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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality (1994)

Chapter: 9 Haemophilus influenzae Type b Vaccines

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Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
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9
Haemophilus influenzae Type b Vaccines

BACKGROUND AND HISTORY

Prior to the introduction of Haemophilus influenzae type b (Hib) vaccines, Hib was the leading cause of bacterial meningitis in the United States among children younger than 4 years of age. Each year, an estimated 10,000 cases of Hib meningitis and 5,000 cases of other severe Hib infections occurred, including pneumonia, septic arthritis, epiglottitis, periorbital cellulitis, and facial cellulitis (Schlech et al., 1985; Todd and Bruhn, 1975). The cumulative incidence of invasive Hib disease in the first 5 years of life in the United States was estimated to be approximately 1 case per 200 children. The mortality rate for children with meningitis was 3 to 6 percent, and 20 to 30 percent of survivors had permanent sequelae, including hearing loss, mental retardation, and seizure disorders (Cochi et al., 1985). Nearly 75 percent of cases of Hib disease occurred in children younger than 2 years of age, and the susceptibility of young children to infection with Hib correlated with their lack of antibody to the type b capsular polysaccharide, polyribosylribitol phosphate (PRP) (Ward and Cochi, 1988).

In the 1970s, a vaccine composed of purified PRP, the plain polysaccharide vaccine, was prepared and was found to be immunogenic in adults and older children. However, responsiveness to PRP was highly age dependent. The vaccine was without protective efficacy in children less than 18 months of age and was of variable efficacy even when given at 2 years of age (Black et al., 1988; Harrison et al., 1988; Osterholm et al., 1988; Peltola et al., 1984; Shapiro et al., 1988). In addition to variable estimates of vaccine

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

efficacy, several investigators noted a possible increased incidence of disease in the immediate postimmunization period (less than 7 days) (Black et al., 1988; Harrison et al., 1988; Osterholm et al., 1988; Shapiro et al., 1988).

In the 1980s, several groups of investigators developed the first Hib polysaccharide-protein conjugate vaccines. Enhancement of the immunogenicity of carbohydrate antigens by chemical conjugation with proteins had been reported in 1929 by Avery and Goebel, but the idea had not been previously applied to the development of vaccines for human use. The Hib conjugate vaccines prepared by Schneerson et al. (1980), Gordon (1984), and Anderson (1983) showed enhanced immunogenicity and T-cell-dependent characteristics, that is, responses in immature animals, booster responses, predominance of immunoglobulin G (IgG) antibodies, and priming by prior carrier immunization.

A series of Hib conjugate vaccines was developed, tested, and licensed in the late 1980s. These vaccines differ in the molecular size of the Hib polysaccharide, the protein used as the carrier, and the methods used to link the polysaccharide to the protein (Table 9-1). Thus, in consideration of the side effects of Hib conjugate vaccines, it is plausible that variations in the type or frequency of adverse effects may occur because of differences in the polysaccharide or protein components of the vaccines.

Routine immunization of infants with Hib conjugate vaccine in a multiple-dose schedule is now recommended in the United States (American Academy of Pediatrics, Committee on Infectious Diseases, 1991b; Centers for Disease Control, 1991a). Because of the need to provide protective immunity during the high-risk period of infancy and for parental convenience, Hib conjugate vaccines are given simultaneously with diphtheria and tetanus toxoids and pertussis vaccine (DPT) and polio vaccines. The efficacies of these schedules on the basis of the results of prelicensure trials were estimated to be greater than 90 percent for PRP-outer membrane protein vaccine (PRP-OMP) in Navajo infants when given at 2 and 4 months of age (Santosham et al., 1992) and 100 percent after three doses of oligosaccharide conjugate Hib (HbOC) vaccine given at 2, 4, and 6 months of age (Black et al., 1992a). A new Hib conjugate vaccine, PRP conjugated to tetanus toxoid (PRP-T), was licensed on March 30, 1993 (Centers for Disease Control and Prevention, 1993). The immunogenicity of this vaccine in infants immunized at ages 2, 4, and 6 months is similar to that of previously licensed Hib conjugate vaccines (Decker et al., 1992). Although controlled trials of the efficacy of PRP-T in the United States had to be terminated because of licensure of other conjugate vaccines, no cases of invasive disease were detected in approximately 100,000 infants given two or more doses in these and other studies (Fritzell and Plotkin, 1992; Greenberg et al., 1991), and a controlled trial in the Oxford region of the United King-

