistic evidence regarding an association between MMR vaccine and CIDP as lacking.

Causality Conclusion

Conclusion 4.16: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and CIDP.

OPSOCLONUS MYOCLONUS SYNDROME

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of opsoclonus myoclonus syndrome (OMS) after the administration of MMR vaccine.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between MMR vaccine and OMS.

Mechanistic Evidence

The committee identified one publication reporting the development of OMS after the administration of rubella vaccine. Lapenna et al. (2000) did not provide evidence of causality beyond a temporal relationship of

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

15 days between vaccine administration and development of OMS after vaccination. The publication did not contribute to the weight of mechanistic evidence.

Weight of Mechanistic Evidence

The symptoms described in the publication referenced above are consistent with those leading to a diagnosis of OMS. Molecular mimicry may contribute to the symptoms of OMS; however, the publication did not provide evidence linking this mechanism to MMR vaccine.

The committee assesses the mechanistic evidence regarding an association between MMR vaccine and OMS as lacking.

Causality Conclusion

Conclusion 4.17: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and OMS.

BRACHIAL NEURITIS

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of brachial neuritis after the administration of MMR vaccine.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between MMR vaccine and brachial neuritis.

Mechanistic Evidence

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of brachial neuritis developing after the administration of MMR vaccine.

Weight of Mechanistic Evidence

Autoantibodies, T cells, and complement activation may contribute to the symptoms of brachial neuritis; however, the committee did not identify literature reporting evidence of these mechanisms after administration of MMR vaccine.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

The committee assesses the mechanistic evidence regarding an association between MMR vaccine and brachial neuritis as lacking.

Causality Conclusion

Conclusion 4.18: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and brachial neuritis.

ANAPHYLAXIS

Epidemiologic Evidence

The committee reviewed ten studies to evaluate the risk of anaphylaxis after the administration of MMR vaccine. These ten studies (Al Awaidy et al., 2010; Bino et al., 2003; Bohlke et al., 2003; D’Souza et al., 2000; DiMiceli et al., 2006; Khetsuriani et al., 2010; Nakayama et al., 1999; Patja et al., 2000; Peng and Jick, 2004; Planchamp et al., 2009) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems or lacked unvaccinated comparison populations.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between MMR vaccine and anaphylaxis.

Mechanistic Evidence

The committee identified 11 publications describing clinical, diagnostic, or experimental evidence of anaphylaxis after the administration of vaccines containing measles, mumps, and rubella alone or in combination that contributed to the weight of mechanistic evidence. These publications are described below.

Aukrust et al. (1980) reported six cases of anaphylaxis postvaccination against measles. Case 1 describes a 12-month-old girl presenting with cough, dyspnea, and cyanosis. Case 2 describes a 14-month-old boy presenting with stridor, urticaria, angioedema, dyspnea, and shock. Case 3 describes a 15-month-old boy presenting with dyspnea, stridor, shock, angioedema, urticaria, and cyanosis. Case 4 describes an 18-month-old girl presenting with urticaria, angioedema, cyanosis, and erythema, who was found to have a positive skin test to the vaccine. Case 5 describes a 16-month-old boy presenting with dyspnea, urticaria, erythema, and cya-

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

nosis. Case 6 describes a 14-month-old girl presenting with angioedema, stridor, dyspnea, vomiting, and erythema.

Baxter (1996) reported the vaccination of 200 egg-allergic children with either a measles or a measles, mumps, and rubella vaccine. Three vaccines were used in the study; two using different viral strains than those distributed in the United States. The remaining vaccine included the U.S. viral strains. One 15-month-old patient developed a positive wheal-and-flare response within 10 minutes of the skin prick test. The patient also developed a local reaction with urticarial lesions, hypotension, diarrhea, and irritability within 10 minutes of the intradermal test. The vaccine eliciting the response was not indicated.

Bohlke et al. (2003) studied anaphylaxis postvaccination using records from participants in the VSD from 1991 through 1997. The authors report three cases of anaphylaxis in patients receiving a measles, mumps, and rubella vaccine out of 848,945 doses administered. Case 1 (case 2 in the report) describes a 16-month-old presenting with wheezing, tachycardia, rash, and erythema within 1 hour after vaccination with MMR. The two other children (cases 3 and 5 in the report) presented with symptoms consistent with anaphylaxis but received vaccines in addition to MMR.

Erlewyn-Lajeunesse et al. (2008) reported two cases of anaphylaxis after administration of a rubella vaccine containing the RA 27/3 rubella strain and one case after administration of a measles vaccine containing the Schwarz strain. Case 1 describes a 15-month-old presenting with cyanosis, tachypnea, and angiodema less than 15 minutes after vaccination with the Schwarz-containing measles vaccine. Case 2 describes an 18-month-old presenting with stridor, erythema, and vomiting less than 5 minutes after vaccination with rubella vaccine. Case 3 describes a 20-month-old presenting with wheezing, cough, vomiting, and a flushed feeling less than 5 minutes after rubella vaccination.

Fasano et al. (1992) reported two cases of anaphylaxis after administration of a measles, mumps, and rubella vaccine in individuals with no history of allergy to egg or chicken meat. Case 1 describes an 8-year-old girl presenting with facial edema, throat tightening, hypotension, and wheezing 15 minutes after vaccination. Postvaccination the patient developed positive responses to intradermal tests against the MMR, measles, mumps, and rubella vaccines. The patient did not develop a response to either an intradermal test against neomycin or skin prick tests against the MMR, measles, mumps, and rubella vaccines and egg. Laboratory tests showed a serum IgE level of 57 IU/L. Case 2 describes a 10-year-old boy presenting with facial edema, wheezing, and generalized urticaria within 5 minutes after vaccination. Postvaccination the patient developed a positive response to skin prick tests against the MMR, measles, mumps, and rubella vaccines. The patient did not develop a response to skin prick tests against egg or

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

neomycin. Laboratory tests showed a serum IgE level of 583 IU/L and an anti-MMR IgE level of 0.088 ng/ml. In addition, the patient developed mild wheezing after vaccination against MMR at 15 months of age.

Giampietro et al. (1993) reported one case of anaphylaxis developing after administration of a measles vaccine containing the Edmonston-Zagreb strain. The patient was a 2-year-old boy presenting with severe dyspnea, lip cyanosis, and rhinoconjunctivitis within a few minutes after vaccination. The patient developed positive responses to skin prick tests against cow’s milk and egg prior to vaccination.

Herman et al. (1983) reported two cases of anaphylaxis developing after administration of MMR vaccine. Case 1 describes a 15-month-old boy, with a history of egg sensitivity, presenting with angioedema, respiratory difficulty, and generalized urticaria within 1 minute after vaccination. Case 2 describes a 15-month-old boy, with a history of egg hypersensitivity, presenting with wheezing, angioedema, and generalized urticaria within 2 minutes after vaccination. Both patients were found to have IgE antibodies to ovalbumin, measles vaccine, and MMR vaccine.

Kelso et al. (1993) described a 17-year-old girl presenting with pruritus, hives, swelling of the hands and face, rhinorrhea, and the sensation of choking 10 minutes after vaccination against measles, mumps, and rubella. The patient was treated with epinephrine and diphenhydramine leading to some resolution of the hives and swelling. The patient complained of throat tightness 90 minutes later. The patient had positive responses to skin prick tests against the MMR vaccine and unflavored number one, lime, cherry, and orange gelatins. Furthermore, laboratory tests showed elevated levels of IgE antibodies to gelatin and the MMR vaccine.

Patja et al. (2001a) performed a prospective follow-up of adverse events reported to a passive surveillance system in Finland from November 1982 through December 1996. Out of 2.99 million doses of the MMR vaccine administered, 18 cases of anaphylaxis developing within 15 minutes after vaccination were identified. Eight cases of anaphylaxis developed after the first dose of vaccine while 10 developed after the second dose. Laboratory tests showed IgE antibodies to gelatin in two patients, IgE antibodies to egg in one patient, and IgE antibodies to chicken in one patient. These cases were also reported in a study by Patja et al. (2000), using data from the same passive surveillance system in Finland.

Pool et al. (2002) identified 57 patients in the Vaccine Adverse Event Reporting System (VAERS) database from 1991 through 1997 who developed anaphylaxis after MMR or measles vaccination. The authors reported that 34 individuals had a history of sensitivity to food, environmental allergens, or drugs. Twenty-two cases provided a serum sample for IgE testing. Of these, 2 received a measles single antigen vaccine alone, 11 received MMR vaccine alone, and 9 received MMR with one or two other

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

vaccines. Five individuals received the first dose of vaccine without incident. Six cases in which a measles vaccine or an MMR vaccine was administered alone were reported in detail. Case 1 described a 4-year-old boy, with a history of egg allergy, presenting with facial flushing, hypotension, cough without wheezing, and hives within 10 minutes after receiving an MMR vaccine. Laboratory tests on the patient’s serum showed IgE antibodies to egg and gelatin. Case 2 described a 17-year-old girl presenting with wheezing, trouble swallowing, and swollen lips within 2 minutes after receiving an MMR vaccine. The patient’s serum showed IgE antibodies to gelatin. Case 3 described a 12-year-old boy presenting with rhinorrhea, sneezing, hives, and tachycardia within 10 minutes after receiving an MMR vaccine. The patient’s serum was positive for antigelatin IgE. Case 10 described a 15-year-old girl, with a history of allergies to pork and lamb, presenting with a rash on the neck and abdomen, edema, redness of the face, coughing, and an itchy throat 15 minutes after receiving an MMR vaccine. The patient’s serum was positive for IgE antibodies to measles. Case 13 described a 15-month-old boy presenting with generalized flushing, facial edema, and upper body urticaria immediately after receiving an MMR vaccine and 5 minutes after receiving a HiB vaccine. The patient’s serum showed antigelatin IgE. Case 14 described a 23-year-old man presenting with visual disturbances, numbness to the lips, flushing, and difficulty swallowing 30 minutes after receiving a measles vaccine. The patient’s serum showed antigelatin IgE.

Puvvada et al. (1993) reported two cases of systemic reactions developing after intradermal testing with a measles, mumps, and rubella vaccine. Case 1 described an 11-month-old boy, with a history of sensitivity to egg, presenting with generalized urticaria and pruritus after undergoing an intradermal test using a 1:100 dilution of a measles, mumps, and rubella vaccine. Case 2 described a 22-month-old girl, with a history of egg allergy, presenting with dyspnea and wheezing within 30 minutes of undergoing an intra-dermal test using a 1:100 dilution of a measles, mumps, and rubella vaccine.

Additional publications reported humoral or cellular immune responses to gelatin in patients developing anaphylaxis after administration of a vaccine containing measles, mumps, and rubella alone or in combination; the vaccines contained viral strains not used in vaccines distributed in the United States (Kumagai et al., 1997; Sakaguchi et al., 1997, 1999a,b). Kumagai et al. (1997) reported the development of gelatin-specific humoral and cellular immune responses in six patients developing anaphylactic symptoms postvaccination. Laboratory tests showed all six patients developed positive IgE responses to gelatin and positive responses to a gelatin-specific IL-2 responsiveness assay.

Sakaguchi et al. (1997) reported that one patient (case 2 in the report) had antigelatin IgE when tested immediately after developing anaphylactic symptoms after a measles vaccination. The authors also report that a sec-

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

ond patient (case 3 in the report) had a high level of antigelatin IgE when tested 8 days after developing anaphylactic symptoms after a mumps vaccination. Furthermore, both patients were positive for IgE antibodies to egg white; however, the levels changed little during the observation period.

Sakaguchi et al. (1999b) reported on the reactivity of IgE to the α1 and α2 chains of bovine type I collagen. The authors reported that 10 patients who developed symptoms of anaphylaxis after a measles, mumps, or rubella vaccination were positive for IgE to gelatin and to type I collagen. Furthermore, IgE from all 10 patients reacted with the α2 chain and not the α1 chain.

Sakaguchi et al. (1999a) reported on the reactivity of IgE from 10 bovinegelatin-sensitive children that developed anaphylaxis postvaccination. Most of the children had IgE specific to porcine gelatin as well as other mammals. Furthermore, sera from three children were used to sensitize mast cells. After sensitization the mast cells released histamine upon challenge with bovine gelatin.

Hori et al. (2002) used serum samples from 15 patients with systemic immediate type reactions, including anaphylaxis postvaccination, to analyze the binding sites of IgE to the α2 chain in bovine type I collagen. The authors used IgE–enzyme-linked immunosorbent assay (ELISA) inhibition to delineate a 10–amino acid sequence in the α2 chain as the minimum IgE epitope of gelatin allergen.

Weight of Mechanistic Evidence

The publications described above presented clinical and experimental evidence sufficient for the committee to conclude the vaccine was a contributing cause of anaphylaxis after administration of vaccines containing measles, mumps, and rubella alone or in combination. The clinical descriptions provided in many of the publications establish a strong temporal relationship between administration of the vaccine and the anaphylactic reaction. In addition, several publications report evidence of allergy or IgE sensitivity to gelatin providing mechanistic evidence for the cause of the reaction in some patients. Gelatin in the MMR vaccine distributed in the United States is in a hydrolyzed form; the extent to which gelatin is hydrolyzed could vary from one vaccine lot to another and affect the development of anaphylaxis. Some patients are allergic to either bovine or porcine gelatin, but not both (Bogdanovic et al., 2009). Although there is considerable cross-reactivity between bovine and porcine gelatin, testing for antibody to one gelatin alone is not necessarily predictive of allergy to the other and may not be predictive of reactivity to the gelatin in MMR vaccine.

The committee assesses the mechanistic evidence regarding an association between MMR vaccine and anaphylaxis as strong based on

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

43 cases5presenting temporality and clinical symptoms consistent with anaphylaxis.

Causality Conclusion

Conclusion 4.19: The evidence convincingly supports a causal relationship between MMR vaccine and anaphylaxis.

TRANSIENT ARTHRALGIA IN WOMEN

Epidemiologic Evidence

The committee reviewed five studies to evaluate the risk of transient arthralgia in women after the administration of rubella vaccine. One controlled study (Polk et al., 1982) had very serious methodological limitations that precluded its inclusion in this assessment. Polk et al. (1982) selected controls from a different population than the exposed group and provided limited detail on the selection criteria.

The four remaining controlled studies (Mitchell et al., 1998; Ray et al., 1997; Slater et al., 1995; Tingle et al., 1997) were included in the weight of epidemiologic evidence and are described below.

Slater et al. (1995) conducted a retrospective cohort study in women enrolled from 1985 through 1990 in the Ministry of Health Mother-Child Health (MHC) stations in Israel. The exposed group was composed of 485 women who received RA 27/3 strain rubella vaccine postpartum because of absent or nonprotective antibody titers. The control group included 493 women who were not vaccinated postpartum because of adequate antibody levels. The control group was selected from the same MHC stations and matched with vaccinated women for neighborhood of residence, date woman gave birth, and age. However, there were ethnic differences between the exposed and control groups. Telephone interviews were completed during 1992–1993 to evaluate the onset of joint symptoms within 4 months of vaccination; women reporting symptoms were invited to participate in personal interviews. Since interviews were conducted several years after vaccination, one limitation of this study was the dependence on subject recall to report symptoms. During the study period, four cases of arthralgia were reported among the exposed group (0.8 percent), compared to three cases in the control group (0.6 percent). The differences were not statistically significant. The authors concluded that no association was present

___________

5 Some cases were from passive surveillance systems; however, it was not possible to know how many represented unique cases or were reported elsewhere.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

between vaccination with RA 27/3 strain rubella and the development of arthralgia in postpartum women.

Ray et al. (1997) conducted a retrospective cohort study in women (aged 15 to 59 years) enrolled in the Northern California Kaiser Permanente Health Plan. Medical records were reviewed to identify women who had serological testing for rubella IgG antibody from 1990 through 1991, and received rubella vaccine within 1 year of testing. A total of 971 seronegative, vaccinated women were defined as the exposed group. The authors identified two control groups for comparison: 2,421 seropositive, unvaccinated women served as age-matched controls, and 924 seronegative, unvaccinated women were used as unmatched controls. Arthropathies or joint complaints (labeled as acute, chronic, or traumatic, but not defined in the study) were identified in inpatient and outpatient records, and confirmed by a rheumatologist. No significant differences in the prevalence of arthropathies were found between the exposed group and either comparison group. Of the five conditions reported in the vaccine group, four were labeled as acute arthralgia and one was indeterminate. Only one acute event was seen in the seropositive, unvaccinated control group. The authors concluded that vaccination with RA 27/3 strain rubella does not appear to increase the prevalence of acute arthropathies in women, but they noted the study’s limitation to detect mild symptoms for which women are less likely to seek medical care.

Tingle et al. (1997) conducted a double-blind, randomized controlled trial in rubella-seronegative women living in Vancouver, Canada. A total of 546 postpartum women (0–12 weeks postpartum) were enrolled in the study from 1989 through 1992. The women were randomly assigned to receive live attenuated monovalent RA 27/3 strain rubellavirus vaccine (270 participants) or saline placebo (276 participants). The presence of arthropathy was evaluated 4 weeks and 12 months after vaccination with a home visit from a research nurse, and also by telephone at 3, 6, and 9 months after vaccination. The odds ratio for the frequency of acute arthralgia or arthritis among postpartum women receiving RA 27/3 strain rubella vaccine compared to placebo was 1.73 (95% CI, 1.17–2.57). Acute arthralgia was reported in 21 and 16 percent of women receiving rubella vaccine and placebo, respectively. The authors concluded that rubella vaccine was significantly associated with the development of acute arthralgia in postpartum women.

Mitchell et al. (1998) conducted a post-hoc analysis of the data provided in Tingle et al. (1997). The study explored the influences of immunogenetic background on the development of acute arthropathy (arthralgia and arthritis) in postpartum women receiving RA 27/3 strain rubella vaccine. Genetic typing for HLA-DR was performed for 283 of the original 313 white women that were enrolled in the vaccine and placebo groups.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

This subgroup analysis revealed that higher frequencies of DR2 (OR, 4.8; 95% CI, 1.2–18.8) and DR5 (OR, 7.5; 95% CI, 1.5–37.5) were associated with an increased risk of women developing acute arthropathy after rubella vaccine during the postpartum period. The authors concluded that certain DR2 and DR5 alleles may influence the development of acute arthropathy in postpartum women receiving rubella vaccine.

Weight of Epidemiologic Evidence

Of the four studies described above, Tingle et al. (1997) most influenced the committee’s judgment. The randomized trial by Tingle et al. (1997) involved active monitoring of subjects in the month following the injection, and found a statistically significant increase in the rate of acute arthralgia among the immunized group. The studies by Ray et al. (1997) and Slater et al. (1995) did not find a significant increased risk of acute arthralgia in the immunized group, but since the studies did not conduct active monitoring of the subjects they could easily have failed to recognize the presence of this symptom. See Table 4-7 for a summary of the studies that contributed to the weight of epidemiologic evidence.

The committee has a moderate degree of confidence in the epidemiologic evidence based on four studies with sufficient validity and precision to assess an association between rubella vaccine and transient arthralgia in women; these studies generally report an increased risk.

The epidemiologic evidence is insufficient or absent to assess an association between measles or mumps vaccine and transient arthralgia in women.

Mechanistic Evidence

The committee identified 16 publications describing transient arthralgia in women after the administration of vaccines containing measles and rubella alone or in combination. Harcourt et al. (1979) did not find a correlation between the development of joint symptoms and human leukocyte antigens after rubella vaccination. Five publications did not provide evidence beyond temporality and therefore did not contribute to the weight of mechanistic evidence (Dudgeon et al., 1969; Grillner et al., 1973; Seager et al., 1994; Tingle et al., 1986, 1989). Two publications reported symptoms of arthralgia after vaccination but did not differentiate between men and women (Freestone et al., 1971; Simon et al., 2007). Three publications reported symptoms of arthralgia but did not indicate the duration

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

TABLE 4-7 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Transient Arthralgia in Women


Citation Operationally Defined Outcome Study Setting Defined Study Population Study Design Sample Size Primary Effect Size Estimatea (95% CI or p value) Heterogeneous Subgroups at Higher Riskb Limitations (Negligible or Serious)c

Slater et al. (1995) Joint symptoms reported during telephone interviews Ministry of Health MHC Stations in Israel Postpartum women enrolled from 1985-1990 Exposed group received rubella vaccine postpartum because of absent or nonprotective antibody titers Control group was not vaccinated postpartum because of adequate antibody levels Retrospective cohort 485 vaccinated women 493 unvaccinated women Vaccinated: four cases of arthralgia (0.8%) Unvaccinated: three cases of arthralgia (0.6%) Differences were not statistically significant None described Serious
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Citation Operationally Defined Outcome Study Setting Defined Study Population Study Design Sample Size Primary Effect Size Estimatea (95% CI or p value) Heterogeneous Subgroups at Higher Riskb Limitations (Negligible or Serious)c

Ray et al. (1997) Arthropathies or joint complaints (acute, chronic, and traumatic) identified in inpatient and outpatient records and confirmed by a rheumatologist Northern California Kaiser Permanente Health Plan Women whose serological testing was performed from 1990 through 1991 Exposed group received rubella vaccine within 1 year following testing Retrospective cohort 971 seronegative, vaccinated women 2,421 seropositive, unvaccinated aged-matched controls 924 seronegative, unvaccinated unmatched controls Vaccinated: Four conditions labeled as acute arthralgias and one as indeterminate Seropositive, unvaccinated controls: One acute event None described Negligible
Tingle et al. (1997) Acute and persistent arthropathy (arthralgia or arthritis) evaluated during home visit from a research nurse and by telephone Participating hospitals in Vancouver, Canada Postpartum, rubella-seronegative women identified from 4/1/1989 through 4/30/1992 Double-blind, randomized controlled trial 268 vaccinated 275 received placebo OR of acute arthralgia or arthritis within 12 months of rubella vaccination: 1.73 (95% CI, 1.17-2.57) See analysis of HLA-DR genetic typing in Mitchell et al. (1998) Negligible
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Mitchell et al. (1998) Post-hoc analysis of data from Tingle et al. (1997) Genetic typing for HLA-DR was performed for 283 of the original 313 white women that were enrolled in the vaccine and placebo groups Participating hospitals in Vancouver, Canada Postpartum, rubellaseronegative, white women identified from 4/1/1989 through 4/30/1992 Doubleblind, randomized controlled trial Presence of DR2: 41 vaccinated 38 received placebo Presence of DR5: 32 vaccinated 27 received placebo OR of acute arthralgia or arthritis within 12 months of rubella vaccination in women expressing DR2: 4.8 (95% CI, 1.2-18.8) OR of acute arthralgia or arthritis within 12 months of rubella vaccination in women expressing DR5: 7.5 (95% CI, 1.5-37.5) None described Serious

a The committee assumed statistical significance below the conventional 0.05 level unless otherwise stated by the authors.
b The risk/effect estimate for the subgroup/alternate definition of exposure or outcome differs significantly (e.g., is heterogeneous with nonoverlapping 95% confidence intervals) compared with the risk/effect estimate reported for the primary group/definition.
c Studies designated as serious had more methodological limitations than those designated as negligible. Studies assessed as having very serious limitations were not considered in the weight of epidemiologic evidence.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

of symptoms (Gershon et al., 1980; Simon et al., 2007; Zimmerman and Pellitieri, 1994). In addition, Zimmerman and Pellitieri (1994) reported the concomitant administration of vaccines making it difficult to determine which, if any, vaccine could have been the precipitating event. Valensin et al. (1987) was not included in the review because the mean age of the vaccinated individuals was 12 years, and the few patients aged 18 and above were not identified. These reports did not contribute to the weight of mechanistic evidence.

Described below are four publications describing clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Best et al. (1974) studied 36 women who were seronegative by hemagglutination inhibition (HAI) assay who received the RA 27/3 rubella vaccine. The authors reported the development of transient arthralgia in 9 of the 36 seronegative women after vaccination and transient arthritis in 6 of the 36 women. The joint symptoms usually commenced between days 13 and 21. The symptoms lasted as long as 8 days. Thirteen of the 36 subjects were tested for rubella viral excretion by culture of nasal and pharyngeal swabs. Seven of the 13 subjects tested were positive for rubella viral excretion between days 11 and 26.

The study by Mitchell et al. (1998) was described in detail in the epide-miologic evidence section on transient arthralgia in women. All 283 white vaccinees included in this study were seronegative by enzyme immunoassay (EIA) (Abbott) prior to vaccination. Patients developing arthralgia postvaccination expressed higher frequencies of the human leukocyte antigens, DR2, DR5, and DR7, but lower frequencies of DR4 and DR6 compared to the frequency of these alleles in women with arthralgia who had received a placebo, not the rubella vaccine. When examining the frequency of acute arthalgia, subjects with DR1, DR2, DR5, and DR7 had a higher rate of acute arthralgia after rubella vaccination than did subjects with these haplotypes after placebo.

Mitchell et al. (2000) reported the development of acute and chronic arthralgia and arthritis in a subset of 18- to 41-year-old women within 28 days after rubella vaccination, which contained RA 27/3. All the subjects were initially considered seronegative based on a result of < 0.999 in the Rubazyme EIA assay (Abbott Laboratories). Additional testing of the prevaccine samples for the presence of antirubella antibodies found that several subjects had rubella-specific IgG suggesting prior exposure to rubella virus. Of the subjects, the ones who developed acute and chronic arthralgia and arthritis were those who had previously been exposed but had the lowest levels of prevaccine antibodies as measured by the additional techniques. This suggests that the inability to respond to wildtype rubella during previous exposures is associated with arthropathy after the vaccine.

Tingle et al. (1983) reported six cases of transient arthralgia postvaccination with rubella vaccine. None of the patients had been previously

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

immunized against rubella. All six were seronegative, based on an HAI assay, prior to vaccination but were later found to have had antibodies prevaccination based on an ELISA assay.

Weight of Mechanistic Evidence

Arthritis and arthralgia have been reported to develop as complications in as many as one third of women with wild-type rubella infection (Gershon, 2010b). The committee considers the effects of natural infection one type of mechanistic evidence.

In addition, the four publications described above, when considered together, presented clinical evidence sufficient for the committee to conclude the vaccine may be a contributing cause of transient arthralgia in women. Evidence of direct rubella infection was presented in one case (Best et al., 1974). Furthermore, three publications suggest that host factors may be involved, particularly the inability to mount a robust immune response to rubella and the expression of certain HLA-DR haplotypes in cases of acute arthralgia after rubella vaccination (Mitchell et al., 1998, 2000; Tingle et al., 1983). The failure to differentiate between wild-type and vaccine strains of rubella, where virus was demonstrated, as well as the failure to demonstrate virus in joints, detracted from the weight of evidence.

The isolation of rubella virus, expression of certain HLA-DR haplotypes, and inadequate antibody response after vaccination suggests direct infection to be the mechanism for transient arthralgia in women after rubella vaccination. Autoantibodies, T cells, immune complexes, and complement activation may contribute to arthralgia as well; however, the publications did not provide evidence linking these mechanisms to MMR vaccine.

The committee assesses the mechanistic evidence regarding an association between rubella vaccine and transient arthralgia in women as intermediate based on clinical evidence and 13 cases.

The committee assesses the mechanistic evidence regarding an association between measles or mumps vaccine and transient arthralgia in women as lacking.

Causality Conclusion

Conclusion 4.20: The evidence favors acceptance of a causal relationship between MMR6 vaccine and transient arthralgia in women.

___________

6 The committee attributes causation to the rubella component of the vaccine.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

TRANSIENT ARTHRALGIA IN CHILDREN

Epidemiologic Evidence

The committee reviewed 12 studies to evaluate the risk of transient arthralgia in children after the administration of vaccines containing measles, mumps, and rubella alone or in combination. Four studies (Bino et al., 2003; D’Souza et al., 2000; Ion-Nedelcu et al., 2001; Vahdani et al., 2005) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations. One controlled study (Black et al., 1976) had very serious methodological limitations that precluded its inclusion in this assessment. Black et al. (1976) conducted a small study (35 participants) that reported arthralgias in 26 percent of the vaccinated group, but only boys were vaccinated in this study and girls were the comparison group.

The seven remaining controlled studies (Benjamin et al., 1992; Davis et al., 1997; dos Santos et al., 2002; Heijstek et al., 2007; LeBaron et al., 2006; Peltola and Heinonen, 1986; Virtanen et al., 2000) contributed to the weight of epidemiologic evidence and are described below.

Peltola and Heinonen (1986) conducted a double-blind, controlled crossover study in 581 twin pairs who received MMR vaccine from November 1982 through October 1983 in Finland. The vaccines were color-coded and administered blind to the participants (aged 14 months to 6 years). One twin of each pair received vaccine at the first visit, then was given placebo 3 weeks later; similarly, one twin received placebo at the first visit and vaccine 3 weeks later. The participants were given color-coded questionnaires at both visits and asked to report any symptoms for 21 days following vaccine or placebo administration. The maximum difference in rate of arthropathy between the MMR vaccine and placebo groups was 0.8 percent (95% CI, 0.2–1.3%), with a peak frequency 7 to 9 days after vaccination. The authors noted the sample size was powered to detect low frequencies of adverse events, but rare reactions were difficult to study with this small sample.

Virtanen et al. (2000) conducted a reanalysis of the double-blind, controlled crossover study from Peltola and Heinonen (1986). In the reanalysis, adverse events from the questionnaires were reported in two age groups: group 1 included twins 14–18 months of age, and group 2 included twins 6 years of age. The adjusted odds ratio for arthralgia in the 14- to 18-month age group within 21 days following MMR vaccination was 3.66 (95% CI, 1.74–7.70). Arthralgia was also associated with MMR vaccination in the 6-year age group, but an odds ratio was not provided.

Benjamin et al. (1992) conducted a retrospective cohort study in children from the South Manchester Health District of the United Kingdom.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

The exposed group included 1,588 children who received MMR vaccine during July 1989 through February 1990. The control group was composed of 1,242 children eligible for MMR vaccination during this same period but who remained unvaccinated. The parents of the vaccinated children were sent a self-report questionnaire 6 weeks after the vaccination date and were asked to describe any joint symptoms. The same questionnaire was sent to parents of the control group. If a parent reported one or more joint symptoms within the last 6 weeks, the child was visited at home by a clinician and the parent’s responses were validated. The clinician was aware of the child’s vaccination status, and the authors note this could have introduced bias in the diagnosis of arthralgia. The vaccinated group and control group achieved a 78 percent and 64 percent response rate, respectively; however, the authors did not compare the characteristics of the excluded children with the remaining study participants. The relative risk of children experiencing arthralgia within 6 weeks of MMR immunization was 4.2 (95% CI, 1.2–14.3). The authors concluded that MMR vaccination was associated with an increased risk of arthralgia in children, but noted the wide confidence interval.

The study by Davis et al. (1997) was described in detail in the section on afebrile seizures. This retrospective cohort study examined the occurrence of joint pain 30 days after MMR vaccination in children (4–6 and 10–12 years of age) enrolled in the GHC and NCK HMOs from March 1991 through December 1994. The 10- to 12-year-olds reported more chart-confirmed visits for joint pain during the risk period (13 cases) compared to the control period (6 cases). The majority of joint pain visits were for acute events. No joint pain visits were reported among the 4- to 6-year-olds in the risk period or control period. The authors concluded that MMR immunization is associated with an increased risk of joint pain in the 10- to 12-year age group.

dos Santos et al. (2002) conducted a double-blind, randomized controlled trial in schoolchildren (6 to 12 years old) selected from 70 public and private schools in Porto Alegre and Santa Maria, Brazil. The participants were randomly separated into four groups: (1) Tresivac was labeled vaccine A and administered to 2,226 children; (2) MMR II was labeled vaccine B and administered to 2,216 children; (3) Trimovax was labeled vaccine C and administered to 2,179 children; and (4) 3,521 children were assigned to a control group that did not receive an MMR vaccine. Vaccines were administered at the schools from August through September 1996. While the students and health professionals were blind to the type of vaccine, the control group was not blinded and was aware of the group assignment. Nurses visited the schools daily over 30 days and recorded any clinical events observed in the vaccinated or control groups. Home and hospital visits were also used when a student was absent from school. Over

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

the 30-day period, eight joint reactions were reported in the MMR II group, compared to none reported in the control group. Most of these reactions were transient arthralgia, and 65 percent were reported in women.

LeBaron et al. (2006) conducted a self-controlled case series (case-crossover) study in 1,800 children receiving care at the Marshfield Clinic in Wisconsin. The patients were enrolled prospectively over 2 years and were separated into three age groups: (1) children aged 12 to 24 months who received a first dose of MMR vaccine; (2) children aged 4 to 6 years who received a second dose of MMR vaccine; and (3) children aged 10 to 12 years who received a second dose of MMR vaccine. The family of each participant was given a prevaccination diary that was completed 2 weeks before vaccination, which served as the control period. The risk period was defined as 4 weeks after vaccination, and a postvaccination diary was given to the family to record any symptoms during this time. No significant increases in joint problems were reported in any of the three groups after MMR vaccination. Even though no significant change was reported, the small sample size was inadequate to detect a rare adverse event, and there were limitations in the use of patient diaries.

Heijstek et al. (2007) conducted a retrospective cohort study in patients with juvenile idiopathic arthritis (JIA) born from 1989 through 1996 in the Netherlands. The enrolled patients (8–9 years of age) provided their date of MMR vaccination, and missing dates were obtained from the National Vaccination Institute. Their disease activity was measured by counts of joints with active arthritis, the Physician’s Global Assessment scale, and the erythrocyte sedimentation rate. A total of 108 patients received MMR vaccine; 86 patients were eligible but not vaccinated against MMR. The nonadjusted odds ratio for flares in JIA patients within 6 months of MMR vaccination was 1.7 (95% CI, 0.9–3.3). Adjusting for JIA type and medication use by propensity scoring, the adjusted odds ratio for flares within 6 months of MMR vaccination was 1.4 (95% CI, 0.7–2.9). The study also included a self-controlled case series analysis among 207 patients (unknown age range) who received MMR vaccine. The number of flares experienced 6 months before vaccination was compared to the disease activity 6 months after vaccination. Before MMR vaccination, 40 flares occurred in 36 patients, which was lower than the 56 flares reported in 50 patients after vaccination. The authors concluded that the risk of active disease was not significantly increased by MMR vaccination; however, they noted the limitations of a retrospective study design, the limited power to detect a significant association, and the likely presence of residual bias in the data set.

Weight of Epidemiologic Evidence

Of the seven studies considered in this analysis, five had negligible limitations, and two of these (Peltola and Heinonen, 1986; Vertanen et al.,

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

2000) were analyses of the same controlled crossover study. The studies consistently report an increased risk of transient arthralgia following MMR vaccination in children, with some limitations. The evidence includes (a) the controlled crossover study of twins in Peltola and Heinonen (1986) and Virtanen et al. (2000) that noted an increased risk of arthralgia following vaccination; (b) the retrospective cohort study of Benjamin et al. (1992) with increased risk though wide confidence interval; (c) the retrospective cohort study of Davis et al. (1997) that observed an increased risk of arthralgia following MMR among those 10–12 years of age, but not among the smaller group of children 4–6 years of age studied; and (d) the randomized controlled trial of dos Santos et al. (2002) that observed rare arthralgias but only among the vaccinated group. Two studies that failed to observe an association had low power (Heijstek et al., 2007), limited generalizability (Heijstek—with a focus exclusively on patients with JIA), and limited control for confounding (LeBaron et al., 2006). See Table 4-8 for a summary of the studies that contributed to the weight of epidemiologic evidence.

The committee has a moderate degree of confidence in the epidemiologic evidence based on seven studies with sufficient validity and precision to assess an association between MMR vaccine and transient arthralgia in children; these studies consistently report an increased risk.

Mechanistic Evidence

The committee identified seven publications of transient arthralgia in children after the administration of rubella or MMR vaccine. The publications did not provide evidence beyond temporality (Balfour et al., 1976; Bottiger et al., 1974; Cassidy et al., 2005; Poyner et al., 1986; Valensin et al., 1987; Weibel et al., 1980a,b). In addition, Cassidy et al. (2005) reported the concomitant administration of vaccines making it difficult to determine which, if any, vaccine could have been the precipitating event. The publications did not contribute to the weight of mechanistic evidence.

Weight of Mechanistic Evidence

While rare, arthritis and arthralgia have been reported as a complication of wild-type rubella infection in children (Gershon, 2010b). The committee considers the effects of natural infection one type of mechanistic evidence.

The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of arthralgia. Autoantibodies, T cells, immune complexes, direct viral infection, and complement activation may contribute to arthralgia; however, the publications did not provide evidence linking these mechanisms to MMR vaccine.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

TABLE 4-8 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Transient Arthralgia in Children


Citation Operationally Defined Outcome Study Setting Defined Study Population Study Design Sample Size Primary Effect Size Estimatea (95% CI or p value) Heterogeneous Subgroups at Higher Riskb Limitations (Negligible or Serious)c

Peltola and Heinonen (1986) Self-report of arthropathy symptoms using questionnaires Finland Twin pairs aged 14 months to 6 years who received MMR vaccine from 11/1/1982 through 10/31/1983 Double-blind, controlled crossover study 581 twin pairs Maximum difference rate of arthropathy between MMR vaccine and placebo groups at 7-9 days after vaccination: 0.8% (95% CI, 0.2-1.3%) See analysis of the 14-18 month age group in Virtanen et al. (2000) Negligible
Virtanen et al. (2000) Reanalysis of data from Peltola and Heinonen (1986) Self-report of arthropathy symptoms using questionnaires Finland Twin pairs aged 14 months to 6 years who received MMR vaccine from 11/1/1982 through 10/31/1983 Double-blind, controlled crossover study 581 twin pairs, separated into two age groups: 14-18 months and 6 years of age Adjusted OR of arthralgia in the 14-18 month age group within 21 days of MMR vaccination: 3.66 (95% CI, 1.74-7.70) OR was not provided for 6 year age group None described Negligible
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Benjamin et al. (1992) Joint symptoms identified with self-report questionnaire and confirmed by clinician at a home visit South Manchester Health District, United Kingdom Children residing in South Manchester Health District from 7/1989 through 2/1990 Retrospective cohort 1,588 vaccinated 1,242 unvaccinated RR of arthralgia within 6 weeks of MMR vaccination: 4.2 (95% CI, 1.2-14.3) None described Negligible
Davis et al. (1997) Chartconfirmed clinic, emergency department, and hospital visits for joint pain GHC and NCK HMOs from 3/1991 through 12/1994 Children aged 4-6 years and 10-12 years Retrospective cohort Risk period: 1 month after MMR vaccination Control period: began 3 months before MMR vaccination and ended 2 months before vaccination 18,036 children ages 10-12 years 8,514 children ages 4-6 years 10-12-year-olds: 13 visits for joint pain 1 month after MMR vaccination Six visits for joint pain 3 months before MMR vaccination 4-6-year-olds: No visits for joint pain None described Negligible
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Citation Operationally Defined Outcome Study Setting Defined Study Population Study Design Sample Size Primary Effect Size Estimatea (95% CI or p value) Heterogeneous Subgroups at Higher Riskb Limitations (Negligible or Serious)c

dos Santos et al. (2002) Clinical events observed by nurses who visited the schools daily Porto Alegre and Santa Maria, Brazil Schoolchildren aged 6-12 years selected from 70 public and private schools Vaccines administered at schools from 8/1996 through 9/1996 Double-blind, randomized control trial 2,216 vaccinated with MMR II 3,521 unvaccinated MMR II group: 8 joint reactions (primarily transient arthralgia) within 30 days of vaccination Control group: No joint reactions 65 percent of the joint reactions were reported in women Negligible
LeBaron et al. (2006) Prospective self-report of joint problems using diaries Marshfield Clinic, Wisconsin Children aged 12-24 months, 4-6 years, and 10-12 years receiving care at the Marshfield Clinic Case-crossover Risk period: 4 weeks after MMR vaccination Control period: 2 weeks before MMR vaccination 1,800 children No significant increases in joint problems were reported in any of the three age groups after MMR vaccination None described Serious
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Heijstek et al. (2007) Disease activity measured by joint counts, Physician's Global Assessment, and erythrocyte sedimentation rate Netherlands JIA patients aged 8-9 years born from 1989 through 1996 Retrospective cohort 108 vaccinated 86 unvaccinated Unadjusted OR of flares within 6 months of MMR vaccination: 1.7 (95% CI, 0.9-3.3) Adjusted OR of flares within 6 months of MMR vaccination: 1.4 (95% CI, 0.7-2.9) None described Serious

a The committee assumed statistical significance below the conventional 0.05 level unless otherwise stated by the authors.
b The risk/effect estimate for the subgroup/alternate definition of exposure or outcome differs significantly (e.g., is heterogeneous with nonoverla pping95% confidence intervals) compared with the risk/effect estimate reported for the primary group/definition.
c Studies designated as serious had more methodological limitations than those designated as negligible. Studies assessed as having very serious limitations were not considered in the weight of epidemiologic evidence.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

The committee assesses the mechanistic evidence regarding an association between rubella vaccine and transient arthralgia in children as weak based on knowledge about the natural infection.