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

TABLE 9-1 Characteristics of Hib Vaccines

Vaccine, (producer, trade name)

Polysaccharide

Protein Carrier

Age of Administration (date of licensure)

PRP

 

 

 

(Praxis, b Capsa 1; Lederle, HibImmune; Connaught, HibVAX)

''Native''

None

>24 mo (4/85)a (>18 mo if high risk)

PRP-D (Connaught, ProHiBit)

Medium

Diphtheria toxoid

18 mo (12/22/87)b 15 mo (12/89)c

HbOC (Lederie-Praxis, Hib-TITER)

Small

CRM197 mutant of Corynebacterium diphtheriae protein

18 mo (12/22/88)d 15 mo (12/89)c 2 mo (10/4/90)e

PRP-OMP (Merck Sharp & Dohme, PedvaxHIB)

Medium

Neisseria meningiditis outer membrane protein complex

15 mo (12/89)c 2 mo (12/13/90)f

PRP-T, (Pasteur Merieux-Connaught Vaccins, ActHIB)

Large

Tetanus toxoid

2 mo (3/30/93)g

a Centers for Disease Control (1985).

b Centers for Disease Control (1988).

c Centers for Disease Control (1990a).

d Centers for Disease Control (1989).

e Centers for Disease Control (1990b).

f Centers for Disease Control (1990d).

g Centers for Disease Control and Prevention (1993).

dom demonstrated efficacy of the vaccine when given at ages 2, 3, and 4 months (Booy et al., 1992). Following the widespread distribution and administration of Hib conjugate vaccines, few cases of vaccine failure (a case of Hib disease occurring more than 14 days after the second or third doses) have been reported (Black et al., 1992a; Holmes et al., 1991; Santosham et al., 1992), and postlicensure studies have shown a marked decrease in the incidence of Hib disease in the United States (Adams et al., 1993; Black et al., 1992b; Broadhurst et al., 1993; Centers for Disease Control, 1990c; Murphy et al., 1993b).

The American Academy of Pediatrics and the Advisory Committee on Immunization Practices recommend that conjugate Hib vaccines be administered as two to three doses beginning at age 2 months and then a booster at 12 to 15 months.

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

BIOLOGIC EVENTS FOLLOWING IMMUNIZATION

The Hib vaccines themselves contain no infective agents, just the organism's capsular polysaccharide; thus, there is no risk of developing Hib infection or clinical manifestations of Hib disease from any of the Hib vaccine components themselves (Granoff and Osterholm, 1987; Weinberg and Granoff, 1988). Occasionally, however, Hib disease is falsely diagnosed following immunization with both plain PRP and conjugated Hib vaccines, on the basis of the results of urine PRP antigen detection tests, because children excrete PRP in their urine for several days following immunization (Goepp et al., 1992; Jones et al., 1991; Spinola et al., 1986). The risk of developing a Hib infection within the first 7 days following immunization with Hib vaccines is discussed later in this chapter.

Rates of local reactions to Hib vaccines, such as pain, tenderness, swelling, and erythema at the site of injection, have varied from study to study, but the overall reaction rates to plain PRP vaccines are lower than those to conjugate vaccines. Approximately 20 to 25 percent of children develop local pain or tenderness, and 5 to 15 percent have redness or swelling at the injection sites in the 24 to 72 hours following immunization. These reactions are almost always mild and transient. Low-grade fever has been reported in the first 24 to 72 hours postimmunization in from 1 to 20 percent of Hib vaccine recipients. Temperatures of 39ºC (102.2ºF) or greater have been reported in less than 2 percent of Hib vaccine recipients. Most investigators have reported irritability in 10 percent or fewer of plain PRP vaccine recipients and about 10 to 25 percent of conjugate vaccine recipients. These systemic reactions are short-lived and are not felt to be serious by parents or physicians (Ahonkhai et al., 1990, 1991; Barkin et al., 1987; Black et al., 1987, 1991b; Campbell et al., 1990; Claesson et al., 1988, 1989, 1991; Clements et al., 1990; Dashefsky et al., 1990; Decker et al., 1992; Eskola et al., 1990a; Ferreccio et al., 1991; Frayha et al., 1991; Fritzell and Plotkin, 1992; Granoff and Cates, 1985; Granoff and Osterholm, 1987; Greenberg et al., 1987; Hendley et al., 1987; Kayhty et al., 1988, 1989; Kovel et al., 1992; Lenoir et al., 1987; Lepow et al., 1984a, 1985, 1986, 1987; Milstien et al., 1987; Parke et al., 1991; Peltola et al., 1977; Popejoy et al., 1989; Rowe et al., 1990; Santosham et al., 1991a; Vadheim et al., 1990; Watemberg et al., 1991; Weinberg and Granoff, 1988).