The committee assesses the mechanistic evidence regarding an association between measles or mumps vaccine and transient arthralgia in children as lacking.

Causality Conclusion

Conclusion 4.21: The evidence favors acceptance of a causal relationship between MMR vaccine and transient arthralgia in children.

CHRONIC ARTHRALGIA IN WOMEN

Epidemiologic Evidence

The committee reviewed two studies to evaluate the risk of chronic arthralgia in women after the administration of rubella vaccine. These two controlled studies (Ray et al., 1997; Tingle et al., 1997) contributed to the weight of epidemiologic evidence and are described below.

Ray et al. (1997) conducted a retrospective cohort study that is described in detail in the section on transient arthralgia in women. None of the seronegative, vaccinated women were diagnosed with chronic arthropathy during the study period. The authors concluded that vaccination with the RA 27/3 strain of rubella does not appear to increase the prevalence of persistent joint symptoms in women, but noted the sample size limited the ability to assess an association.

The study by Tingle et al. (1997) was described in detail in the section on transient arthralgia in women. The authors defined persistent arthropathy as the “occurrence of arthralgia or arthritis at any time during the 12 months after vaccination in women who experienced acute arthropathy and for whom joint complaints could not be attributed to other causes” (Tingle et al., 1997). This randomized controlled trial reported an odds ratio of 1.59 (95% CI, 1.01–2.45) for the frequency of persistent arthralgia or arthritis among postpartum women receiving rubella vaccine compared to placebo. This comparison included 268 vaccine participants and 275 placebo participants that completed 1 month to 12 months of follow-up. The authors concluded that marginally significant differences of persistent arthralgia or arthritis occurred after rubella vaccination, and a study with more participants would be necessary to establish an association.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Weight of Epidemiologic Evidence

The two studies described above had negligible limitations but inconsistent results; one study had limited generalizability. A large retrospective cohort study (Ray et al., 1997) with appropriately defined exposed and control groups found no evidence of an association between immunization and chronic arthropathy. A randomized controlled trial (Tingle et al., 1997) involving a moderate number of postpartum women with careful follow-up by both history and physical examination, and appropriate adjustment for confounders, did find higher rates of persistent arthralgia or arthritis among the immunized group, but the difference was of marginal statistical significance. Additionally, this trial was restricted to one subgroup of women (postpartum period) when the physiologic milieu is quite different from other times in a woman’s life. See Table 4-9 for a summary of the studies that contributed to the weight of epidemiologic evidence.

The committee has limited confidence in the epidemiologic evidence, based on two studies that lacked validity and precision to assess an association between rubella vaccine and chronic arthralgia in women.

The epidemiologic evidence is insufficient or absent to assess an association between measles or mumps vaccine and chronic arthralgia in women.

Mechanistic Evidence

The committee identified eight publications describing chronic arthralgia in women after the administration of rubella or MMR vaccine. Five publications did not provide evidence beyond temporality and therefore did not contribute to the weight of mechanistic evidence (Boling, 1980; Frenkel et al., 1996; Tingle et al., 1986, 1989; Weibel and Benor, 1996).

Described below are three reports describing clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Mitchell et al. (1993) reported two cases of chronic arthralgia developing after vaccination with rubella strain RA 27/3. Significant in these cases is the finding of rubella virus RNA in the peripheral blood long after vaccination. Case 1 describes a 22-year-old postpartum woman presenting with aching in the wrists that worsened as the day progressed 5–6 weeks after receiving a rubella vaccine. Over the next 3 months the arthralgias evolved to include the neck, elbows, wrists, and knees. Four months postvaccination the patient was hospitalized for fever, diffuse rashes, and worsening joint pain. Serologic studies were negative for cytomegalovirus

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

TABLE 4-9 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Chronic Arthralgia in Women


Citation Operationally Defined Outcome Study Setting Defined Study Population Study Design Sample Size Primary Effect Size Estimatea (95% CI or p value) Heterogeneous Subgroups at Higher Riskb Limitations (Negligible or Serious)c

Ray et al. (1997) Arthropathies or joint complaints (acute, chronic, and traumatic) identified in inpatient and outpatient records and confirmed by a rheumatologist Northern California Kaiser Permanente Health Plan Women whose serological testing was performed from 1990 through 1991 Exposed group received rubella vaccine within 1 year following testing Retrospective cohort 971 seronegative, vaccinated women 2,421 seropositive, unvaccinated aged-matched controls 924 seronegative, unvaccinated unmatched controls None of the seronegative, vaccinated women were diagnosed with chronic arthralgia during the study period None described Negligible
Tingle et al. (1997) Acute and persistent arthropathy (arthralgia or arthritis) evaluated during home visit from a research nurse and by telephone Participating hospitals in Vancouver, Canada Postpartum, rubella-seronegative women identified from 4/1/1989 through 4/30/1992 Double-blind, randomized control trial 268 vaccinated 275 received placebo OR of persistent arthralgia or arthritis within 12 months of rubella vaccination: 1.59 (95% CI, 1.01-2.45) None described Negligible

a The committee assumed statistical significance below the conventional 0.05 level unless otherwise stated by the authors.
b The risk/effect estimate for the subgroup/alternate definition of exposure or outcome differs significantly (e.g., is heterogeneous with nonoverlapping 95% confidence intervals) compared with the risk/effect estimate reported for the primary group/definition.
c Studies designated as serious had more methodological limitations than those designated as negligible. Studies assessed as having very serious limitations were not considered in the weight of epidemiologic evidence.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

and hepatitis B virus, positive for Epstein-Barr virus, and weakly positive for parvovirus B19. The patient did not produce antirubella neutralizing antibodies. Rubella virus RNA was detected by PCR in peripheral blood mononuclear cells 10 months postvaccination. The patient began treatment with prednisone 6 months postvaccination and was asymptomatic 20 months postvaccination. Case 2 describes a 26-year-old woman presenting with an erythematous maculopapular rash on the trunk and extremities followed by fatigue, myalgia, and arthralgias involving the large joints 4 weeks after receiving a rubella vaccine. Serologic tests were negative for hepatitis B virus, cytomegalovirus, and Borrelia burgdorferi and showed past infections of Epstein-Barr virus and parvovirus. Rubella virus RNA was detected by PCR in peripheral blood mononuclear cells 8 months postvaccination. The patient began treatment with prednisone 13 months postvaccination; however, the patient was still symptomatic 30 months postvaccination. In neither case was the strain of rubella delineated from the RNA isolated.

Tingle et al. (1985) reported two cases of chronic arthralgia developing postvaccination with rubella strain RA 27/3. Case 1 (number 5 in the article) describes a woman in the postpartum period presenting with polyarthritis 3 weeks after vaccination. Subsequently the patient developed arthralgia involving the shoulders, elbows, wrists, hips, and knees. The patient was followed for 2 years, 9 months. Rubella virus was demonstrated in peripheral blood mononuclear cells 15 months postvaccination. Case 2 (number 6 in the article) describes a woman in the postpartum period presenting with polyarthritis 3 weeks after vaccination. Subsequently the patient developed a continuing arthritis and arthralgia. The patient was followed for 2 years, 2 months. Rubella virus was demonstrated in peripheral blood mononuclear cells and breast milk mononuclear cells 7 and 9 months postvaccination, respectively. Both patients had titers of HAI antirubella antibodies of < 1:8, but significantly elevated levels of antirubella IgG antibodies prior to vaccination. Furthermore, both patients showed a delayed time course and lower peak hemagglutination inhibition titers than women immunized with the rubella strain HPV-77 DE/5. Two years or more after vaccination the patients’ antirubella antibody levels declined to those detected prevaccination. In neither case was the strain of rubella delineated from the virus isolated.

Mitchell et al. (2000) was described in detail in the section on transient arthralgia in women. The authors reported the development of acute and chronic arthralgia and arthritis in a subset of 18- to 41-year-old women within 28 days after rubella vaccination, which contained RA 27/3. The subjects who developed acute and chronic arthralgia and arthritis were those who had previously been exposed but had the lowest levels of prevaccine antibodies as measured by the additional techniques. This suggests that

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

the inability to respond to wild-type rubella during previous exposures is associated with arthropathy after the vaccine.

Weight of Mechanistic Evidence

It has been reported that as many as one-third of women with a wild-type rubella infection develop arthralgia (Gershon, 2010b). The committee considers the effects of natural infection one type of mechanistic evidence.

The three publications described above, when considered together, presented clinical evidence suggestive but not sufficient for the committee to conclude the vaccine may be a contributing cause of chronic arthralgia in women after vaccination against rubella. Lower peak hemagglutination inhibition titers or the lack of production of antirubella-neutralizing antibodies after vaccination were reported in three cases (Mitchell et al., 1993; Tingle et al., 1985). Furthermore, two publications reported the development of arthralgia postvaccination in women initially thought to be seronegative prior to administration of the vaccine; further tests showed the women had not mounted a robust antibody response to a prior exposure to rubella (Mitchell et al., 2000; Tingle et al., 1985). The isolation of rubella virus or viral RNA > 7 months postvaccination suggests the development of a persistent rubella infection (Mitchell et al., 1993; Tingle et al., 1985). The association of persistent viremia and inadequate antibody formation suggests persistent viral infection to be the mechanism for chronic arthralgia in women after rubella vaccination. The latency between vaccination and the development of arthralgia symptoms in the cases described above ranged from 12 days to 6 weeks.

The failure to differentiate between wild-type and vaccine strains of rubella, where virus was demonstrated, detracted from the weight of evidence. In addition, the publications described above were produced by one group; the results of these studies have not been reported by another group.

Autoantibodies, T cells, immune complexes, and complement activation may contribute to arthralgia as well; however, the publications did not provide evidence linking these mechanisms to MMR vaccine.

The committee assesses the mechanistic evidence regarding an association between rubella vaccine and chronic arthralgia in women as low-intermediate based on clinical evidence in four cases.

The committee assesses the mechanistic evidence regarding an association between measles or mumps vaccine and chronic arthralgia in women as lacking.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Causality Conclusion

Conclusion 4.22: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and chronic arthralgia in women.

CHRONIC ARTHRITIS IN WOMEN

Epidemiologic Evidence

The committee reviewed two studies to evaluate the risk of chronic arthritis in women after the administration of rubella vaccine. These two controlled studies (Ray et al., 1997; Tingle et al., 1997) contributed to the weight of epidemiologic evidence and are described below.

Ray et al. (1997) conducted a retrospective cohort study that is described in detail in the section on transient arthralgia in women. No cases of chronic arthropathy were diagnosed in the exposed group of seronegative, vaccinated women. Only one case of rheumatoid arthritis was diagnosed in the study population; this case was reported in the seropositive, unimmunized control group. The authors concluded that vaccination with RA 27/3 strain rubella does not appear to increase the prevalence of persistent joint symptoms in women, but noted the sample size may limit the ability to assess an association.

The study by Tingle et al. (1997) was described in detail in the section on transient arthralgia in women. This randomized controlled trial reported an odds ratio of 1.58 (95% CI, 1.01–2.45) for the frequency of persistent arthralgia or arthritis among postpartum women receiving rubella vaccine compared to placebo. The authors concluded that marginally significant differences of persistent arthralgia or arthritis occurred after rubella vaccination, and a study with more participants may be necessary to establish an association.

Weight of Epidemiologic Evidence

The two studies described above had negligible limitations but inconsistent results; one study had limited generalizability. A large retrospective cohort study (Ray et al., 1997) with appropriately defined exposed and control groups found no evidence of an association between immunization and chronic arthropathy. A randomized controlled trial (Tingle et al., 1997) involving a moderate number of postpartum women with careful follow-up by both history and physical examination, and appropriate adjustment for confounders, did find higher rates of persistent arthralgia or arthritis among the immunized group, but the difference was of marginal statisti-

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

cal significance. Additionally, this trial was restricted to one subgroup of women (postpartum period) when the physiologic milieu is quite different from other times in a woman’s life. See Table 4-10 for a summary of the studies that contributed to the weight of epidemiologic evidence.

The committee has limited confidence in the epidemiologic evidence, based on two studies that lacked validity and precision to assess an association between rubella vaccine and chronic arthritis in women.

The epidemiologic evidence is insufficient or absent to assess an association between measles or mumps vaccine and chronic arthritis in women.

Mechanistic Evidence

The committee identified seven publications describing chronic arthritis in women after the administration of rubella or MMR vaccine. In two publications, chronic arthropathy was not distinguished from chronic arthritis; these publications did not contribute to the weight of mechanistic evidence (Mitchell et al., 2000; Tingle et al., 1989). Three publications did not provide evidence beyond temporality and therefore did not contribute to the weight of mechanistic evidence (Tingle et al., 1986; von Wehren and von Torklus, 1983; Weibel and Benor, 1996).

Described below are two publications describing clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Tingle et al. (1983) reported the development of arthritis involving the metacarpophalangeal joints, wrists, and knees in four women after vaccination with rubella strain RA 27/3. None of the patients had been previously immunized against rubella. All four were seronegative, based on an HAI assay, prior to vaccination but were later found, based on an ELISA assay, to have had antibodies prevaccination. The patients had recurrent episodes of arthritis involving the same joints over a 6-month period after vaccination. The authors pointed out that the patients who developed arthritis had more acute symptoms of infection (posterior cervical lymphadenitis and pharyngitis) than patients who did not develop arthritis.

The case reported by Tingle et al. (1985) was described in detail in the section on chronic arthralgia in women. The authors reported one case of a woman in the postpartum period who developed continuing arthralgia and arthritis after rubella vaccination. The patient was followed for 2 years and 2 months. Rubella virus was demonstrated in peripheral blood mononuclear cells and breast milk mononuclear cells at 7 and 9 months postvac-

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

TABLE 4-10 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Chronic Arthritis in Women


Citation Operationally Defined Outcome Study Setting Defined Study Population Study Design Sample Size Primary Effect Size Estimatea (95% CI or p value) Heterogeneous Subgroups at Higher Riskb Limitations (Negligible or Serious)c

Ray et al. (1997) Arthropathies or joint complaints (acute, chronic, and traumatic) identified in inpatient and outpatient records and confirmed by a rheumatologist Northern California Kaiser Permanente Health Plan Women whose serological testing was performed from 1990 through 1991 Exposed group received rubella vaccine within 1 year following testing Retrospective cohort 971 seronegative, vaccinated women 2,421 seropositive, unvaccinated aged-matched controls 924 seronegative, unvaccinated unmatched controls None of the seronegative, vaccinated women were diagnosed with chronic arthritis during the study period None described Negligible
Tingle et al. (1997) Acute and persistent arthropathy (arthralgia or arthritis) evaluated during home visit from a research nurse and by telephone Participating hospitals in Vancouver, Canada Postpartum, rubella-seronegative women identified from 4/1/1989 through 4/30/1992 Double-blind, randomized control trial 268 vaccinated 275 received placebo OR of persistent arthralgia or arthritis within 12 months of rubella vaccination: 1.58 (95% CI, 1.01-2.45) None described Negligible

a The committee assumed statistical significance below the conventional 0.05 level unless otherwise stated by the authors.
b The risk/effect estimate for the subgroup/alternate definition of exposure or outcome differs significantly (e.g., is heterogeneous with nonoverlapping 95% confidence intervals) compared with the risk/effect estimate reported for the primary group/definition.
c Studies designated as serious had more methodological limitations than those designated as negligible. Studies assessed as having very serious limitations were not considered in the weight of epidemiologic evidence.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

cination, respectively. Similar to other reports, this patient was determined to be seronegative by HAI prior to vaccination, but further tests showed the patient had prevaccination antibodies to rubella. The patient showed a delayed time course and lower peak hemagglutination inhibition titers after vaccination as compared to other patients receiving the HPV-77 DE/5 rubella vaccine. Two years or more after vaccination the patient’s antirubella antibody levels declined to those detected prevaccination.

Weight of Mechanistic Evidence

While rare, chronic arthritis has been associated with wild-type rubella infection (Gershon, 2010b). Rubella has been demonstrated in the joint in cases of acute or recurrent arthritis, as well as from peripheral blood mononuclear cells in cases of chronic arthritis, suggesting persistent rubella infection (Gershon, 2010b). The committee considers the effects of natural infection one type of mechanistic evidence.

The two publications described above, when considered together, presented clinical evidence suggestive but not sufficient for the committee to conclude the vaccine may be a contributing cause of chronic arthritis in women after vaccination against rubella. Evidence of persistent rubella infection in monocytes was presented in one case (Tingle et al., 1985). Furthermore, the cases suggest that a host factor may be involved, particularly, the inability to mount a robust immune response to rubella in six cases. The association of persistent viremia and inadequate antibody response suggests persistent viral infection may be a mechanism for chronic arthritis in women after rubella vaccination. The latency between vaccination and the development of arthritis symptoms in the cases described above ranged from 18 days to 3 weeks.

The failure to differentiate between wild-type and vaccine strains of rubella, where virus was demonstrated, as well as the failure to demonstrate virus in joints, detracted from the weight of evidence. In addition, the publications described above were produced by one group; the results of these studies have not been reproduced by another group.

Autoantibodies, T cells, immune complexes, and complement activation may contribute to arthritis as well; however, the publications did not provide evidence linking these mechanisms to MMR vaccine.

The committee assesses the mechanistic evidence regarding an association between rubella vaccine and chronic arthritis in women as low-intermediate based on clinical evidence in five cases.

The committee assesses the mechanistic evidence regarding an association between measles or mumps vaccine and chronic arthritis in women as lacking.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Causality Conclusion

Conclusion 4.23: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and chronic arthritis in women.

CHRONIC ARTHROPATHY IN CHILDREN

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of chronic arthropathy (arthralgia or arthritis) in children after the administration of MMR vaccine.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between MMR vaccine and chronic arthropathy in children.

Mechanistic Evidence

The committee identified five publications describing chronic arthropathy in children after the administration of vaccines containing measles, mumps, and rubella alone or in combination. Two publications did not provide evidence beyond temporality (Balfour et al., 1980; Bottiger et al., 1974). In addition, the patient described in Bottiger et al. (1974) developed symptoms following strep throat. Since it is well appreciated that streptococcal infection can cause joint symptoms, it is not possible to solely attribute the symptoms in this individual to the rubella vaccine. Borte et al. (2009) did not observe exacerbation of juvenile idiopathic arthritis after MMR vaccination. These publications did not contribute to the weight of mechanistic evidence.

Described below are two publications reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Peters and Horowitz (1984) report one case of a 10-year-old girl presenting with lower extremity pain 1 week after receiving a measles and rubella vaccine. Subsequently, the patient developed bilateral thigh pain, fever, and a macular rash over the anterior trunk. Eight months postvaccination laboratory tests showed hemaglutination titers of 1:32 and 1:8 for rubella and measles, respectively, and an IgM specific rubella antibody titer of < 1:4. The patient had recurrent symptoms over 4 years leading to a diagnosis of pauciarticular juvenile rheumatoid arthritis.

Geiger et al. (1995) reported the case of a 16-year-old boy, diagnosed

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

with acute lymphoblastic leukemia, who was undergoing maintenance treatment with methotrexate and 6-mercaptopurine when he was inadvertently given the rubella vaccine. This patient had been seronegative prior to chemotherapy 15 months earlier. Fifty-one days after vaccination, the patient presented with arthritis of the wrist, metacarpophalangeal, carpal, proximal, and distal interphalangeal joints. The arthritis resolved over 8 weeks with therapy. Nucleic acid specific for rubella was detected in whole blood and in stimulated and unstimulated mononuclear cells obtained 8 months after vaccination. The test for rubella nucleic acid involved reverse transcription followed by nested PCR. Sequence analysis was not performed to determine if the nucleic acid was from wild-type or vaccine virus.

Weight of Mechanistic Evidence

While rare, arthritis and arthralgia have been reported as a complication of wild-type rubella infection in children (Gershon, 2010b). The committee considers the effects of natural infection one type of mechanistic evidence.

The publications, described above, did not present clinical evidence sufficient for the committee to conclude the vaccine may be a contributing cause of chronic arthropathy in children. The failure to differentiate between wild-type and vaccine strains of rubella, where virus was demonstrated, as well as the failure to demonstrate virus in the joints, detracted from the weight of evidence.

The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of chronic arthropathy. Autoantibodies, T cells, immune complexes, persistent viral infection, and complement activation may contribute to chronic arthropathy; however, the publications did not provide evidence linking these mechanisms to MMR vaccine.

The committee assesses the mechanistic evidence regarding an association between rubella vaccine and chronic arthropathy in children as weak based on knowledge about the natural infection and two cases.

The committee assesses the mechanistic evidence regarding an association between measles or mumps vaccine and chronic arthropathy in children as lacking.

Causality Conclusion

Conclusion 4.24: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and chronic arthropathy in children.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

ARTHROPATHY IN MEN

Epidemiologic Evidence

The committee reviewed four studies to evaluate the risk of arthropathy in men after the administration of rubella or MMR vaccine. Two studies (Geier and Geier, 2001; Stetler et al., 1985) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations.

Two controlled studies (Chen et al., 1991; Pattison et al., 2008) were included in the weight of epidemiologic evidence and are described below.

Chen et al. (1991) conducted a retrospective cohort study of undergraduate students living in dormitories at Boston University (BU) and Massachusetts Institute of Technology (MIT) in March 1985. As a result of a measles outbreak, an increased number of students were vaccinated with MMR from February through March 1985. Self-administered questionnaires were used to determine the incidence of adverse events after MMR vaccination at BU and MIT. Only students vaccinated at BU or MIT were included in the exposed group (401 and 133, respectively); those vaccinated by a private physician, with a history of measles disease, or unknown vaccination status were excluded. The remaining students not vaccinated during the measles outbreak served as the control group at BU (391 students) and MIT (352 students). The study had multiple limitations including a low survey response rate (62 percent of BU students and 31 percent of MIT students), inadequate definition of exposed and control groups, and reliance on self-reported data. The authors concluded that the incidence of joint swelling, or joint ache or pain, was not increased among students vaccinated with MMR or measles, compared to respective controls.

Pattison et al. (2008) conducted a case-control study in 125 patients with psoriatic arthritis and 163 psoriasis controls in the United Kingdom. The cases were identified through a nationwide campaign and confirmed by local consultant rheumatologists, whereas controls were recruited from the Psoriasis Clinic at the Dermatology Centre, Hope Hospital, Salford. The psoriatic arthritis patients experienced their first joint swelling within 5 years of the start of the study. A self-report questionnaire was sent to the cases and controls to assess exposures in the 10 years before disease onset; 82.7 percent of the cases and 50.0 percent of the controls responded to the questionnaire. The authors reported an increased risk of psoriatic arthritis after rubella vaccination (OR, 12.4; 95% CI, 1.20–122.14); however, these results were not generalizable to men.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Weight of Epidemiologic Evidence

The two studies described above had serious limitations and low precision. One study by Pattison et al. (2008) found an association but studied men with psoriasis, and thus the results could not be generalized to all men. The study by Chen et al. (1991) found no association. See Table 4-11 for a summary of the studies that contributed to the weight of epidemiologic evidence.

The committee has limited confidence in the epidemiologic evidence, based on two studies that lacked validity and precision, to assess an association between MMR vaccine and arthropathy in men.

Mechanistic Evidence

The committee identified four publications of chronic or transient arthropathy in men after the administration of vaccines containing measles, mumps, and rubella alone or in combination. Two publications did not provide evidence beyond temporality (Seager et al., 1994; Weibel and Benor, 1996). Two publications reported symptoms of arthralgia after vaccination but did not differentiate between men and women (Freestone et al., 1971; Simon et al., 2007). These publications did not contribute to the weight of mechanistic evidence.

Weight of Mechanistic Evidence

While rare, arthritis and arthralgia have been reported as complications of wild-type rubella infection in men (Gershon, 2010b). The committee considers the effects of natural infection one type of mechanistic evidence.

The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of arthropathy. Autoantibodies, T cells, immune complexes, direct viral infection, persistent viral infection, and complement activation may contribute to arthropathy; however, the publications did not provide evidence linking these mechanisms to MMR vaccine.

The committee assesses the mechanistic evidence regarding an association between rubella vaccine and arthropathy in men as weak based on knowledge about the natural infection.

The committee assesses the mechanistic evidence regarding an association between measles or mumps vaccine and arthropathy in men as lacking.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

TABLE 4-11 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Arthropathy in Men


Citation Operationally Defined Outcome Study Setting Defined Study Population Study Design Sample Size Primary Effect Size Estimatea (95% CI or p value) Heterogeneous Subgroups at Higher Riskb Limitations (Negligible or Serious)c

Chen et al. (1991) Joint swelling or joint ache/pain identified with self-administered questionnaires BU and MIT during 3/1985 Undergraduate students living in dormitories at BU or MIT Exposed group included students who received MMR or measles vaccine on their college campus Cohort BU: 401 vaccinated 391 unvaccinated MIT: 133 vaccinated 352 unvaccinated No increased risk of joint swelling or joint ache/pain following MMR or measles vaccination None described Serious
Pattison et al. (2008) Psoriatic arthritis confirmed by local consultant rheumatologists United Kingdom Cases: Psoriatic arthritis patients identified by nationwide campaign Controls: Psoriasis patients identified at the Psoriasis Clinic at the Dermatology Centre, Hope Hospital, Salford Case-control 125 patients with psoriatic arthritis 163 patients with psoriasis OR for psoriatic arthritis after rubella vaccination: 12.4 (95% CI, 1.20-122.14) None described Serious

a The committee assumed statistical significance below the conventional 0.05 level unless otherwise stated by the authors.
b The risk/effect estimate for the subgroup/alternate definition of exposure or outcome differs significantly (e.g., is heterogeneous with nonoverlapping 95% confidence intervals) compared with the risk/effect estimate reported for the primary group/definition.
c Studies designated as serious had more methodological limitations than those designated as negligible. Studies assessed as having very serious limitations were not considered in the weight of epidemiologic evidence.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Causality Conclusion

Conclusion 4.25: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and arthropathy in men.

TYPE 1 DIABETES

Epidemiologic Evidence

The committee reviewed eight studies to evaluate the risk of type 1 diabetes after the administration of MMR vaccine. One study (Fescharek et al., 1990) was not considered in the weight of epidemiologic evidence because it provided data from a passive surveillance system and lacked an unvaccinated comparison population. Two controlled studies (Karavanaki et al., 2008; Telahun et al., 1994) had very serious methodological limitations that precluded their inclusion in this assessment. Karavanaki et al. (2008) and Telahun et al. (1994) conducted case-control studies in diabetic children and hospital controls using a self-report questionnaire, but did not validate vaccination histories with medical records or adequately adjust for age or date of diagnosis.

The five remaining controlled studies (Altobelli et al., 2003; Blom et al., 1991; DeStefano et al., 2001; Hviid et al., 2004; Patterson, 2000) contributed to the weight of epidemiologic evidence and are described below.

Blom et al. (1991) conducted a case-control study in diabetic children (0 to 14 years of age) enrolled in the Swedish Childhood Diabetes Register from September 1985 through August 1986. A total of 393 children with type 1 diabetes were matched to 786 controls (two controls for each case matched on age, sex, and county) from the official Swedish population register. The dates of vaccination were ascertained from questionnaires that were sent to the parents of cases and their matched controls within 4 weeks of disease diagnosis. Questionnaires were returned for 86 percent of the cases and 67 percent of the controls. There were no systematic differences in the age, sex, and county categories of those that returned the questionnaire compared to those that did not, but other factors that were not reported in the study could suggest selection bias. Self-report vaccination data were compared to vaccination records from the local child health care centers and school health units. The authors were able to validate the vaccination status of 88.5 percent and 82.1 percent of the cases and controls, respectively. Since the relative risk ratio of matched and unmatched data remained close to 1, the case and control matching was removed to avoid losing information during the analysis. The odds ratio for diabetes diagnosis any time after vaccination was assessed for MMR vaccine, 0.95 (95% CI, 0.71–1.28); measles vaccine, 0.74 (95% CI, 0.55–1.00); mumps

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

vaccine, 1.75 (95% CI, 0.54–5.70); and rubella vaccine, 1.24 (95% CI, 0.41–3.73). The authors concluded that MMR vaccine does not increase the risk of type 1 diabetes in children, and measles vaccine may have a protective effect that should be investigated.

Patterson (2000) conducted a case-control study in children (under 15 years of age) with type 1 diabetes enrolled at seven centers participating in the EURODIAB ACE Group from 1989 to 1995. Controls were selected at each center from population registers, general practitioners’ lists, or school rolls, and matched to cases by age. Of the 1,028 cases and 3,044 controls invited to participate in the study, 900 (87.5 percent) and 2,302 (75.6) responded, respectively. The authors did not provide any information on the nonresponders. Vaccination data were obtained from parent interviews or questionnaires depending on the center, and were validated with official records or child health care booklets in 74 percent of the cases and 78 percent of the controls. A diagnosis date was assigned to each control based on the midpoint of the recruitment period for the corresponding diabetic child. The Mantel Haenszel approach was used to stratify the analysis by center, and the odds ratio for diabetes diagnosis any time after rubella vaccination was 1.18 (95% CI, 0.91–1.53). A logistic regression analysis was used to adjust for confounding variables, and the odds ratio for diabetes diagnosis any time after rubella vaccination was 1.27 (95% CI, 0.93–1.72). The authors concluded that administration of rubella vaccine does not increase the risk of type 1 diabetes in children.

DeStefano et al. (2001) conducted a case-control study in children (10 months to 10 years of age) enrolled in four HMOs participating in the VSD. A total of 252 type 1 diabetes cases and 768 matched controls were included in the analysis. The study required participants to be born from 1988 through 1997, enrolled in the HMO since birth, and continuously enrolled for the first 6 months of life. Additionally, cases had to be enrolled at least 12 months before the diabetes diagnosis except when diagnosis occurred before 12 months of age. The case index date was defined as the first date of type 1 diabetes diagnosis in the medical record; controls were assigned the same index date as their matched case. At least three controls were matched to each case on sex, date of birth (within 7 days), HMO, and length of enrollment in the HMO (up to the index date). Trained chart abstractors obtained complete vaccination histories from the medical records of the cases and controls. Vaccination histories were similar for the cases and controls with 92.1 percent and 90.6 percent exposed to MMR vaccine, respectively. The results of two conditional logistic regression models were provided: Model 1 stratified by the matching variables; Model 2 stratified by the matching variables and race, ethnicity, and family history of type 1 diabetes (additional variables also obtained from medical records). The odds ratio for diabetes diagnosis any time after MMR vaccination using

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Model 1 was 1.36 (95% CI, 0.70–2.63) and using Model 2 was 1.43 (95% CI, 0.71–2.86). The authors concluded that vaccination with MMR does not increase the risk of type 1 diabetes in children.

Altobelli et al. (2003) conducted a case-control study in children (under 15 years of age) with type 1 diabetes enrolled in the diabetes register of the Abruzzo region of Italy from 1990 through 1996. A total of 136 cases (52.9 percent men and 47.1 percent women) and 272 controls (50.7 percent men and 49.3 percent women) participated in the study. The controls were identified in the National Health System records and were matched to cases on age (within 1 year) and registration with the same family pediatrician. The pediatricians certified that all controls were free of diabetes and none were diagnosed with diabetes during the study period. Trained physicians collected immunization information from the parents of diabetic cases and controls using a questionnaire at the first diabetologic examination or pediatric examination, respectively. The vaccination data were verified with records from the National Health System. A larger proportion of the controls were exposed to MMR vaccine and measles vaccine when compared to the cases: MMR vaccination in 8.1 percent of cases and 18.7 percent of controls; measles vaccination in 10.3 percent of cases and 12.9 percent of controls. The odds ratio for diabetes diagnosis any time after MMR vaccination was 0.382 (95% CI, 0.201–0.798) and measles vaccination was 0.777 (95% CI 0.403–1.498). The authors concluded that administration of MMR vaccine or measles vaccine does not increase the risk of type 1 diabetes in children.

Hviid et al. (2004) conducted a retrospective cohort study in children born from January 1990 through December 2000 and who resided in Denmark through December 2001 (end of study period). The participants were identified in the Danish Civil Registration System, and linked to information on type 1 diabetes diagnosis in the Danish National Hospital Register and vaccination data from the National Board of Health. The children were followed from birth and removed from the study at the first occurrence of an outcome of interest. The study outcomes included diagnosis of type 1 diabetes, loss to follow-up or emigration, reaching 12 years of age, and death. Vaccination status was considered a time-varying variable and was classified according to the number of doses administered (zero, one, two, or three doses of each vaccine). A total of 739,694 children were included in the study, of whom 16,421 were prematurely removed from the analysis because of loss to follow-up, emigration, or death. The rate ratio for diabetes diagnosis any time after one dose of MMR vaccine (compared to the unvaccinated) was 1.14 (95% CI, 0.90–1.45). The study also evaluated the rate ratios of diabetes diagnosis 1, 2, 3, 4, and > 4 years after MMR vaccination and found no significant differences. The authors

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

concluded that MMR vaccination does not increase the risk of type 1 diabetes in children.

Weight of Epidemiologic Evidence

The five observational studies consistently reported no increased risks of type 1 diabetes following MMR vaccination, and two had negligible methodological limitations (Hviid et al., 2004; Patterson, 2000). The five studies had relatively large sample sizes and were representative of European and U.S. populations of children across a broad range of ages and varying time periods at risk of type 1 diabetes following vaccination. See Table 4-12 for a summary of the studies that contributed to the weight of epidemiologic evidence.

The committee has a high degree of confidence in the epidemiologic evidence based on five studies with validity and precision to assess an association between MMR vaccine and type 1 diabetes; these studies consistently report a null association.

Mechanistic Evidence

The committee identified five publications reporting type 1 diabetes developing after the administration of vaccines containing measles and mumps alone or in combination. The publications did not provide evidence beyond temporality, some too long or too short based on the possible mechanisms involved (Ehrengut and Zastrow, 1989; Fescharek et al., 1990; Helmke et al., 1986; Otten et al., 1984; Sinaniotis et al., 1975). Long latencies between vaccine administration and development of symptoms make it impossible to rule out other possible causes. In addition, Otten et al. (1984) reported that one patient contracted mumps 2 years after vaccination and 4 years before development of type 1 diabetes making it impossible to attribute the development of type 1 diabetes to vaccination. Two publications studied antibodies to mumps in patients developing type 1 diabetes or autoantibodies associated with the development of type 1 diabetes in patients after mumps infection or vaccination. Vaandrager et al. (1986) tested sera from patients after mumps infection or vaccination for the presence of autoantibodies associated with type 1 diabetes. The authors isolated autoantibodies from patients after mumps infection or vaccination but reported that the patients did not develop type 1 diabetes. Hyoty et al. (1993) tested sera collected from patients before and after receiving an MMR vaccination. The authors reported a decline of mumps antibodies in type 1 diabetes patients. The publications did not contribute to the weight of mechanistic evidence.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

TABLE 4-12 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Type 1 Diabetes


Citation Operationally Defined Outcome Study Setting Defined Study Population Study Design Sample Size Primary Effect Size Estimatea (95% CI or p value) Heterogeneous Subgroups at Higher Riskb Limitations (Negligible or Serious)c

Blom et al. (1991) Type 1 diabetes reported to the Swedish Childhood Diabetes Register Sweden Children aged 0-14 years Cases were enrolled in the Swedish Childhood Diabetes Register from 9/1/1985 through 8/31/1986 Controls were identified in the official Swedish population register Case-control 393 children with type 1 diabetes 786 controls matched on age, sex, and county OR for type 1 diabetes diagnosis any time after MMR vaccination: 0.95 (95% CI, 0.71-1.28) OR for type 1 diabetes diagnosis any time after measles vaccination: 0.74 (95% CI, 0.55-1.00) OR for type 1 diabetes diagnosis any time after mumps vaccination: 1.75 (95% CI, 0.54-5.70) OR for type 1 diabetes diagnosis any time after rubella vaccination: 1.24 (95% CI, 0.41-3.73) None described Serious
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Patterson (2000) Type 1 diabetes diagnosed by the EURODIAB ACE Group Europe (Austria, Latvia, Lithuania, Luxemburg, Romania, United Kingdom) Children under 15 years of age enrolled at seven centers participating in the EURODIAB ACE Group from 1989 through 1995 Controls were selected at each center from population registers, general practitioners' lists, or school rolls Case-control 900 children with type 1 diabetes 2,302 controls matched on age OR for type 1 diabetes diagnosis any time after rubella vaccination using the Mantel Haenszel approach: 1.18 (95% CI, 0.91-1.53; p = .21) OR for type 1 diabetes diagnosis any time after rubella vaccination using a logistic regression analysis: 1.27 (95% CI, 0.93-1.72; p = .13) None described Negligible
DeStefano et al. (2001) First date of type 1 diabetes diagnosis in the medical record Four HMOs participating in the VSD Children born from 1988 through 1997, ages 10 months to 10 years Case-control 252 children with type 1 diabetes 768 controls matched on sex, date of birth, HMO, and length of enrollment in the HMO OR for type 1 diabetes diagnosis any time after MMR vaccination using Model 1: 1.36 (95% CI, 0.70-2.63) OR for type 1 diabetes diagnosis any time after MMR vaccination using Model 2: 1.43 (95% CI, 0.71-2.86) None described Serious
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Citation Operationally Defined Outcome Study Setting Defined Study Population Study Design Sample Size Primary Effect Size Estimatea (95% CI or p value) Heterogeneous Subgroups at Higher Riskb Limitations (Negligible or Serious)c

Altobelli et al. (2003) Type 1 diabetes diagnosis in the diabetes register Abruzzo region of Italy Children under 15 years of age with type 1 diabetes in the diabetes register of the Abruzzo region from 1990 to 1996 Controls identified in the National Health System records of Italy Case-control 136 children with type 1 diabetes 272 controls matched on age and registration with the same family pediatrician OR for type 1 diabetes diagnosis any time after MMR vaccination: 0.382 (95% CI, 0.201-0.798) OR for type 1 diabetes diagnosis any time after measles vaccination: 0.777 (95% CI, 0.403-1.498) None described Serious
Hviid et al. (2004) Type 1 diabetes diagnosis in the Danish National Hospital Register Denmark Children born from 1/1/1990 through 12/31/2000, residing in Denmark through 12/2001 Retrospective cohort 739,694 children Rate ratio for type 1 diabetes diagnosis any time after one dose of MMR vaccine compared to the unexposed: 1.14 (95% CI, 0.90-1.45) None described Negligible

a The committee assumed statistical significance below the conventional 0.05 level unless otherwise stated by the authors.
b The risk/effect estimate for the subgroup/alternate definition of exposure or outcome differs significantly (e.g., is heterogeneous with nonoverlapping 95% confidence intervals) compared with the risk/effect estimate reported for the primary group/definition.
c Studies designated as serious had more methodological limitations than those designated as negligible. Studies assessed as having very serious limitations were not considered in the weight of epidemiologic evidence.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Weight of Mechanistic Evidence

The association of type 1 diabetes with wild-type mumps infection is controversial. Several publications have reported cases of type 1 diabetes developing after mumps infection (Litman and Baum, 2010). Epidemiologic studies report a 3- to 4-year lag time between mumps infection and type 1 diabetes (Litman and Baum, 2010), which would be consistent with a slow loss of islet cells not clinically apparent for several years; however, it would also be consistent with numerous other triggers. In addition, a decrease in the frequency of type 1 diabetes has not been associated with a decrease in the frequency of mumps infection after implementation of mumps vaccines (Litman and Baum, 2010). Owing to the uncertainty the committee did not consider mumps infection when determining the weight of mechanistic evidence.

The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of type 1 diabetes. Autoantibodies, T cells, molecular mimicry, and complement activation may contribute to type 1 diabetes; however, the publications did not provide evidence linking these mechanisms to MMR vaccine.

The committee assesses the mechanistic evidence regarding an association between MMR vaccine and type 1 diabetes as lacking.

Causality Conclusion

Conclusion 4.26: The evidence favors rejection of a causal relationship between MMR vaccine and type 1 diabetes.

HEPATITIS

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of hepatitis after the administration of MMR vaccine.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between MMR vaccine and hepatitis.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Mechanistic Evidence

The committee identified two publications reporting the development of hepatitis after the administration of vaccines containing measles, mumps, and rubella alone or in combination. Saliba and Elias (2005) did not provide evidence beyond temporality. Jorch et al. (1984) described a 2-year-old presenting with meningoencephalitis 7 days after administration of a measles and mumps vaccine and 3 days prior to brain death and cardiac arrest. Hepatitis was not reported as a symptom after vaccination and the liver was not enlarged, but a liver biopsy showed paramyxovirus-like intranuclear filaments suggesting the presence of measles virus or mumps virus or both. There was no attempt to identify virus in the liver either by culture or PCR, although vaccine-strain viremia is likely to be present at 7 days postvaccination. The publications did not contribute to the weight of mechanistic evidence.