Rates of local and systemic reactions to Hib vaccines have usually been similar to or lower than those to injections with placebo or DPT, inactivated polio vaccine, or measles-mumps-rubella vaccine (MMR) alone or to those vaccines plus Hib vaccines (Ahonkhai et al., 1991; Black et al., 1991b; Campbell et al., 1990; Clements et al., 1990; Eskola et al., 1987; Lepow et al., 1984a, 1987; Vadheim et al., 1990; Watemberg et al., 1991). Exceptions include a study by Dashefsky et al. (1990), in which 71 percent of

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

infants receiving the PRP-OMP vaccine plus MMR were reported to develop irritability compared with 35 percent for groups receiving either vaccine alone, and a study by Ferreccio et al. (1991), which found a 7 to 20 percent increase in fever in children who received PRP-T with DPT than in those who received DPT alone.

Immunization with the first-generation Hib polysaccharide, or purified PRP, vaccine stimulates production of anti-PRP antibody in the same manner as natural infection (Granoff and Cares, 1985; Norden et al., 1976; Trollfors et al., 1992). This immune response is felt to be T-cell independent. In contrast, the immune responses to PRP conjugate vaccines appear to use T cells as well as B cells (Robbins and Schneerson, 1990; Steinhoff et al., 1991; Weinberg and Granoff, 1988). Antibodies produced in response to the intact organism, plain PRP vaccines, and conjugate vaccines have subtle differences, but all have been demonstrated to have in vitro opsonic and bactericidal activities and to be protective in animal models of Hib disease as well as in human trials (Adams, 1992; Anderson et al., 1972; Black, 1992; Black et al., 1988, 1991a,b; Cates, 1985; Cates et al., 1985; Eskola et al., 1987, 1990a,b, 1992; Fothergill and Wright, 1933; Fritzell and Plotkin, 1992; Gray, 1990; Kulhanjian, 1992; Loughlin et al., 1992; Musher et al., 1988; Newman et al., 1973; Peltola, 1992; Peltola et al., 1984; Robbins et al., 1973; Santosham et al., 1991b; Schneerson et al., 1971; Schreiber et al., 1986; Smith et al., 1989; Vadheim, 1992).

The difference in reliance on T cells for antibody production results in differences in the age at which the antibody response occurs, the amount of antibody produced, and the ability to boost antibody production by revaccination or exposure to the organism. The conjugate vaccines stimulate anti-PRP antibody responses in young infants, whereas the plain PRP vaccines do not provide protective amounts of antibody in most individuals until after the age of 2 years. The conjugate vaccines also induce larger amounts of anti-PRP antibodies in vaccinees of all ages, and they induce an anti-PRP antibody response in many individuals who do not respond well to natural infection with Hib or to the plain PRP vaccine, including patients with Hib disease before the age of 2 years and those with splenectomy; sickle cell disease; malignancy; IgG2 deficiency; Navajo, Apache, and Alaskan natives; and allogeneic bone marrow recipients (Barra et al., 1992; Edwards et al., 1989; Feldman et al., 1990; Frank et al., 1988; Gigliotti et al., 1989, 1991; Granoff et al., 1989; Kafidi and Rotschafer, 1988; Kaplan et al., 1988; Marcinak et al., 1991; Rubin et al., 1989, 1992; Santosham et al., 1992; Siber et al., 1990; Steinhoff et al., 1991; Walter et al., 1990; Weinberg and Granoff, 1990; Weisman et al., 1987).