Weight of Mechanistic Evidence

On rare occasions, infection with wild-type measles, mumps, and rubella viruses has been associated with hepatitis (Gershon, 2010a,b; Litman and Baum, 2010). The committee considers the effects of natural infection one type of mechanistic evidence.

The symptoms described above are consistent with those leading to a diagnosis of hepatitis. Autoantibodies, T cells, direct viral infection, and complement activation may contribute to the symptoms of hepatitis; however, the publications did not provide evidence linking these mechanisms to MMR vaccine.

The committee assesses the mechanistic evidence regarding an association between MMR vaccine and hepatitis as weak based on knowledge about the natural infection.

Causality Conclusion

Conclusion 4.27: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and hepatitis.

CHRONIC FATIGUE SYNDROME

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of chronic fatigue syndrome after the administration of MMR vaccine.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between MMR vaccine and chronic fatigue syndrome.

Mechanistic Evidence

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of chronic fatigue syndrome after the administration of MMR vaccine.

Weight of Mechanistic Evidence

The committee assesses the mechanistic evidence regarding an association between MMR vaccine and chronic fatigue syndrome as lacking.

Causality Conclusion

Conclusion 4.28: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and chronic fatigue syndrome.

FIBROMYALGIA

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of fibromyalgia after the administration of MMR vaccine.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between MMR vaccine and fibromyalgia.

Mechanistic Evidence

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of fibromyalgia after the administration of MMR vaccine.

Weight of Mechanistic Evidence

The committee assesses the mechanistic evidence regarding an association between MMR vaccine and fibromyalgia as lacking.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Causality Conclusion

Conclusion 4.29: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and fibromyalgia.

HEARING LOSS

Epidemiologic Evidence

The committee reviewed one study to evaluate the risk of hearing loss after the administration of MMR vaccine. This one study (Asatryan et al., 2008) was not considered in the weight of epidemiologic evidence because it provided data from a passive surveillance system and lacked an unvaccinated comparison population.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between MMR vaccine and hearing loss.

Mechanistic Evidence

The committee identified 11 publications reporting hearing loss after the administration of vaccines containing measles, mumps, and rubella alone or in combination. Two publications described multiple cases, some did not provide a time frame between vaccination and development of hearing loss while others did not provide evidence beyond temporality, some too long or too short based on the possible mechanisms involved (Asatryan et al., 2008; Jayarajan and Sedler, 1995). Long latencies between vaccine administration and development of symptoms make it impossible to rule out other possible causes. These cases did not contribute to the weight of mechanistic evidence. Four publications did not provide evidence beyond a temporal relationship between administration of either a mumps vaccine or MMR vaccine and development of hearing loss (Garcia Callejo et al., 2005; Healy, 1972; Nabe-Nielsen and Walter, 1988a,b). These publications did not contribute to the weight of mechanistic evidence.

Described below are eight publications reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence. In most of the cases, fever develops between days 5 and 12 after vaccination, a time frame consistent with studies researching fevers after immunization. The committee included some cases in which fever developed outside this time frame when in association with other symptoms suggestive of involvement of the ear, such as tinnitus and gait disturbance.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Angerstein (1995) described a 24-month-old patient presenting with horizontal spontaneous nystagmus to the right, a sudden tendency to fall to the left, and left caloric excitability of the labyrinth 7 days after administration of a measles and mumps vaccine. Four years after vaccination laboratory evaluation detected complete failure of the caloric labyrinth on the left with good excitability on the right.

Asatryan et al. (2008) identified 202 reports, received by VAERS from January 1990 through December 2003, of hearing loss developing after vaccination against measles, mumps, and rubella. Of these 158 met the exclusion criteria or were duplicate submissions. Of the remaining 44 reports the authors summarized the 14 cases providing the most detailed clinical information. The following cases provided clinical evidence in addition to a temporal relationship between vaccination and the development of hearing loss that contributed to the weight of mechanistic evidence. Case 1 (number 6 in the report) describes a 1-year-old girl presenting with a fever within 1 month, and possibly as early as 1 week, after administration of measles, mumps, and rubella and Haemophilus influenzae type B (HiB) vaccines. The patient was diagnosed with bilateral hearing loss 3 years after vaccination. Case 2 (number 7 in the report) describes a 4-year-old boy presenting with fever and decreased hearing 2 weeks after simultaneous administration of measles, mumps, and rubella, diphtheria-tetanus-acellular pertussis (DTaP), HiB, and oral polio vaccines. Case 3 (number 8 in the report) describes a 1.5-year-old girl presenting with fever and exanthem subitum 2 weeks after administration of a measles, mumps, and rubella vaccine. Ataxia and bilateral hearing loss were reported 1 month and 4 months after vaccination, respectively.

Brodsky and Stanievich (1985) describe a 3-year-old presenting with fever, ataxia, irritability, headache, nausea, vomiting, and nystagmus 10 days after administration of a measles, mumps, and rubella vaccine at 15 months of age. Decreased hearing became a concern of the parents soon thereafter. A diagnosis of persistent otitis media led to the insertion of tympanostomy tubes at 2.5 years of age. No change in hearing was noted after the insertion of the tubes, and the patient was subsequently diagnosed as having bilateral hearing loss. The patient’s father had sensorineural hearing loss in the left ear thought to be caused by a mumps infection in childhood.

Hulbert et al. (1991) describe a 27-year-old woman presenting with generalized arthralgia, fever, headache, tinnitus, vomiting, dizziness, and gait disturbance 3 days after receiving a measles and rubella vaccine. The patient experienced progressive hearing loss 22 days after vaccination. Serologic tests were negative for Epstein-Barr virus, St. Louis encephalitis virus, western equine and eastern equine encephalomyelitis viruses, systemic lupus, and syphilis.

Landrigan (1972) responded to a question presented by C. Herbert

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Crane regarding hearing loss after vaccination. The patient presented with a febrile illness lasting 2.5 days 10 days after administration of a measles vaccine at 1 year of age. Hearing loss in the high-frequency range was observed at 30 months.

Watson (1990) described a 14-month-old girl presenting with a generalized pink blotchy rash starting on the neck 12 days after administration of a measles vaccine. The rash became a dull pink the following day and disappeared in 2 days. While afflicted with the rash, the patient repeatedly pulled at both ears. Two weeks later the mother noticed the patient would not respond to commands leading to the realization that the patient was unable to hear. A hearing assessment performed at 11 months of age had been normal.

Two publications provided experimental evidence for an association between the development of hearing loss and vaccination against measles or mumps. Fukuda et al. (2001) examined antimumps IgG and IgM in the sera of 69 cases of idiopathic sudden sensorineural hearing loss diagnosed at the Otolaryngology Department, Hokkaido University Hospital, from February 1992 through December 1999. The etiologies leading to hearing loss were not known. The authors were studying the association of silent mumps infection with idiopathic sudden sensorineural hearing loss. The authors demonstrated antimumps IgM in seven patients. Of these seven patients antimumps IgG were demonstrated in six. Antimumps IgG were demonstrated in an additional 36 patients.

Fukuda et al. (1994) used a hamster model to study acute measles infection of the cochlea. The authors used a hamster-adapted neurotropic strain of measles to inoculate the perilymphatic compartment of the ipsilateral cochlea in Syrian gold hamsters. Four to five days after virus inoculation the temporal bones were removed and subjected to indirect immunofluorescence using antimeasles virus antisera. Positive immunofluorescence was observed in the inflammatory cell infiltrates in the cochlear ducts and the lining of the perilymphatic structure.

Weight of Mechanistic Evidence

Wild-type mumps virus infection has been associated with transient high-frequencyrange deafness in 4.4 percent of mumps cases in the military (Litman and Baum, 2010). Permanent unilateral deafness has been reported to occur in 1 in 20,000 cases of mumps virus infection (Litman and Baum, 2010). Similarly, infection with wild-type measles virus has been associated with bilateral sensorineural hearing loss in 5–10 percent of measles cases (McKenna, 1997). The committee considers the effects of natural infection one type of mechanistic evidence.

In addition, the eight publications described above presented clinical

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

and experimental evidence suggestive but not sufficient for the committee to conclude the vaccine may be a contributing cause of hearing loss after administration of vaccines containing measles, mumps, and rubella alone or in combination. The publications presented a symptomology of fever, rash, and nystagmus consistent with direct infection of the measles or mumps viruses leading to hearing loss. The diagnosis of hearing loss after vaccination ranged from 6 days to 4 years after vaccination. Furthermore, the demonstration of antimumps antibodies in patients with idiopathic sudden sensorineural hearing loss and detection of measles antigen in the cochlear ducts in a hamster model of measles infection suggest the involvement of measles and mumps viruses in the pathogenesis of hearing loss. The animal model suggests the measles virus may replicate in the perilymph. However, the committee recognizes the limitations of this model.

The latency between vaccination and the development of the symptomology described above ranged from hours to 12 days after administration of a vaccine containing measles, mumps, and rubella alone or in combination, suggesting direct viral infection as the mechanism.

The committee assesses the mechanistic evidence regarding an association between measles or mumps vaccine and hearing loss as low-intermediate based on knowledge about the natural infection, experimental evidence, and eight cases.

The committee assesses the mechanistic evidence regarding an association between rubella vaccine and hearing loss as lacking.

Causality Conclusion

Conclusion 4.30: The evidence is inadequate to accept or reject a causal relationship between MMR vaccine and hearing loss.

CONCLUDING SECTION

Table 4-13 provides a summary of the epidemiologic assessments, mechanistic assessments, and causality conclusions for MMR vaccine.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

TABLE 4-13 Summary of Epidemiologic Assessments, Mechanistic Assessments, and Causality Conclusions for Measles, Mumps, and Rubella Vaccine

Vaccine Adverse Event Epidemiologic Assessment Studies Contributing to the Epidemiologic Assessment Mechanistic Assessment Cases Contributing to the Mechanistic Assessment Causality Conclusion
MMR Measles Inclusion Body Encephalitis Insufficient None Strong (measles; in individuals with demonstrated immunodeficiencies)
Lacking (mumps or rubella)
1
None
Convincingly Supportsa (in individuals with demonstrated immunodeficiencies)
MMR Encephalitis Limited 3 Weak 3 Inadequate
MMR Encephalopathy Limited 3 Weak 1 Inadequate
MMR Febrile Seizures High (increase) 7 Intermediate 12 Convincingly Supports
MMR Afebrile Seizures Limited 2 Lacking None Inadequate
MMR Meningitisb Moderate (null) 3 Weak (mumps)
Lacking (measles or rubella)
4
None
Inadequate
MMR Ataxia Insufficient None Weak (measles or mumps)
Lacking (rubella)
1
None
Inadequate
MMR Autism High (null) 4 Lacking None Favors Rejection
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
MMR Acute Disseminated Encephalomyelitis Insufficient None Weak None Inadequate
MMR Transverse Myelitis Insufficient None Weak 3 Inadequate
MMR Optic Neuritisb Limited 1 Weak 2 Inadequate
MMR Neuromyelitis Opticab Insufficient None Weak (rubella) Lacking (measles or mumps) 1
None
Inadequate
MMR Multiple Sclerosis Onset in Adults Limited 2 Lacking None Inadequate
MMR Multiple Sclerosis Onset in Children Limited 1 Lacking None Inadequate
MMR Guillain-Barre Syndrome Insufficient None Weak None Inadequate
MMR Chronic Inflammatory Disseminated Polyneuropathy Insufficient None Lacking None Inadequate
MMR Opsoclonus Myoclonus Syndrome Insufficient None Lacking None Inadequate
MMR Brachial Neuritis Insufficient None Lacking None Inadequate
MMR Anaphylaxis Insufficient None Strong 43c Convincingly Supports
MMR Transient Arthralgia in Women Moderate (increase) (rubella) Insufficient (measles or mumps) 4 None Intermediate (rubella) Lacking (measles or mumps) 13 None Favors Acceptanced
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Vaccine Adverse Event Epidemiologic Assessment Studies Contributing to the Epidemiologic Assessment Mechanistic Assessment Cases Contributing to the Mechanistic Assessment Causality Conclusion
MMR Transient Arthralgia in Children Moderate (increase) 7 Weak (rubella) Lacking (measles or mumps) None None Favors Acceptance
MMR Chronic Arthralgia in Women Limited (rubella) 2 Low-Intermediate (rubella) 4 Inadequate
Insufficient (measles or mumps) None Lacking (measles or mumps) None
MMR Chronic Arthritis in Women Limited (rubella) 2 Low-1 ntermediate (rubella) 5 Inadequate
Insufficient (measles or mumps) None Lacking (measles or mumps) None
MMR Chronic Arthropathy in Children Insufficient None Weak (rubella) Lacking (measles or mumps) 2 None Inadequate
MMR Arthropathy in Men Limited 2 Weak (rubella) Lacking (measles or mumps) None None Inadequate
MMR Type 1 Diabetes High (null) 5 Lacking None Favors Rejection
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
MMR Hepatitis Insufficient None Weak None Inadequate
MMR Chronic Fatigue Syndrome Insufficient None Lacking None Inadequate
MMR Fibromyalgia Insufficient None Lacking None Inadequate
MMR Hearing Loss Insufficient None Low-Intermediate (measles or mumps) Lacking (rubella) 8 None Inadequate

a The committee attributes causation to the measles component of the vaccine.

b Although not originally charged to the committee by the sponsor, the committee considered this adverse event in its review of the literature.

c Some cases were from passive surveillance systems; however, it was not possible to know how many represented unique cases or were reported elsewhere.

d The committee attributes causation to the rubella component of the vaccine.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

REFERENCES

Abe, T., C. Nonaka, M. Hiraiwa, H. Ushijima, and R. Fujii. 1985. Acute and delayed neurologic reaction to inoculation with attenuated live measles virus. Brain and Development 7(4):421-423.

Ahlgren, C., A. Oden, K. Toren, and O. Andersen. 2009a. Multiple sclerosis incidence in the era of measles-mumps-rubella mass vaccinations. Acta Neurologica Scandinavica 119(5):313-320.

Ahlgren, C., K. Toren, A. Oden, and O. Andersen. 2009b. A population-based case-control study on viral infections and vaccinations and subsequent multiple sclerosis risk. European Journal of Epidemiology 24(9):541-552.

Al Awaidy, S., S. Bawikar, K. R. Prakash, B. Al Rawahi, and A. J. Mohammed. 2010. Surveillance of adverse events following immunization: 10 years’ experience in Oman. Eastern Mediterranean Health Journal 16(5):474-480.

Altobelli, E., R. Petrocelli, A. Verrotti, and M. Valenti. 2003. Infections and risk of type I diabetes in childhood: A population-based case-control study. European Journal of Epidemiology 18(5):425-430.

Andelman, S. L., M. B. Andelman, J. Zackler, and A. Schwarz. 1963. Experimental vaccination against measles: Clinical evaluation of a highly attenuated live measles vaccine. Journal of the American Medical Association 184(9):721-723.

Anderson, L. J., and J. F. Seward. 2008. Mumps epidemiology and immunity—the anatomy of a modern epidemic. Pediatric Infectious Disease Journal 27(10):S75-S79.

Andrews, N., J. Stowe, E. Miller, and B. Taylor. 2007. Post-licensure safety of the meningococcal group C conjugate vaccine. Human Vaccines 3(2):59-63.

Angerstein, W. 1995. Evaluation of possible causal connections between isolated vestibulo-cochlear lesions and vaccinations in early childhood [in German]. Oto-Rhino-Laryngo-logia Nova 5(2):67-75.

Asatryan, A., V. Pool, R. T. Chen, K. S. Kohl, R. L. Davis, J. K. Iskander, and V. Team. 2008. Live attenuated measles and mumps viral strain-containing vaccines and hearing loss: Vaccine Adverse Event Reporting System (VAERS), United States, 1990-2003. Vaccine 26(9):1166-1172.

Aukrust, L., T. L. Almeland, D. Refsum, and K. Aas. 1980. Severe hypersensitivity or intolerance reactions to measles vaccine in six children. Clinical and immunological studies. Allergy: European Journal of Allergy and Clinical Immunology 35(7):581-587.

Aydin, K., S. Elmas, and E. A. Guzes. 2006. Reversible posterior leukoencephalopathy and Adie’s pupil after measles vaccination. Journal of Child Neurology 21(6):525-527.

Babbott, F. L., and J. E. Gordon. 1954. Modern measles. American Journal of the Medical Sciences 228(3):334-361.

Bakshi, N., J. Lawson, R. Hanson, C. Ames, and H. V. Vinters. 1996. Fatal mumps meningeoncephalitis in a child with severe combined immunodeficiency after bone marrow transplantation. Journal of Child Neurology 11(2):159-162.

Balfour, H. H., Jr., C. L. Balfour, C. K. Edelman, and P. A. Rierson. 1976. Evaluation of wistar RA27/3 rubella virus vaccine in children. American Journal of Diseases of Children 130(10):1089-1091.

Balfour, H. H., Jr., K. E. Groth, and C. K. Edelman. 1980. RA27/3 rubella vaccine. A four-year follow-up. American Journal of Diseases of Children 134(4):350-353.

Baram, T. Z., I. Gonzalez-Gomez, Z. D. Xie, D. Yao, F. H. Gilles, M. D. Nelson, Jr., H. T. Nguyen, and J. Peters. 1994. Subacute sclerosing panencephalitis in an infant: Diagnostic role of viral genome analysis. Annals of Neurology 36(1):103-108.

Barlow, W. E., R. L. Davis, J. W. Glasser, P. H. Rhodes, R. S. Thompson, J. P. Mullooly, S. B. Black, H. R. Shinefield, J. I. Ward, S. M. Marcy, F. DeStefano, and R. T. Chen. 2001. The risk of seizures after receipt of whole-cell pertussis or measles, mumps, and rubella vaccine. New England Journal of Medicine 345(9):656-661.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Baxter, D. N. 1996. Measles immunization in children with a history of egg allergy. Vaccine 14(2):131-134.

Behan, P. O. 1977. Diffuse myelitis associated with rubella vaccination. British Medical Journal 1(6054):166.

Benjamin, C. M., G. C. Chew, and A. J. Silman. 1992. Joint and limb symptoms in children after immunisation with measles, mumps, and rubella vaccine. British Medical Journal 304(6834):1075-1078.

Best, J. M., J. E. Banatvala, and J. M. Bowen. 1974. New Japanese rubella vaccine: Comparative trials. British Medical Journal 3(5925):221-224.

Bino, S., E. Kakarriqi, M. Xibinaku, N. Ion-Nedelcu, M. Bukli, N. Emiroglu, and A. Uzicanin. 2003. Measles-rubella mass immunization campaign in Albania, November 2000. Journal of Infectious Diseases 187(Suppl. 1):S223-S229.

Bitnun, A., P. Shannon, A. Durward, P. A. Rota, W. J. Bellini, C. Graham, E. Wang, E. L. Ford-Jones, P. Cox, L. Becker, M. Fearon, M. Petric, and R. Tellier. 1999. Measles inclusion-body encephalitis caused by the vaccine strain of measles virus. Clinical Infectious Diseases 29(4):855-861.

Black, F. L., S. H. Lamm, J. E. Emmons, and F. P. Pinheiro. 1976. Reactions to rubella vaccine and persistence of antibody in virgin-soil populations after vaccination and wild-virus-induced immunization. Journal of Infectious Diseases 133(4):393-398.

Black, S., H. Shinefield, P. Ray, E. Lewis, R. Chen, J. Glasser, S. Hadler, J. Hardy, P. Rhodes, E. Swint, R. Davis, R. Thompson, J. Mullooly, M. Marcy, C. Vadheim, J. Ward, S. Rastogi, and R. Wise. 1997. Risk of hospitalization because of aseptic meningitis after measles-mumps-rubella vaccination in one- to two-year-old children: An analysis of the Vaccine Safety Datalink (VSD) project. Pediatric Infectious Disease Journal 16(5):500-503.

Blom, L., L. Nystrom, and G. Dahlquist. 1991. The Swedish childhood diabetes study. Vaccinations and infections as risk determinants for diabetes in childhood. Diabetologia 34(3):176-181.

Bogdanovic, J., N. A. Halsey, R. A. Wood, and R. G. Hamilton. 2009. Bovine and porcine gelatin sensitivity in children sensitized to milk and meat. Journal of Allergy and Clinical Immunology 124(5):1108-1110.

Bohlke, K., R. L. Davis, S. M. Marcy, M. M. Braun, F. DeStefano, S. B. Black, J. P. Mullooly, and R. S. Thompson. 2003. Risk of anaphylaxis after vaccination of children and adolescents. Pediatrics 112(4):815-820.

Boling, H. L. 1980. An adult’s reaction to measles vaccine. American Journal of Nursing 80(8):1442-1443.

Borte, S., U. G. Liebert, M. Borte, and U. Sack. 2009. Efficacy of measles, mumps, and rubella revaccination in children with juvenile idiopathic arthritis treated with methotrexate and etanercept. Rheumatology 48(2):144-148.

Bottiger, M., L. Heller, and S. I. Rollof. 1974. Rubella vaccination of teen-age girls [in Swedish]. Lakartidningen 71(19):1949-1951.

Bray, P. F. 1972. Mumps: A cause of hydrocephalus? Pediatrics 49(3):446-449.

Brodsky, L., and J. Stanievich. 1985. Sensorineural hearing loss following live measles virus vaccination. International Journal of Pediatric Otorhinolaryngology 10(2):159-163.

Cassidy, W. M., G. Jones, K. Williams, A. Deforest, B. Forghani, G. Virella, and C. Venters. 2005. Safety and immunogenicity of concomitant versus nonconcomitant administration of hepatitis B, tetanus-diphtheria, and measles-mumps-rubella vaccines in healthy eleven-to twelve-year-olds. Journal of Adolescent Health 36(3):187-192.

CDC (Centers for Disease Control and Prevention). 1998. Measles, mumps, and rubella— vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: Recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbidity & Mortality Weekly Report 47(RR-8):1-57.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

CDC. 2010. National, state, and local area vaccination coverage among children aged 19-35 months—United States, 2009. Morbidity & Mortality Weekly Report 59(36):1171-1177.

Chaudary, S., and B. E. Jaski. 1989. Fulminant mumps myocarditis. Annals of Internal Medicine 110(7):569-570.

Chen, R. T., J. W. Glasser, P. H. Rhodes, R. L. Davis, W. E. Barlow, R. S. Thompson, J. P. Mullooly, S. B. Black, H. R. Shinefield, C. M. Vadheim, S. Michael Marcy, J. I. Ward, R. P. Wise, S. G. Wassilak, S. C. Hadler, E. Swint, J. R. Hardy, T. Payne, V. Immanuel, P. Benson, J. Draket, L. Drew, B. Mendius, P. Ray, N. Lewis, B. H. Fireman, J. Jing, M. Wulfsohn, M. M. Lugg, P. Osborne, S. Rastogi, P. Patriarca, and V. Caserta. 1997. Vaccine safety datalink project: A new tool for improving vaccine safety monitoring in the United States. Pediatrics 99(6):765-773.

Chen, R. T., J. M. Moses, L. E. Markowitz, and W. A. Orenstein. 1991. Adverse events following measles-mumps-rubella and measles vaccinations in college students. Vaccine 9(5):297-299.

Chen, W., S. Landau, P. Sham, and E. Fombonne. 2004. No evidence for links between autism, MMR and measles virus. Psychological Medicine 34(3):543-553.

Cizman, M., M. Pokorn, and D. Osredkar. 2005. Re: Transverse myelitis after measles and rubella vaccination. Journal of Paediatrics & Child Health 41(8):460.

Cohen, H. A., A. Ashkenazi, M. Nussinovitch, J. Amir, J. Hart, and M. Frydman. 1992. Mumps-associated acute cerebellar-ataxia. American Journal of Diseases of Children 146(8):930-931.

D’Souza, R. M., S. Campbell-Lloyd, D. Isaacs, M. Gold, M. Burgess, F. Turnbull, and E. O’Brien. 2000. Adverse events following immunisation associated with the 1998 Australian measles control campaign. Communicable Diseases Intelligence 24(2):27-33.

Dales, L., S. J. Hammer, and N. J. Smith. 2001. Time trends in autism and in MMR immunization coverage in California. Journal of the American Medical Association 285(9): 1183-1185.

Davis, L. E. 2008. Nervous system complications of systemic viral infections. In Neurology and general medicine, 4th ed., edited by M. J. Aminoff. Philadelphia, PA: Churchill Livingstone Elsevier. Pp. 827-850.

Davis, R. L., E. Marcuse, S. Black, H. Shinefield, B. Givens, J. Schwalbe, P. Ray, R. S. Thompson, R. Chen, J. W. Glasser, P. H. Rhodes, E. Swint, L. A. Jackson, W. E. Barlow, V. H. Immanuel, P. J. Benson, J. P. Mullooly, L. Drew, B. Mendius, N. Lewis, B. H. Fireman, J. I. Ward, C. M. Vadheim, S. M. Marcy, J. Jing, M. Wulfson, M. Lugg, P. Osborne, R. P. Wise, S. Rastogi, P. Patriarca, and V. Caserta. 1997. MMR2 immunization at 4 to 5 years and 10 to 12 years of age: A comparison of adverse clinical events after immunization in the Vaccine Safety Datalink project. Pediatrics 100(5):767-771.

de Jong, J. G. 1965. Survival of measles virus in air in relation to epidemiology of measles. Archiv fur Die Gesamte Virusforschung Archives of Virology 16(1-5):97-102.

DeStefano, F., T. K. Bhasin, W. W. Thompson, M. Yeargin-Allsopp, and C. Boyle. 2004. Age at first measles-mumps-rubella vaccination in children with autism and school-matched control subjects: A population-based study in metropolitan atlanta. Pediatrics 113(2):259-266.

DeStefano, F., J. P. Mullooly, C. A. Okoro, R. T. Chen, S. M. Marcy, J. I. Ward, C. M. Vadheim, S. B. Black, H. R. Shinefield, R. L. Davis, and K. Bohlke. 2001. Childhood vaccinations, vaccination timing, and risk of type 1 diabetes mellitus. Pediatrics 108(6):E112.

DeStefano, F., T. Verstraeten, L. A. Jackson, C. A. Okoro, P. Benson, S. B. Black, H. R. Shinefield, J. P. Mullooly, W. Likosky, and R. T. Chen. 2003. Vaccinations and risk of central nervous system demyelinating diseases in adults. Archives of Neurology 60(4):504-509.

DiMiceli, L., V. Pool, J. M. Kelso, S. V. Shadomy, and J. Iskander. 2006. Vaccination of yeast sensitive individuals: Review of safety data in the US Vaccine Adverse Event Reporting System (VAERS). Vaccine 24(6):703-707.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

dos Santos, B. A., T. S. Ranieri, M. Bercini, M. T. Schermann, S. Famer, R. Mohrdieck, T. Maraskin, and M. B. Wagner. 2002. An evaluation of the adverse reaction potential of three measles-mumps-rubella combination vaccines. Revista Panamericana de Salud Publica/Pan American Journal of Public Health 12(4):240-246.

Dudgeon, J. A., W. C. Marshall, and C. S. Peckham. 1969. Rubella vaccine trials in adults and children. Comparison of three attenuated vaccines. American Journal of Diseases of Children 118(2):237-243.

Ehrengut, W., and K. Zastrow. 1989. Complications after preventive mumps vaccination in West Germany (including multiple preventive vaccinations) [in German]. Monatsschrift Kinderheilkunde Organ der Deutschen Gesellschaft fur Kinderheilkunde 137(7):398-402.

Enders, J. F. 1946. Mumps; techniques of laboratory diagnosis, tests for susceptibility, and experiments on specific prophylaxis. Journal of Pediatrics 29(2):129-142.

Enders, J. F. 1962. Measles virus: Historical review, isolation, and behaviour in various systems. American Journal of Diseases of Children 103(3):282-287.

Enders, J. F., and T. C. Peebles. 1954. Propagation in tissue cultures of cytopathogenic agents from patients with measles. Proceedings of the Society for Experimental Biology and Medicine 86(2):277-286.

Erlewyn-Lajeunesse, M., R. Manek, R. Lingam, A. Finn, and A. Emond. 2008. Anaphylaxis following single component measles and rubella immunisation. Archives of Disease in Childhood 93(11):974-975.

Esteghamati, A., M. M. Gouya, A. A. Keshtkar, and F. Mahoney. 2008. Relationship between occurrence of Guillain-Barré syndrome and mass campaign of measles and rubella immunization in Iranian 5-14 years old children. Vaccine 26(39):5058-5061.

Farrington, C. P., E. Miller, and B. Taylor. 2001. MMR and autism: Further evidence against a causal association. Vaccine 19(27):3632-3635.

Farrington, P., S. Pugh, A. Colville, A. Flower, J. Nash, P. Morgan-Capner, M. Rush, and E. Miller. 1995. A new method for active surveillance of adverse events from diphtheria/ tetanus/pertussis and measles/mumps/rubella vaccines. Lancet 345(8949):567-569.

Fasano, M. B., R. A. Wood, S. K. Cooke, and H. A. Sampson. 1992. Egg hypersensitivity and adverse reactions to measles, mumps, and rubella vaccine. Journal of Pediatrics 120(6):878-881.

Fescharek, R., U. Quast, G. Maass, W. Merkle, and S. Schwarz. 1990. Measles-mumps vaccination in the FRG: An empirical analysis after 14 years of use. II. Tolerability and analysis of spontaneously reported side effects. Vaccine 8(5):446-456.

Fogel, A., C. B. Gerichter, B. Barnea, R. Handsher, and E. Heeger. 1978. Response to experimental challenge in persons immunized with different rubella vaccines. Journal of Pediatrics 92(1):26-29.

Fombonne, E., and S. Chakrabarti. 2001. No evidence for a new variant of measles-mumps-rubella-induced autism. Pediatrics 108(4):E58.

Fombonne, E., R. Zakarian, A. Bennett, L. Y. Meng, and D. McLean-Heywood. 2006. Pervasive developmental disorders in Montreal, Quebec, Canada: Prevalence and links with immunizations. Pediatrics 118(1):E139-E150.

Forster, J., and R. Urbanek. 1982. Encephalitis following measles-mumps vaccination simultaneous to an EBV-infection [in German]. Klinische Padiatrie 194(1):29-30.

Freeman, A. F., D. A. Jacobsohn, S. T. Shulman, W. J. Bellini, P. Jaggi, G. De Leon, G. F. Keating, F. Kim, L. M. Pachman, M. Kletzel, and R. E. Duerst. 2004. A new complication of stem cell transplantation: Measles inclusion body encephalitis. Pediatrics 114(5):e657-e660.

Freestone, D. S., J. Prydie, S. G. Smith, and G. Laurence. 1971. Vaccination of adults with wistar RA 27/3 rubella vaccine. Journal of Hygiene 69(3):471-477.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Frenkel, L. M., K. Nielsen, A. Garakian, R. Jin, J. S. Wolinsky, and J. D. Cherry. 1996. A search for persistent rubella virus infection in persons with chronic symptoms after rubella and rubella immunization and in patients with juvenile rheumatoid arthritis. Clinical Infectious Diseases 22(2):287-294.

Fukuda, S., E. Chida, T. Kuroda, M. Kashiwamura, and Y. Inuyama. 2001. An anti-mumps IgM antibody level in the serum of idiopathic sudden sensorineural hearing loss. Auris, Nasus, Larynx 28:S3-S5.

Fukuda, S., K. Ishikawa, and Y. Inuyama. 1994. Acute measles infection in the hamster cochlea. Acta Oto-Laryngologica 514:111-116.

Garcia Callejo, F. J., I. Costa Alcacer, C. De Paula Vernetta, and J. Marco Algarra. 2005. Sudden bilateral deafness after measles, mumps and rubella vaccination [in Spanish]. Anales de Pediatria 62(5):482-483.

Geier, D. A., and M. R. Geier. 2001. Rubella vaccine and arthritic adverse reactions: An analysis of the vaccine adverse events reporting system (VAERS) database from 1991 through 1998. Clinical and Experimental Rheumatology 19(6):724-726.

Geier, D. A., and M. R. Geier. 2004. A comparative evaluation of the effects of MMR immunization and mercury doses from thimerosal-containing childhood vaccines on the population prevalence of autism. Medical Science Monitor 10(3):PI33-PI39.

Geier, M. R., and D. A. Geier. 2003. Pediatric MMR vaccination safety. International Pediatrics 18(2):203-208.

Geiger, R., F. M. Fink, B. Solder, M. Sailer, and G. Enders. 1995. Persistent rubella infection after erroneous vaccination in an immunocompromised patient with acute lymphoblastic-leukemia in remission. Journal of Medical Virology 47(4):442-444.

Gershon, A. A. 2010a. Measles virus (rubeola). In Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 7th ed. 2 vols. Vol. 2, edited by G. L. Mandell, J. E. Bennett, and R. Dolin. Philadelphia, PA: Churchill Livingstone Elsevier. Pp. 2229-2236.

Gershon, A. A. 2010b. Rubella virus (German measles). In Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 7th ed. 2 vols. Vol. 2, edited by G. L. Mandell, J. E. Bennett, and R. Dolin. Philadelphia, PA: Churchill Livingstone Elsevier. Pp. 2127-2132.

Gershon, A. A., H. M. Frey, W. Borkowsky, and S. Steinberg. 1980. Live attenuated rubella virus vaccine: Comparison of responses to HPV-77-DE5 and RA 27/3 strains. American Journal of the Medical Sciences 279(2):95-97.

Giampietro, P. G., G. Bruno, M. Grandolfo, and L. Businco. 1993. Adverse reaction to measles immunization. European Journal of Pediatrics 152(1):80.

Gomez Sanchez, E., F. Mateos Beato, J. I. Sanchez Diaz, R. Simon De Las Heras, and Y. Ballestero Diaz. 2005. Acute disseminated encephalomyelitis. Experience of a tertiary hospital in Spain [in Spanish]. Anales de Pediatria 63(3):203-211.

Gordon, S. C., and C. B. Lauter. 1984. Mumps arthritis—a review of the literature. Reviews of Infectious Diseases 6(3):338-344.

Gregg, N. M. 1941. Congenital cataract following German measles in the mother. Transactions of the Ophthalmological Society of Australia 3:35-46.

Griffin, M. R., W. A. Ray, E. A. Mortimer, G. M. Fenichel, and W. Schaffner. 1991. Risk of seizures after measles-mumps-rubella immunization. Pediatrics 88(5):881-885.

Grillner, L., C. E. Hedstrom, and H. Bergstrom. 1973. Vaccination against rubella of newly delivered women. Scandinavian Journal of Infectious Diseases 5(4):237-241.

Grose, C., and I. Spigland. 1976. Guillain-Barré syndrome following administration of live measles vaccine. American Journal of Medicine 60(3):441-443.

Habel, K. 1945. Cultivation of mumps virus in the developing chick embryo and its application to studies of immunity to mumps in man. Public Health Reports 60(8):201-212.

Habel, K. 1946. Preparation of mumps vaccines and immunization of monkeys against experimental mumps infection. Public Health Reports 61(46):1655-1664.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Habel, K. 1951. Vaccination of human beings against mumps—vaccine administered at the start of an epidemic. 1. Incidence and severity of mumps in vaccinated and control groups. American Journal of Hygiene 54(3):295-311.

Harcourt, G. C., J. M. Best, J. E. Banatvala, and L. A. Kennedy. 1979. HLA antigens and responses to rubella vaccination. Journal of Hygiene 83(3):405-412.

Harel, L., J. Amir, O. Reish, A. H. Cohen, I. Varsano, and N. Varsano. 1990. Mumps arthritis in children. Pediatric Infectious Disease Journal 9(12):928-929.

Healy, C. E. 1972. Mumps vaccine and nerve deafness. American Journal of Diseases of Children 123(6):612.

Heijstek, M. W., G. C. S. Pileggi, E. Zonneveld-Huijssoon, W. Armbrust, E. Hoppenreijs, C. Uiterwaal, W. Kuis, and N. M. Wulffraat. 2007. Safety of measles, mumps and rubella vaccination in juvenile idiopathic arthritis. Annals of the Rheumatic Diseases 66(10):1384-1387.

Helmke, K., A. Otten, and W. R. Willems. 1986. Islet cell antibodies and the development of diabetes mellitus in relation to mumps infection and mumps vaccination. Diabetologia 29(1):30-33.

Herman, J. J., R. Radin, and R. Schneiderman. 1983. Allergic reactions to measles (rubeola) vaccine in patients hypersensitive to egg protein. Journal of Pediatrics 102(2):196-199.

Hilleman, M. R., E. B. Buynak, R. E. Weibel, J. Stokes, J. E. Whitman, and M. B. Leagus. 1968. Development and evaluation of moraten measles virus vaccine. Journal of the American Medical Association 206(3):587-590.

Hilleman, M. R., E. B. Buynak, J. E. Whitman, R. W. Weibel, and J. Stokes. 1969. Live attenuated rubella virus vaccines—experiences with duck embryo cell preparations. American Journal of Diseases of Children 118(2):166-171.

Holt, S., D. Hudgins, K. R. Krishnan, and E. M. Critchley. 1976. Diffuse myelitis associated with rubella vaccination. British Medical Journal 2(6043):1037-1038.

Honda, H., Y. Shimizu, and M. Rutter. 2005. No effect of MMR withdrawal on the incidence of autism: A total population study. Journal of Child Psychology and Psychiatry and Allied Disciplines 46(6):572-579.

Hori, H., S. Hattori, S. Inouye, A. Kimura, S. Irie, H. Miyazawa, and M. Sakaguchi. 2002. Analysis of the major epitope of the alpha2 chain of bovine type I collagen in children with bovine gelatin allergy. Journal of Allergy and Clinical Immunology 110(4):652-657.

Hornig, M., T. Briese, T. Buie, M. L. Bauman, G. Lauwers, U. Siemetzki, K. Hummel, P. A. Rota, W. J. Bellini, J. J. O’Leary, O. Sheils, E. Alden, L. Pickering, and W. I. Lipkin. 2008. Lack of association between measles virus vaccine and autism with enteropathy: A case-control study. PLoS ONE 3(9)(e3140).

Hulbert, T. V., R. A. Larsen, C. L. Davis, and P. D. Holtom. 1991. Bilateral hearing loss after measles and rubella vaccination in an adult. New England Journal of Medicine 325(2):134.

Hviid, A., M. Stellfeld, J. Wohlfahrt, and M. Melbye. 2004. Childhood vaccination and type 1 diabetes. New England Journal of Medicine 350(14):1398-1404.

Hyoty, H., M. Hiltunen, A. Reunanen, P. Leinikki, T. Vesikari, R. Lounamaa, J. Tuomilehto, H. K. Akerblom, L. Toivanen, E. A. Kaprio, A. Fagerlund, M. Flittner, B. Gustafsson, C. Haggqvist, A. Hakulinen, L. Herva, T. Huhtamaki, N. P. Huttunen, and T. Huupponen. 1993. Decline of mumps antibodies in type 1 (insulin-dependent) diabetic children and a plateau in the rising incidence of type 1 diabetes after introduction of the mumps-measles-rubella vaccine in finland. Diabetologia 36(12):1303-1308.

Ion-Nedelcu, N., D. Craciun, D. Pitigoi, M. Popa, K. Hennessey, C. Roure, R. Aston, G. Zimmermann, M. Pelly, N. Gay, and P. Strebel. 2001. Measles elimination: A mass immunization campaign in Romania. American Journal of Public Health 91(7):1042-1045.

Jagdis, F., C. Langston, and M. Gurwith. 1975. Encephalitis after administration of live measles vaccine. Canadian Medical Association Journal 112(8):972-975.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Jayarajan, V., and P. A. Sedler. 1995. Hearing loss following measles vaccination. Journal of Infection 30(2):184-185.

Jin, L., S. Beard, A. Hale, W. Knowles, and D. W. G. Brown. 2000. The genomic sequence of a contemporary wild-type mumps virus strain. Virus Research 70(1-2):75-83.

Johnson, C. D., and E. W. Goodpasture. 1934. An investigation of the etiology of mumps. Journal of Experimental Medicine 59(1):1-19.

Johnson, R. T., D. E. Griffin, R. L. Hirsch, J. S. Wolinsky, S. Roedenbeck, I. L. Desoriano, and A. Vaisberg. 1984. Measles encephalomyelitis—clinical and immunological studies. New England Journal of Medicine 310(3):137-141.

Jorch, G., M. Kleine, and H. Erwig. 1984. Coincidence of virus encephalitis and measles-mumps vaccination [in German]. Monatsschrift Kinderheilkunde Organ der Deutschen Gesellschaft fur Kinderheilkunde 132(5):299-300.

Joyce, K. A., and J. E. Rees. 1995. Transverse myelitis after measles, mumps, and rubella vaccine. British Medical Journal 311(7002):422.

Karavanaki, K., E. Tsoka, C. Karayianni, V. Petrou, E. Pippidou, M. Brisimitzi, M. Mavrikiou, K. Kakleas, I. Konstantopoulos, M. Manoussakis, and C. Dacou-Voutetakis. 2008. Prevalence of allergic symptoms among children with diabetes mellitus type 1 of different socioeconomic status. Pediatric Diabetes 9(4 Pt 2):407-416.