It is evident that the different Hib vaccines produce not only different quantities of anti-PRP antibody but also that this antibody differs in such characteristics as IgG subclass, avidity, and affinity (Ambrosino et al., 1992;

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

Decker et al., 1992; Granoff et al., 1988; Hetherington and Lepow, 1992; Holmes et al., 1991; Insel and Anderson, 1986; Parke et al., 1991; Schlesinger and Granoff, 1992; Shackelford and Granoff, 1988). These differences produce subtle functional differences in vitro, but the implications for protective activity in vivo are unknown (Amir et al., 1990a,b).

Individuals who produce protective levels of antibody to Hib vaccines generally do so within 1 month of immunization (Kayhty et al., 1989; Peltola et al., 1977). Good immune responses to the conjugate vaccines have been demonstrated as soon as 1 week after immunization in older children and adults (Daum et al., 1989; Marchant et al., 1989).

Unlike plain PRP vaccines, PRP conjugate vaccines stimulate memory B cells capable of generating booster responses to immunization with either plain PRP or PRP conjugate vaccines and, thus, presumably, to the intact Hib organism (Weinberg et al., 1987). PRP conjugate vaccines reduce the Hib oropharyngeal carrier state (Barbour, 1992; Mohle-Boetani, 1992; Murphy, 1991; Takala et al., 1991).

TRANSVERSE MYELITIS

Clinical Description

Myelitis is inflammation of the spinal cord. Transverse myelitis is myelitis in which the inflammatory process principally involves one or more spinal cord segments, showing the manifestations of a transverse cord lesion that usually develops acutely. Initially, many cases of transverse myelitis are not complete. Early symptoms in some patients include sphincter paralysis associated with a total or partial loss of sensation below the level of the lesion. As the acute spinal shock resolves, the paraplegia becomes spastic. Acute multiple sclerosis and postinfective myelitis are among the commonest causes of this syndrome. The annual incidence of transverse myelitis in Rochester, Minnesota, from 1970 to 1980 was 0.83 per 100,000 people (Beghi et al., 1982).

History of Suspected Association

The history of a suspected association between Hib vaccines and transverse myelitis is based solely on three case reports in the Vaccine Adverse Event Reporting System (VAERS). There are no reports in the literature of an association between Hib vaccines and transverse myelitis.

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

Evidence for Association

Biologic Plausibility

A general discussion of transverse myelitis and vaccination can be found in Chapter 3. There are no data specifically bearing on the biologic plausibility of a causal relation between Hib vaccines and transverse myelitis.

Case Reports, Case Series, and Uncontrolled Observational Studies

There have been three cases reported in VAERS (submitted between November 1990 and July 1992) labeled as "transverse myelitis" following Hib vaccination. HbOC vaccine was the Hib vaccine used in all three cases. In one patient (there appeared to be two reports of this one case), the HbOC vaccine was administered alone, in the second the HbOC vaccine was administered with DPT and oral polio vaccine (OPV), and in the third HbOC vaccine was administered with DPT, OPV, and MMR. Only the third case provided sufficient evidence to establish a diagnosis of transverse myelitis. This child developed transverse myelitis 14 days after immunization with the HbOC, DPT, OPV, and MMR. She had a diffuse rash, diarrhea, and a fever 10 days after vaccination and 4 days prior to the onset of transverse myelitis. This case report was the only one to provide information on follow-up. At 4.5 months following vaccination, a magnetic resonance image (MRI) of the thoracic spine showed extensive atrophic change of the thoracic cord, extending from the seventh thoracic vertebra (T-7) through T-12. At 10 months postvaccination there was "persistent transverse myelitis" at the T-8 through T-10 level.

Insufficient data were provided for the other two cases to determine whether the children actually had transverse myelitis. One of these children developed a temperature of 40.6ºC (105ºF) and "extreme floppiness and toxic appearance" 24 to 36 hours after immunization with the HbOC vaccine alone. He had a "multitude of lab tests and MRI" and was hospitalized for 30 days. The other baby was noted to be unable to crawl 12 days after immunization with the HbOC vaccine, DPT, and OPV. The mother reported that a neurologist felt that this child had possible transverse myelitis from polio vaccine. She reported that the lumbar puncture and brain scan were normal. The child was hospitalized for 2 days, and no further follow-up information was provided.

There have been no cases of transverse myelitis reported in any case series or uncontrolled observational studies of Hib vaccines (Ahonkhai et al., 1990, 1991; Black et al., 1987; Claesson et al., 1991; Fritzell and Plotkin, 1992; Milstien et al., 1987; Parke et al., 1991; Popejoy et al., 1989; Rowe et al., 1990; Santosham et al., 1991a; Vadheim et al., 1990).

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×
Controlled Observational Studies

There have been no controlled observational studies investigating an association between Hib vaccines and transverse myelitis.

Controlled Clinical Trials

Transverse myelitis has not been reported in any of the controlled clinical trials of plain PRP or PRP conjugate vaccines that have been performed (Barkin et al., 1987; Black et al., 1991b; Campbell et al., 1990; Claesson et al., 1988, 1989; Clements et al., 1990; Dashefsky et al., 1990; Decker et al., 1992; Eskola et al., 1987, 1990a,b; Ferreccio et al., 1991; Frayha et al., 1991; Granoff and Osterholm, 1987; Greenberg et al., 1987; Hendley et al., 1987; Kayhty et al., 1988, 1989; Kovel et al., 1992; Lenoir et al., 1987; Lepow et al., 1984a,b, 1985, 1986, 1987; Peltola et al., 1977; Santosham et al., 1992; Watemberg et al., 1991).

Causality Argument

There is no animal model or other data supporting the association between Hib vaccines and transverse myelitis. There are three cases reported in VAERS labeled "transverse myelitis" in children aged 6, 9, and 15 months occurring following the administration of HbOC vaccine during a period when an estimated several million doses of HbOC vaccine were administered. One of these children received HbOC vaccine alone, and the interval between immunization and the development of neurologic symptoms in this child was brief (less than 48 hours). A second child also received DPT and OPV. The patient for whom sufficient documentation of transverse myelitis was provided also had received DPT, OPV, and MMR. No cases of transverse myelitis have been reported following administration of the other Hib vaccines, nor have any cases been reported in the literature.

Conclusion

The evidence is inadequate to accept or reject a causal relation between Hib vaccines and transverse myelitis.

GUILLAIN-BARRÉ SYNDROME

Clinical Description

The Guillain-Barré syndrome (GBS) is an acute polyneuropathy that gives rise to muscular weakness, paralysis, and areflexia usually in an as-

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

cending pattern. About one-third of patients with GBS require assisted ventilation, but rarely is the condition fatal. In most patients there is spontaneous improvement after weeks or months, usually leading to complete recovery. The annual incidence of GBS appears to be approximately 1 per 100,000 for adults. The data are not definitive, but the annual incidence of GBS in children under age 5 years appears to be approximately the same. The annual incidence of GBS in children over age 5 years and teenagers appears to be lower. Chapter 3 contains a detailed discussion of GBS.

History of Suspected Association

In 1989, D'Cruz and coworkers reported three cases of GBS following immunization with the Hib conjugate vaccine PRP-diphtheria toxoid (PRP-D). Two children received the PRP-D vaccine alone, but the third child received DPT and OPV as well. The onset of symptoms in this child occurred 1 day following immunization. One day is too short a period of time, as described in Chapter 3, to support the notion that the GBS attack was plausibly related to the vaccination.

Evidence for Association

Biologic Plausibility

A general discussion of GBS and vaccination can be found in Chapter 3. There are no data specifically bearing on the biologic plausibility of a causal relation between Hib vaccines and GBS.

Case Reports, Case Series, and Uncontrolled Observational Studies

A total of seven cases labeled GBS have been described following immunization with the three Hib conjugate vaccines that are currently licensed for use in the United States. The three cases following administration of the PRP-D vaccine noted above occurred during a period when approximately 6.2 million doses of PRP-D vaccine were distributed (D'Cruz et al., 1989). None of these children were noted to have an antecedent infection. A different lot of PRP-D vaccine was used in each child.

A fourth case of GBS following vaccination with PRP-D vaccine was reported recently by Gervaix and colleagues (1993). A 4-year-old girl developed signs of GBS (progressive weakness in legs with hypotonia and complete loss of tendon reflexes, difficulty in swallowing, and bilateral facial weakness) 10 days after receiving PRP-D Hib vaccine. The report documented decreased nerve conduction velocities and prolonged distal latencies. Serological tests were negative for cytomegalovirus, herpesvirus, Epstein-Barr virus, Borrelia burgdorferi, and Campylobacter species. IgM

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

antibodies to PRP in plasma were high 15 days after immunization. The child responded to intravenous immunoglobulin therapy.