Katz, S. L. 1969. The effect of live attenuated measles-virus vaccine on the central nervous system. International Archives of Allergy and Applied Immunology 36(Suppl.):125-133.

Kaye, J. A., M. D. Melero-Montes, and H. Jick. 2001. Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: A time trend analysis. British Medical Journal 322(7284):460-463.

Kazarian, E. L., and W. E. Gager. 1978. Optic neuritis complicating measles, mumps, and rubella vaccination. American Journal of Ophthalmology 86(4):544-547.

Kelso, J. M., R. T. Jones, and J. W. Yunginger. 1993. Anaphylaxis to measles, mumps, and rubella vaccine mediated by IgE to gelatin. Journal of Allergy and Clinical Immunology 91(4):867-872.

Kempe, C. H., and V. A. Fulginiti. 1965. Pathogenesis of measles virus infection. Archiv fur Die Gesamte Virusforschung 16(1-5):103-128.

Khetsuriani, N., P. Imnadze, L. Baidoshvili, L. Jabidze, N. Tatishili, G. Kurtsikashvili, T. Lezhava, E. Laurent, and R. Martin. 2010. Impact of unfounded vaccine safety concerns on the nationwide measles-rubella immunization campaign, Georgia, 2008. Vaccine 28(39):6455-6462.

Ki, M., T. Park, S. G. Yi, J. K. Oh, and B. Y. Choi. 2003. Risk analysis of aseptic meningitis after measles-mumps-rubella vaccination in Korean children by using a case-crossover design. American Journal of Epidemiology 157(2):158-165.

Kilham, L., J. Levens, and J. F. Enders. 1949. Nonparalytic poliomyelitis and mumps meningoencephalitis—differential diagnosis. Journal of the American Medical Association 140(11):934-936.

Kim, T. M., H. R. Brown, S. H. Lee, C. V. Powell, P. Bethune, N. L. Goller, H. T. Tran, and J. S. Mackay. 1992. Delayed acute measles inclusion body encephalitis in a 9-year-old girl: Ultrastructural, immunohistochemical, and in situ hybridization studies. Modern Pathology 5(3):348-352.

Kline, L. B., S. L. Margulies, and S. J. Oh. 1982. Optic neuritis and myelitis following rubella vaccination. Archives of Neurology 39(7):443-444.

Klock, L. E., and G. S. Rachelefsky. 1973. Failure of rubella herd immunity during an epidemic. New England Journal of Medicine 288(2):69-72.

Konkel, G., C. Runge, U. Szillat, S. Wiersbitzky, R. Bruns, and U. Schmidt. 1993. Cerebral convulsions: Encephalitis following MMR, OPV, HiB or DPT vaccination? [in German]. Kinderarztliche Praxis 61(6):232-234.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Koturoglu, G., Z. Kurugol, H. Tekgul, T. Ozcan, and C. Dizdarer. 2008. Two cases of Guillain-Barré syndrome during measles elimination campaign in Izmir. Minerva Pediatrica 60(6):1455-1457.

Kumagai, T., T. Yamanaka, Y. Wataya, A. Umetsu, N. Kawamura, K. Ikeda, H. Furukawa, K. Kimura, S. Chiba, S. Saito, N. Sugawara, F. Kurimoto, M. Sakaguchi, and S. Inouye. 1997. Gelatin-specific humoral and cellular immune responses in children with immediate-and nonimmediate-type reactions to live measles, mumps, rubella, and varicella vaccines. Journal of Allergy and Clinical Immunology 100(1):130-134.

Kumar, R., R. Chandra, V. Bhushan, and B. C. Srivastava. 1982. Adverse reaction after measles immunization in a rural population. Indian Pediatrics 19(7):605-610.

Lacroix, C., S. Blanche, E. Dussaix, and M. Tardieu. 1995. Acute necrotizing measles encephalitis in a child with AIDS. Journal of Neurology 242(4):249-251.

Lahat, E., M. Aladjem, J. Schiffer, and R. Starinsky. 1993. Hydrocephalus due to bilateral obstruction of the foramen of monro—a possible late complication of mumps encephalitis. Clinical Neurology and Neurosurgery 95(2):151-154.

Landrigan, P. J. 1972. Can measles vaccine cause hearing-loss. Journal of the American Medical Association 219(1):92.

Landrigan, P. J., and J. J. Witte. 1973. Neurologic disorders following live measles-virus vaccination. Journal of the American Medical Association 223(13):1459-1462.

Lapenna, F., L. Lochi, M. de Mari, G. Iliceto, and P. Lamberti. 2000. Post-vaccinic opsoclonus-myoclonus syndrome: A case report. Parkinsonism & Related Disorders 6(4):241-242.

LeBaron, C. W., D. Bi, B. J. Sullivan, C. Beck, and P. Gargiullo. 2006. Evaluation of potentially common adverse events associated with the first and second doses of measles-mumps-rubella vaccine. Pediatrics 118(4):1422-1430.

Lim, S., S. M. Park, H. S. Choi, D. K. Kim, H. B. Kim, B. G. Yang, and J. K. Lee. 2004. Transverse myelitis after measles and rubella vaccination. Journal of Paediatrics and Child Health 40(9-10):583-584.

Litman, N., and S. G. Baum. 2010. Mumps virus. In Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 7th ed. 2 vols. Vol. 2, edited by G. L. Mandell, J. E. Bennett, and R. Dolin. Philadelphia, PA: Churchill Livingstone Elsevier. Pp. 2201-2206.

Madsen, K. M., A. Hviid, M. Vestergaard, D. Schendel, J. Wohlfahrt, P. Thorsen, J. Olsen, and M. Melbye. 2002. A population-based study of measles, mumps, and rubella vaccination and autism. New England Journal of Medicine 347(19):1477-1482.

Makela, A., J. P. Nuorti, and H. Peltola. 2002. Neurologic disorders after measles-mumps-rubella vaccination. Pediatrics 110(5):957-963.

Martinon-Torres, F. 1999. Self-limited acute encephalopathy related to measles component of viral triple vaccine [in Spanish]. Revista de Neurologia 28(9):881-882.

Maspero, A., B. Sesana, and P. Ferrante. 1984. Adverse reactions to measles vaccine. Bollettino dell Istituto Sieroterapico Milanese 63(2):125-129.

McKenna, M. J. 1997. Measles, mumps, and sensorineural hearing loss. Annals of the New York Academy of Sciences 830:291-298.

Menniti-Ippolito, F., R. Da Cas, M. Bolli, A. Capuano, L. Saglioca, G. Traversa, G. Messi, F. Marchetti, M. Lazzerini, F. Rovere, E. Tripaldi, L. Da Dalt, E. Bressan, A. Capretta, E. Falcon, F. Intini, B. Mongillo, C. Morando, P. Di Pietro, R. Rossi, P. Barbino, C. Bianchi, S. Renna, N. Dorozzi, C. Ceccheti, V. Iori, M. Lauri, U. Rauchi, A. Reale, F. Vetrano, G. Saggiamo, F. M. Giuliano, and V. Tipo. 2007. A multicenter study on drug safety in children [in Italian]. Quaderni ACP 14(3):98-102.

Merck & Co., Inc. 2007. M-M-R II [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Merck & Co., Inc. 2009. ProQuad [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.

Meyer, H. M., P. D. Parkman, T. E. Hobbins, H. E. Larson, W. J. Davis, J. P. Simsaria, and H. E. Hopps. 1969. Attenuated rubella viruses: Laboratory and clinical characteristics. American Journal of Diseases of Children 118(2):155-165.

Miller, C. 1987. Live measles-vaccine—a 21 year follow-up. British Medical Journal 295(6589): 22-24.

Miller, C. L. 1982. Surveillance after measles vaccination in children. Practitioner 226(1365): 535-537.

Miller, E., N. Andrews, J. Stowe, A. Grant, P. Waight, and B. Taylor. 2007. Risks of convulsion and aseptic meningitis following measles-mumps-rubella vaccination in the United Kingdom. American Journal of Epidemiology 165(6):704-709.

Miller, E., M. Goldacre, S. Pugh, A. Colville, P. Farrington, A. Flower, J. Nash, L. Macfarlane, and R. Tettmar. 1993. Risk of aseptic meningitis after measles, mumps, and rubella vaccine in UK children. Lancet 341(8851):979-982.

Mitchell, L. A., A. J. Tingle, M. Grace, P. Middleton, and A. C. Chalmers. 2000. Rubella virus vaccine associated arthropathy in postpartum immunized women: Influence of preimmunization serologic status on development of joint manifestations. Journal of Rheumatology 27(2):418-423.

Mitchell, L. A., A. J. Tingle, L. MacWilliam, C. Home, P. Keown, L. K. Gaur, and G. T. Nepom. 1998. HLA-DR class II associations with rubella vaccine-induced joint manifestations. Journal of Infectious Diseases 177(1):5-12.

Mitchell, L. A., A. J. Tingle, R. Shukin, J. A. Sangeorzan, J. McCune, and D. K. Braun. 1993. Chronic rubella vaccine-associated arthropathy. Archives of Internal Medicine 153(19):2268-2274.

Miyake, S., M. Fujita, C. Endo, N. Taoka, and M. Kuzuhara. 2001. Recurrence of febrile convulsions after the first diphtheria-pertussis-tetanus vaccination and measles vaccination in children with febrile convulsions: A questionnaire survey in Takamatsu City [in Japanese]. No to Hattatsu 33(4):336-341.

Morley, D. C., M. Woodland, S. Krugman, H. Friedman, and B. Grab. 1964. Measles and measles vaccination in an African village. Bulletin of the World Health Organization 30:733-739.

Mrozek-Budzyn, D., and A. Kieltyka. 2008. The relationship between MMR vaccination level and the number of new cases of autism in children [in Polish]. Przeglad Epidemiologiczny 62(3):597-604.

Mrozek-Budzyn, D., A. Kieltyka, and R. Majewska. 2010. Lack of association between measles-mumps-rubella vaccination and autism in children: A case-control study. Pediatric Infectious Disease Journal 29(5):397-400.

Murphy, F. A., P. E. Halonen, and A. K. Harrison. 1968. Electron microscopy of development of rubella virus in BHK-21 cells. Journal of Virology 2(10):1223-1227.

Mustafa, M. M., S. D. Weitman, N. J. Winick, W. J. Bellini, C. F. Timmons, and J. D. Siegel. 1993. Subacute measles encephalitis in the young immunocompromised host: Report of two cases diagnosed by polymerase chain reaction and treated with ribavirin and review of the literature. Clinical Infectious Diseases 16(5):654-660.

Nabe-Nielsen, J., and B. Walter. 1988a. Unilateral deafness as a complication of the mumps, measles, and rubella vaccination. British Medical Journal 297(6646):489.

Nabe-Nielsen, J., and B. Walter. 1988b. Unilateral total deafness as a complication of the measles-mumps-rubella vaccination. Scandinavian Audiology Supplementum 30:69-70.

Nader, P. R., and R. J. Warren. 1968. Reported neurologic disorders following live measles vaccine. Pediatrics 41(5):997-1001.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Nakayama, T., C. Aizawa, and H. Kuno-Sakai. 1999. A clinical analysis of gelatin allergy and determination of its causal relationship to the previous administration of gelatin-containing acellular pertussis vaccine combined with diphtheria and tetanus toxoids. Journal of Allergy and Clinical Immunology 103(2):321-325.

Oldfelt, V. 1949. Sequelae of mumps-meningoencephalitis. Acta Medica Scandinavica 134(6): 405-414.

Oran, B., A. Ceri, H. Yilmaz, N. Kabakus, A. Aycicek, and I. Erkul. 1995. Hydrocephalus in mumps meningoencephalitis—case-report. Pediatric Infectious Disease Journal 14(8):724-725.

Otten, A., K. Helmke, T. Stief, G. Mueller-Eckhard, W. R. Willems, and K. Federlin. 1984. Mumps, mumps vaccination, islet cell antibodies and the first manifestation of diabetes mellitus type I. Behring Institute Mitteilungen (75):83-88.

Parisi, G., A. Chiarelli, M. Brandani, and A. D’Onofrio. 1991. Transient alkaline hyperphosphatasemia in childhood. A report of 4 clinical cases and etiopathogenetic hypotheses [in Italian]. Minerva Pediatrica 43(4):337-341.

Parkman, P. D., M. S. Artenstein, and E. L. Buescher. 1962. Recovery of rubella virus from army recruits. Proceedings of the Society for Experimental Biology and Medicine 111(1):225-230.

Patja, A., I. Davidkin, T. Kurki, M. J. T. Kallio, M. Valle, and H. Peltola. 2000. Serious adverse events after measles-mumps-rubella vaccination during a fourteen-year prospective follow-up. Pediatric Infectious Disease Journal 19(12):1127-1134.

Patja, A., S. Makinen-Kiljunen, I. Davidkin, M. Paunio, and H. Peltola. 2001a. Allergic reactions to measles-mumps-rubella vaccination. Pediatrics 107(2):E27.

Patja, A., M. Paunio, E. Kinnunen, O. Junttila, T. Hovi, and H. Peltola. 2001b. Risk of Guillain-Barré syndrome after measles-mumps-rubella vaccination. Journal of Pediatrics 138(2):250-254.

Patterson, C. C. 2000. Infections and vaccinations as risk factors for childhood type I (insulin-dependent) diabetes mellitus: A multicentre case-control investigation. Diabetologia 43(1):47-53.

Pattison, E., B. J. Harrison, C. E. M. Griffiths, A. J. Silman, and I. N. Bruce. 2008. Environmental risk factors for the development of psoriatic arthritis: Results from a case-control study. Annals of the Rheumatic Diseases 67(5):672-676.

Pekmezovic, T., M. Jarebinski, and J. Drulovic. 2004. Childhood infections as risk factors for multiple sclerosis: Belgrade case-control study. Neuroepidemiology 23(6):285-288.

Peltola, H., and O. P. Heinonen. 1986. Frequency of true adverse reactions to measles-mumps-rubella vaccine. Lancet 327(8487):939-942.

Peltola, H., A. Patja, P. Leinikki, M. Valle, I. Davidkin, and M. Paunio. 1998. No evidence for measles, mumps, and rubella vaccine-associated inflammatory bowel disease or autism in a 14-year prospective study. Lancet 351(9112):1327-1328.

Peng, M. M., and H. Jick. 2004. A population-based study of the incidence, cause, and severity of anaphylaxis in the United Kingdom. Archives of Internal Medicine 164(3):317-319.

Peters, M. E., and S. Horowitz. 1984. Bone changes after rubella vaccination. American Journal of Roentgenology 143(1):27-28.

Philip, R. N., K. R. Reinhard, and D. B. Lackman. 1959. Observations on a mumps epidemic in a virgin population. American Journal of Hygiene 69(2):91-111.

Planchamp, F., K. A. Nguyen, T. Vial, S. Nasri, E. Javouhey, Y. Gillet, B. Ranchin, F. Villard, D. Floret, P. Cochat, F. Gueyffier, and B. Kassai. 2009. Active drug monitoring of adverse drug reactions in pediatric emergency department [in French]. Archives de Pediatrie 16(2):106-111.

Plesner, A. M., F. Juul Hansen, K. Taudorf, L. Holme Nielsen, C. Brenner Larsen, and E. Pedersen. 2000. Gait disturbance interpreted as cerebellar ataxia after MMR vaccination at 15 months of age: A follow-up study. Acta Paediatrica, International Journal of Paediatrics 89(1):58-63.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Plotkin, S., and S. E. Reef. 2008. Chapter 29. Rubella vaccines. In Vaccines, edited by S. A. Plotkin, W. A. Orenstein, and P. A. Offit. Philadelphia, PA: Saunders/Elsevier. Pp. 735-771.

Plotkin, S., and S. Rubin. 2008. Chapter 20. Mumps vaccines. In Vaccines, edited by S. A. Plotkin, W. A. Orenstein, and P. A. Offit. Philadelphia, PA: Saunders/Elsevier. Pp. 435-465.

Poling, J. S., R. E. Frye, J. Shoffner, and A. W. Zimmerman. 2006. Developmental regression and mitochondrial dysfunction in a child with autism. Journal of Child Neurology 21(2):170-172.

Polk, B. F., J. F. Modlin, J. A. White, and P. C. DeGirolami. 1982. A controlled comparison of joint reactions among women receiving one or two rubella vaccines. American Journal of Epidemiology 115(1):19-25.

Pollock, T. M., and J. Morris. 1983. A 7-year survey of disorders attributed to vaccination in North West Thames region. Lancet 321(8327):753-757.

Pool, V., M. M. Braun, J. M. Kelso, G. Mootrey, R. T. Chen, J. W. Yunginger, R. M. Jacobson, P. M. Gargiullo, and V. Team. 2002. Prevalence of anti-gelatin IgE antibodies in people with anaphylaxis after measles-mumps-rubella vaccine in the United States. Pediatrics 110(6):e71.

Poon, T. P., V. Tchertkoff, and H. Win. 1998. Subacute measles encephalitis with AIDS diagnosed by fine needle aspiration biopsy—a case report. Acta Cytologica 42(3):729-733.

Popovic-Miocinovic, L., S. Smerdel, Z. Grubesic, and A. Miklousic. 1994. The postvaccinal immunity for measles in children on the long-term anticonvulsant therapy [in Serbian]. Lijecnicki Vjesnik 116(3-4):74-78.

Poyner, M., R. Beaver, P. Elton, and K. Bryett. 1986. The reactogenicity of rubella vaccine in a population of United Kingdom schoolgirls. British Journal of Clinical Practice 40(11):468-471.

Prinzie, A., C. Huygelen, J. Gold, J. Farquhar, and J. McKee. 1969. Experimental live attenuated rubella virus vaccine: Clinical evaluation of Cendehill strain. American Journal of Diseases of Children 118(2):172-177.

Pritchard, J., R. Mukherjee, and R. A. C. Hughes. 2002. Risk of relapse of Guillain-Barré syndrome or chronic inflammatory demyelinating polyradiculoneuropathy following immunisation. Journal of Neurology, Neurosurgery, and Psychiatry 73(3):348-349.

Puvvada, L., B. Silverman, C. Bassett, and L. T. Chiaramonte. 1993. Systemic reactions to measles-mumps-rubella vaccine skin testing. Pediatrics 91(4):835-836.

Ramagopalan, S. V., W. Valdar, D. A. Dyment, G. C. Deluca, I. M. Yee, G. Giovannoni, G. C. Ebers, and A. D. Sadovnick. 2009. Association of infectious mononucleosis with multiple sclerosis. Neuroepidemiology 32(4):257-262.

Ray, P., S. Black, H. Shinefield, A. Dillon, J. Schwalbe, S. Holmes, S. Hadler, R. Chen, S. Cochi, and S. Wassilak. 1997. Risk of chronic arthropathy among women after rubella vaccination. Journal of the American Medical Association 278(7):551-556.

Ray, P., J. Hayward, D. Michelson, E. Lewis, J. Schwalbe, S. Black, H. Shinefield, M. Marcy, K. Huff, J. Ward, J. Mullooly, R. Chen, and R. Davis. 2006. Encephalopathy after whole-cell pertussis or measles vaccination: Lack of evidence for a causal association in a retrospective case-control study. Pediatric Infectious Disease Journal 25(9):768-773.

Reuter, D., and J. Schneider-Schaulies. 2010. Measles virus infection of the CNS: Human disease, animal models, and approaches to therapy. Medical Microbiology and Immunology 199(3):261-271.

Richler, J., R. Luyster, S. Risi, W. L. Hsu, G. Dawson, R. Bernier, M. Dunn, S. Hepburn, S. L. Hyman, W. M. McMahon, J. Goudie-Nice, N. Minshew, S. Rogers, M. Sigman, M. A. Spence, W. A. Goldberg, H. Tager-Flusberg, F. R. Volkmar, and C. Lord. 2006. Is there a “regressive phenotype” of autism spectrum disorder associated with the measles-mumps-rubella vaccine? A CPEA study. Journal of Autism and Developmental Disorders 36(3):299-316.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Riikonen, R. S. 1995. Retinal vasculitis caused by rubella. Neuropediatrics 26(3):174-176.

Riordan, F. A., J. A. Sills, A. P. Thomson, and C. A. Hart. 1995. Bacterial meningitis after MMR immunisation. Postgraduate Medical Journal 71(842):745-746.

Roberts, W. C., and S. M. Fox. 1965. Mumps of heart clinical and pathologic features. Circulation 32(3):342-345.

Ross, L. A. R., and A. S. Yeager. 1977. Measles encephalitis in an immunized child. Journal of Pediatrics 90(1):156-157.

Sakaguchi, M., H. Hori, T. Ebihara, S. Irie, M. Yanagida, and S. Inouye. 1999a. Reactivity of the immunoglobulin E in bovine gelatin-sensitive children to gelatins from various animals. Immunology 96(2):286-290.

Sakaguchi, M., H. Hori, S. Hattori, S. Irie, A. Imai, M. Yanagida, H. Miyazawa, M. Toda, and S. Inouye. 1999b. IgE reactivity to alpha1 and alpha2 chains of bovine type I collagen in children with bovine gelatin allergy. Journal of Allergy and Clinical Immunology 104(3 I):695-699.

Sakaguchi, M., T. Yoshida, T. Asahi, T. Aoki, Y. Miyatani, and S. Inouye. 1997. Development of IgE antibody to gelatin in children with systemic immediate-type reactions to vaccines. Journal of Allergy and Clinical Immunology 99(5):720-721.

Saliba, W. R., and M. Elias. 2005. Acute hepatitis following MMR vaccination. European Journal of Internal Medicine 16(5):379.

Schessl, J., B. Luther, J. Kirschner, G. Mauff, and R. Korinthenberg. 2006. Infections and vaccinations preceding childhood Guillain-Barré syndrome: A prospective study. European Journal of Pediatrics 165(9):605-612.

Schlipköter, U., N. Mühlberger, R. von Kries, and J. Weil. 2002. Surveillance of measles-mumps-rubella vaccine-associated aseptic meningitis in Germany. Infection 30(6):351-355.

Schneck, S. A. 1968. Vaccination with measles and central nervous system disease. Neurology 18(1 Pt 2):78-82.

Scholtes, F. B. J., W. O. Renier, and H. Meinardi. 1996. Status epilepticus in children. Seizure 5(3):177-184.

Schuil, J., E. M. van de Putte, C. M. Zwaan, F. D. Koole, and F. M. Meire. 1998. Retinopathy following measles, mumps, and rubella vaccination in an immuno-incompetent girl. International Ophthalmology 22(6):345-347.

Schultz, S. T., H. S. Klonoff-Cohen, D. L. Wingard, N. A. Akshoomoff, C. A. Macera, and M. Ji. 2008. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder—the results of a parent survey. Autism 12(3):293-307.

Schwarz, A. J. F. 1964. Immunization against measles: Development and evaluation of highly attenuated live measles vaccine. Annales Paediatrici 202(4):241-252.

Schwarz, A. J. F., and J. T. Anderson. 1965. Immunization of children with a further attenuated live measles vaccine. Archiv fur Die Gesamte Virusforschung 16(1/5):273-278.

Schwarz, A. J. F., J. T. Anderson, M. Romas-Alvarez, M. B. Andelman, J. F. Crosby, J. A. MacKay, and M. Medalie. 1967. Extensive clinical evaluations of a highly attenuated live measles vaccine. Journal of the American Medical Association 199(1):26-30.

Seager, C., J. Moriarity, A. Ngai, B. O. Staehle, and D. R. Nalin. 1994. Low incidence of adverse experiences after measles or measles-rubella mass revaccination at a college campus. Vaccine 12(11):1018-1020.

Sharrard, M. 2010. Clinical presentation of mitochondrial diseases in children with progressive intellectual and neurological deterioration. Developmental Medicine and Child Neurology 52(5):407-408.

Shuper, A. 2011. Suspected measles-mumps-rubella vaccine-related encephalitis: Two cases. Scandinavian Journal of Infectious Diseases 43(1):75-78.

Simon, J. K., M. F. Pasetti, J. F. Viret, R. Mischler, A. Munoz, R. Lagos, M. M. Levine, and J. D. Campbell. 2007. A clinical study to assess the safety and immunogenicity of attenuated measles vaccine administered intranasally to healthy adults. Human Vaccines 3(2):54-58.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Sinaniotis, C. A., E. Daskalopoulou, P. Lapatsanis, and S. Doxiadis. 1975. Letter: Diabetes mellitus after mumps vaccination. Archives of Disease in Childhood 50(9):749-750.

Slater, P. E., T. Ben-Zvi, A. Fogel, M. Ehrenfeld, and S. Ever-Hadani. 1995. Absence of an association between rubella vaccination and arthritis in underimmune postpartum women. Vaccine 13(16):1529-1532.

Smeeth, L., C. Cook, P. E. Fombonne, L. Heavey, P. L. C. Rodrigues, P. P. G. Smith, and P. A. J. Hall. 2004. MMR vaccination and pervasive developmental disorders: A case-control study. Lancet 364(9438):963-969.

Souayah, N., A. Nasar, M. F. K. Suri, and A. I. Qureshi. 2009. Guillain-Barré syndrome after vaccination in United States: Data from the Centers for Disease Control and Prevention/ Food and Drug Administration Vaccine Adverse Event Reporting System (1990-2005). Journal of Clinical Neuromuscular Disease 11(1):1-6.

Spitzer, W. O., K. J. Aitken, S. Dell’Aniello, and M. W. L. Davis. 2001. The natural history of autistic syndrome in British children exposed to MMR. Adverse Drug Reactions and Toxicological Reviews 20(3):160-163.

Steffenburg, S., U. Steffenburg, and C. Gillberg. 2003. Autism spectrum disorders in children with active epilepsy and learning disability: Comorbidity, pre- and perinatal background, and seizure characteristics. Developmental Medicine and Child Neurology 45(11): 724-730.

Stetler, H. C., J. R. Mullen, and J. P. Brennan. 1985. Adverse events following immunization with DTP vaccine. Developments in Biological Standardization 61:411-421.

Stevenson, V. L., J. F. Acheson, J. Ball, and G. T. Plant. 1996. Optic neuritis following measles/rubella vaccination in two 13-year-old children. British Journal of Ophthalmology 80(12):1110-1111.

Strebel, P. M., M. J. Papania, G. H. Dayan, and N. Halsey. 2008. Chapter 18. Measles vaccines. In Vaccines, edited by S. A. Plotkin, W. A. Orenstein, and P. A. Offit. Philadelphia, PA: Saunders/Elsevier. Pp. 353-398.

Sultz, H. A., B. A. Hart, M. Zielezny, and E. R. Schlesinger. 1975. Is mumps virus an etiologic factor in juvenile diabetes-mellitus? Journal of Pediatrics 86(4):654-656.

Takahashi, H., S. Arai, K. Tanaka-Taya, and N. Okabe. 2001. Autism and infection/immunization episodes in Japan. Japanese Journal of Infectious Diseases 54(2):78-79.

Takahashi, H., S. Suzumura, F. Shirakizawa, N. Wada, K. Tanaka-Taya, S. Arai, N. Okabe, H. Ichikawa, and T. Sato. 2003. An epidemiological study on Japanese autism concerning routine childhood immunization history. Japanese Journal of Infectious Diseases 56(3):114-117.

Tanaka, K., S. Fukuda, Y. Terayama, M. Toriyama, J. Ishidoya, Y. Ito, and A. Sugiura. 1988. Experimental mumps labyrinthitis in monkeys (Macaca irus)—immunohistochemical and ultrastructural studies. Auris, Nasus, Larynx 15(2):89-96.

Taylor, B., E. Miller, C. P. Farrington, M. C. Petropoulos, I. Favot-Mayaud, J. Li, and P. A. Waight. 1999. Autism and measles, mumps, and rubella vaccine: No epidemiological evidence for a causal association. Lancet 353(9169):2026-2029.

Taylor, B., E. Miller, R. Lingam, N. Andrews, A. Simmons, and J. Stowe. 2002. Measles, mumps, and rubella vaccination and bowel problems or developmental regression in children with autism: Population study. British Medical Journal 324(7334):393-396.

Telahun, M., J. Abdulkadir, and E. Kebede. 1994. The relation of early nutrition, infections and socio-economic factors to the development of childhood diabetes. Ethiopian Medical Journal 32(4):239-244.

Tenembaum, S., N. Chamoles, and N. Fejerman. 2002. Acute disseminated encephalomyelitis: A long-term follow-up study of 84 pediatric patients. Neurology 59(8):1224-1231.

Timmons, G. D., and K. P. Johnson. 1970. Aqueductal stenosis and hydrocephalus after mumps encephalitis. New England Journal of Medicine 283(27):1505-1507.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Tingle, A. J., M. Allen, R. E. Petty, G. D. Kettyls, and J. K. Chantler. 1986. Rubella-associated arthritis. I. Comparative study of joint manifestations associated with natural rubella infection and RA 27/3 rubella immunisation. Annals of the Rheumatic Diseases 45(2): 110-114.

Tingle, A. J., J. K. Chantler, K. H. Pot, D. W. Paty, and D. K. Ford. 1985. Postpartum rubella immunization: Association with development of prolonged arthritis, neurological sequelae, and chronic rubella viremia. Journal of Infectious Diseases 152(3):606-612.

Tingle, A. J., L. A. Mitchell, M. Grace, P. Middleton, R. Mathias, L. MacWilliam, and A. Chalmers. 1997. Randomised double-blind placebo-controlled study on adverse effects of rubella immunisation in seronegative women. Lancet 349(9061):1277-1281.

Tingle, A. J., K. H. Pot, F. P. Yong, M. L. Puterman, and E. J. Hancock. 1989. Kinetics of isotype-specific humoral immunity in rubella vaccine-associated arthropathy. Clinical Immunology and Immunopathology 53(2 Pt 2):S99-S106.

Tingle, A. J., T. Yang, and M. Allen. 1983. Prospective immunological assessment of arthritis induced by rubella vaccine. Infection and Immunity 40(1):22-28.

Tonelli, D., P. D. C. Neves Sacco, D. Calegari, G. Cimerman, C. M. Dos Santos, and R. G. Farath. 2005. Anesthesia in Guillain-Barré pediatric patient after measles vaccination. Case report [in Portuguese]. Revista Brasileira de Anestesiologia 55(6):665-668.

Trump, R. C., and T. R. White. 1967. Cerebellar ataxia presumed due to live, attenuated measles virus vaccine. Journal of the American Medical Association 199(2):129-130.

Uchiyama, T., M. Kurosawa, and Y. Inaba. 2007. MMR-vaccine and regression in autism spectrum disorders: Negative results presented from Japan. Journal of Autism and Developmental Disorders 37(2):210-217.

Usonis, V., V. Bakasenas, A. Kaufhold, K. Chitour, and R. Clemens. 1999. Reactogenicity and immunogenicity of a new live attenuated combined measles, mumps and rubella vaccine in healthy children. Pediatric Infectious Disease Journal 18(1):42-48.

Vaandrager, G. J., J. L. Molenaar, G. J. Bruining, A. D. Plantinga, and E. J. Ruitenberg. 1986. Islet cell antibodies, mumps infection and mumps vaccination. Diabetologia 29(6): 406-407.

Vahdani, P., Z. Aminzadeh, M. Alimardani, and A. Sharafi. 2005. Measles and rubella vaccination of two million Iranians: Complications in vaccinees aged 5-25 years. Scandinavian Journal of Infectious Diseases 37(11-12):913-915.

Valensin, P. E., G. M. Rossolini, M. G. Cusi, A. Zanchi, C. Cellesi, and A. Rossolini. 1987. Specific antibody patterns over a two-year period after rubella immunization with RA 27/3 live attenuated vaccine. Vaccine 5(4):289-294.

Valmari, P., M. Lanning, H. Tuokko, and K. Kouvalainen. 1987. Measles virus in the cerebro-spinal fluid in postvaccination immunosuppressive measles encephalopathy. Pediatric Infectious Disease Journal 6(1):59-63.

Verity, C. M., L. S. Stellitano, and A. M. Winstone. 2011. The PIND study found no association between vaccination and autism in mitochondrial disease—correction. Developmental Medicine and Child Neurology 53(5):477.

Verity, C. M., A. M. Winstone, L. Stellitano, D. Krishnakumar, R. Will, and R. McFarland. 2010. The clinical presentation of mitochondrial diseases in children with progressive intellectual and neurological deterioration: A national, prospective, population-based study. Developmental Medicine and Child Neurology 52(5):434-440.

Vestergaard, M., A. Hviid, K. M. Madsen, J. Wohlfahrt, P. Thorsen, D. Schendel, M. Melbye, and J. Olsen. 2004. MMR vaccination and febrile seizures: Evaluation of susceptible subgroups and long-term prognosis. Journal of the American Medical Association 292(3):351-357.

Virtanen, M., H. Peltola, M. Paunio, and O. P. Heinonen. 2000. Day-to-day reactogenicity and the healthy vaccinee effect of measles-mumps-rubella vaccination. Pediatrics 106(5):E62.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

von Wehren, U., and D. von Torklus. 1983. Arthritis following rubella immunization [in German]. Zeitschrift fur Orthopadie und Ihre Grenzgebiete 121(6):749-750.

Wakefield, A. J., S. H. Murch, A. Anthony, J. Linnell, D. M. Casson, M. Malik, M. Berelowitz, A. P. Dhillon, M. A. Thomson, P. Harvey, A. Valentine, S. E. Davies, and J. A. Walker-Smith. 1998. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 351(9103):637-641.

Ward, K. N., N. J. Bryant, N. J. Andrews, J. S. Bowley, A. Ohrling, C. M. Verity, E. M. Ross, and E. Miller. 2007. Risk of serious neurologic disease after immunization of young children in Britain and Ireland. Pediatrics 120(2):314-321.

Watson, J. G. 1990. Letter to the editor. International Journal of Pediatric Otorhinolaryngology 19(2):189-190.

Weibel, R. E., and D. E. Benor. 1996. Chronic arthropathy and musculoskeletal symptoms associated with rubella vaccines: A review of 124 claims submitted to the national vaccine injury compensation program. Arthritis and Rheumatism 39(9):1529-1534.

Weibel, R. E., A. J. Carlson, Jr., and V. M. Villarejos. 1980a. Clinical and laboratory studies of combined live measles, mumps, and rubella vaccines using the RA 27/3 rubella virus. Proceedings of the Society for Experimental Biology and Medicine 165(2):323-326.

Weibel, R. E., V. Caserta, D. E. Benor, and G. Evans. 1998. Acute encephalopathy followed by permanent brain injury or death associated with further attenuated measles vaccines: A review of claims submitted to the national vaccine injury compensation program. Pediatrics 101(3 Pt 1):383-387.

Weibel, R. E., J. Stokes, E. B. Buynak, J. E. Whitman, and M. R. Hilleman. 1967. Live attenuated mumps-virus vaccine: Clinical and serologic aspects in a field evaluation. New England Journal of Medicine 276(5):245-251.

Weibel, R. E., V. M. Villarejos, and E. B. Klein. 1980b. Clinical and laboratory studies of live attenuated RA 27/3 and HPV 77-DE rubella virus vaccines. Proceedings of the Society for Experimental Biology and Medicine 165(1):44-49.

Weller, T. H., and F. A. Neva. 1962. Propagation in tissue culture of cytopathic agents from patients with rubella-like illness. Proceedings of the Society for Experimental Biology and Medicine 111(1):215-225.

Wiersbitzky, S., R. Bruns, and B. Beyer. 1992a. Incubation vaccination (“post-exposure vaccination”) with MMR vaccine during a mumps epidemic? The pediatric vaccine counseling unit [in German]. Kinderarztliche Praxis 60(7):207-208.

Wiersbitzky, S., R. Bruns, and R. Mentel. 1993a. Exanthema with high fever and cerebral seizure susceptibility after mumps-measles-rubella (MMR) preventive vaccination? [in German]. Kinderarztliche Praxis 61(6):227-228.

Wiersbitzky, S., R. Bruns, A. Peters, and R. Mentel. 1992b. Encephalitis, meningitis serosa and parotitis after MMR preventive vaccination? The pediatric vaccination counseling unit [in German]. Kinderarztliche Praxis 60(7):203-205.

Wiersbitzky, S., R. Bruns, and U. Schmidt. 1993b. Cerebral seizures and/or encephalitis after MMR, oral polio, HiB or DPT vaccination? [in German]. Kinderarztliche Praxis 61(6):232-234.

Wiersbitzky, S., C. Burtzlaff, H. Wiersbitzky, and R. Bruns. 1995. Postvaccinal convulsions and epilepsy [in German]. Sozialpadiatrie und Kinderarztliche Praxis 17(9):517-519.

Wiersbitzky, S., C. Schroder, and C. Burtzlaff. 1991. Vaccination encephalopathy after measles vaccination simulating recurrent cardiovascular dysregulation? The pediatric vaccination counseling unit [in German]. Kinderarztliche Praxis 59(6):187-188.

Zheng, D. P., T. K. Frey, J. Icenogle, S. Katow, E. S. Abernathy, K. J. Song, W. B. Xu, V. Yarulin, R. G. Desjatskova, Y. Aboudy, G. Enders, and M. Croxson. 2003. Global distribution of rubella virus genotypes. Emerging Infectious Diseases 9(12):1523-1530.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Zimmerman, R. K., and T. R. Pellitieri. 1994. Inadvertent administration of DTP and DT after age six as recorded in the Vaccine Adverse Event Reporting System. Family Practice Research Journal 14(4):353-358.

Zorzon, M., R. Zivadinov, D. Nasuelli, P. Dolfini, A. Bosco, A. Bratina, M. A. Tommasi, L. Locatelli, and G. Cazzato. 2003. Risk factors of multiple sclerosis: A case-control study. Neurological Sciences 24(4):242-247.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

This page intentionally left blank.

Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 103
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 104
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 105
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 106
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 107
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 108
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 109
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 110
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 111
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 112
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 113
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 114
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 115
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 116
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 117
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 118
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 119
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 120
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 121
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 122
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 123
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 124
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 125
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 126
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 127
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 128
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 129
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 130
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 131
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 132
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 133
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 134
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 135
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 136
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 137
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 138
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 139
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 140
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 141
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 142
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 143
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 144
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 145
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 146
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 147
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 148
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 149
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 150
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 151
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 152
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 153
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 154
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 155
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 156
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 157
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 158
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 159
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 160
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 161
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 162
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 163
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 164
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 165
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 166
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 167
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 168
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 169
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 170
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 171
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 172
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 173
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 174
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 175
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 176
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 177
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 178
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 179
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 180
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 181
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 182
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 183
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 184
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 185
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 186
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 187
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 188
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 189
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 190
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 191
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 192
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 193
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 194
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 195
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 196
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 197
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 198
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 199
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 200
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 201
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 202
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 203
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 204
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 205
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 206
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 207
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 208
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 209
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 210
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 211
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 212
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 213
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 214
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 215
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 216
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 217
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 218
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 219
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 220
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 221
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 222
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 223
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 224
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 225
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 226
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 227
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 228
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 229
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 230
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 231
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 232
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 233
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 234
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 235
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 236
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 237
Suggested Citation:"4 Measles, Mumps, and Rubella Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×
Page 238
Next: 5 Varicella Virus Vaccine »
Adverse Effects of Vaccines: Evidence and Causality Get This Book
×
Buy Hardback | $90.00 Buy Ebook | $69.99
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

In 1900, for every 1,000 babies born in the United States, 100 would die before their first birthday, often due to infectious diseases. Today, vaccines exist for many viral and bacterial diseases. The National Childhood Vaccine Injury Act, passed in 1986, was intended to bolster vaccine research and development through the federal coordination of vaccine initiatives and to provide relief to vaccine manufacturers facing financial burdens. The legislation also intended to address concerns about the safety of vaccines by instituting a compensation program, setting up a passive surveillance system for vaccine adverse events, and by providing information to consumers. A key component of the legislation required the U.S. Department of Health and Human Services to collaborate with the Institute of Medicine to assess concerns about the safety of vaccines and potential adverse events, especially in children.

Adverse Effects of Vaccines reviews the epidemiological, clinical, and biological evidence regarding adverse health events associated with specific vaccines covered by the National Vaccine Injury Compensation Program (VICP), including the varicella zoster vaccine, influenza vaccines, the hepatitis B vaccine, and the human papillomavirus vaccine, among others. For each possible adverse event, the report reviews peer-reviewed primary studies, summarizes their findings, and evaluates the epidemiological, clinical, and biological evidence. It finds that while no vaccine is 100 percent safe, very few adverse events are shown to be caused by vaccines. In addition, the evidence shows that vaccines do not cause several conditions. For example, the MMR vaccine is not associated with autism or childhood diabetes. Also, the DTaP vaccine is not associated with diabetes and the influenza vaccine given as a shot does not exacerbate asthma.

Adverse Effects of Vaccines will be of special interest to the National Vaccine Program Office, the VICP, the Centers for Disease Control and Prevention, vaccine safety researchers and manufacturers, parents, caregivers, and health professionals in the private and public sectors.