The other three reports of GBS following the administration of Hib conjugate vaccines were detected by VAERS (submitted between November 1990 and July 1992). Two of the three children developed an infection between the time of immunization and the onset of the neurologic symptoms. These two children developed GBS (within the time frame described by the committee as plausible) following immunization with HbOC vaccine. One of these children also had received MMR, and the other child had received DPT and OPV at the time of the HbOC immunization. The former developed GBS 12 days following immunization and 6 days following the onset of otitis media and bronchospasm. The latter developed GBS 6 days after immunization and was noted to be on amoxicillin, but the indication for antibiotic therapy was not specified.

The third VAERS report described a child who was immunized as part of a PRP-OMP vaccine safety trial and was not noted to have received any other vaccine. This child developed an unsteady gait and decreased deep tendon reflexes 44 days after immunization and had otitis media, an upper respiratory tract infection, and a rash about 1 month following receipt of Hib vaccine and 2 weeks prior to the onset of neurologic symptoms. The child's discharge diagnosis was GBS. Although the latency is close to the window specified by the committee as reasonable (see Chapter 2), the other antecedent events (infection and rash) also suggest that if this child had GBS, it was far more likely related to these antecedent events.

In one of the PRP-D vaccine recipients (D'Cruz et al., 1989) and one of the HbOC vaccine recipients reported by VAERS, OPV was given concurrently. An increased incidence of GBS was reported to have coincided with a national OPV immunization campaign in Finland, as discussed in Chapter 8 (Farkkila et al., 1991; Kinnunen et al., 1989; Uhari et al., 1989).

The time of onset of symptoms following Hib vaccine administration ranged from 1 day (D'Cruz et al., 1989) to 44 days (a report from VAERS) in seven patients, with the onset of symptoms in five of the patients beginning 6 to 12 days after vaccination. The cases beginning 1 and 44 days after vaccination are not considered likely to be related to vaccination (see Chapter 3). The ages of the patients whose GBS began 6 to 12 days after vaccination were 15, 19, 20, and 33 months and 4 years. The symptoms of GBS resolved in three of these patients, and the outcomes for the others were not reported.

There have been no cases of GBS reported in any case series or uncontrolled observational studies of Hib vaccines (Ahonkhai et al., 1990, 1991; Black et al., 1987; Claesson et al., 1991; Fritzell and Plotkin, 1992; Milstien et al., 1987; Parke et al., 1991; Popejoy et al., 1989; Rowe et al., 1990; Santosham et al., 1991a; Vadheim et al., 1990).

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×
Controlled Observational Studies

There have been no controlled observational studies investigating an association between Hib vaccines and GBS.

Controlled Clinical Trials

GBS has not been reported in any of the controlled clinical trials of plain PRP or PRP conjugate vaccines that have been performed (Barkin et al., 1987; Black et al., 1991b; Campbell et al., 1990; Claesson et al., 1988, 1989; Clements et al., 1990; Dashefsky et al., 1990; Decker et al., 1992; Eskola et al., 1987, 1990a,b; Ferreccio et al., 1991; Frayha et al., 1991; Granoff and Osterholm, 1987; Greenberg et al., 1987; Hendley et al., 1987; Kayhty et al., 1988, 1989; Kovel et al., 1992; Lenoir et al., 1987; Lepow et al., 1984a,b, 1985, 1986, 1987; Peltola et al., 1977; Santosham et al., 1992; Watemberg et al., 1991).

Causality Argument

There are no animal models of GBS following immunization for Hib; however, Chapter 3 presents evidence that GBS is biologically plausible as a consequence of vaccines in general. Data bearing on causality are limited to case reports. Seven cases labeled as GBS were reported to occur following immunization with three different Hib conjugate vaccines over a period when an estimated several million doses of Hib conjugate vaccines were distributed. Five of these cases fit the criteria for possible vaccine-related GBS discussed in Chapter 3. Hib conjugate vaccine administration was the only potential predisposing factor cited for the development of GBS in three of the five children who fit the case definition of GBS following immunization for Hib. Gervaix and colleagues (1993) speculated that the anti-PRP IgM antibodies detected in the plasma of the patient they described might have cross-reacted with glycoproteins of peripheral nerve myelin, leading to GBS. Two of the five children who developed GBS following immunization with Hib vaccine had possible predisposing factors (infections, OPV immunization) other than Hib immunization.

Conclusion

The evidence is inadequate to accept or reject a causal relation between Hib vaccines and GBS.

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

THROMBOCYTOPENIA

Clinical Description

Thrombocytopenia is a decrease in the number of platelets, the cells involved in blood clotting. Thrombocytopenia may stem from the failure of platelet production, a shortened platelet life span, or an abnormal distribution of platelets within the body (Lee et al., 1993). Thrombocytopenia occurs in children of all ages, with an incidence of 31.9 cases per 1 million children per year (Cohn, 1976). Approximately 70 percent of cases occur following viral illnesses (Lightsey, 1980). In most cases, thrombocytopenia in children is mild and transient, and it is often discovered only incidentally when a complete blood count is performed. Severe thrombocytopenia associated with spontaneous bleeding, including bleeding into the skin, is called thrombocytopenic purpura.

History of Suspected Association

A possible association of Hib vaccine with thrombocytopenia was noted by Granoff et al. (1984) in a trial of the PRP-D vaccine in adults. Thirty subjects were randomly assigned to receive two doses of either the PRP or the PRP-D vaccine. Because this was one of the first trials of Hib conjugate vaccine in human subjects, multiple hematologic, renal, and hepatic tests were performed after the administration of each dose. One subject developed transient, asymptomatic thrombocytopenia after receiving the second injection of PRP-D vaccine. His platelet count fell from 173,000/mm3 before the second injection to 80,000/mm3 7 days after the injection. There was no associated evidence of bleeding, and the platelet count was 153,000/mm3 12 days later (normal range, 150,000 to 50,000/mm3). The causal relation between PRP-D vaccine and thrombocytopenia in this subject was not clear because he had received tetanus toxoid 4 weeks earlier and also was taking a number of medications for migraine headaches. None of the other subjects in that study experienced a decrease in platelet count, including the remaining 14 subjects who received PRP-D vaccine and the 15 subjects who received PRP vaccine. A second study of the effect of two doses of PRP and PRP-D vaccines on hematologic indices was conducted in 61 adults (Lepow et al., 1984b). No effect of either vaccine on platelet count was observed.

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

Evidence for Association

Biologic Plausibility

There are no studies in experimental animals or human subjects to suggest a possible mechanism by which Hib polysaccharide or its protein conjugates might produce thrombocytopenia. Natural infections with live viruses may induce thrombocytopenia by damage to megakaryocytes, destruction of circulating platelets, or induction of vital antigen-antibody complexes that sensitize platelets to increased destruction or sequestration (Kaplan et al., 1992; Lee et al., 1993). In patients with severe bacterial infections, including Hib infections, thrombocytopenia frequently occurs as a manifestation of disseminated intravascular coagulation (DIC). Thrombocytopenia also has been reported in adult patients with gram-negative and gram-positive septicemia but without evidence of DIC (Keltow et al., 1979). The thrombocytopenia in these patients was thought to result from the interaction of platelets with immune complexes.

Thrombocytopenia without evidence of DIC also has been observed in children with bacterial septicemia, including systemic Hib infections (Corrigan, 1974: Thomas and O'Brien, 1986). The mechanism by which the decreased platelet count occurs in these children is unknown, but it should be noted that intact Hib organisms contain many components not present in Hib vaccines. Some of these components, such as lipooligosaccharide, can induce an inflammatory response, including activation of platelet-activating factor and the coagulation cascade. These events can induce platelet aggregation and thus decrease the intravascular platelet count. There is no evidence that the capsular polysaccharide of Hib causes a similar inflammatory response (Quagliarello and Scheld, 1992; Saez-Llorens et al., 1990; Syrogiannopoulos et al., 1988). No published data from studies in animals were found, but Lepow et al. (1984b) referred to hematologic studies in rats, including serial bone marrow evaluations, that failed to demonstrate any effect of PRP-D vaccine on platelet counts.

Case Reports, Case Series, and Uncontrolled Observational Studies

Five cases of thrombocytopenia following immunization for Hib were reported through VAERS between November 1990 and July 1992, a period during which approximately 29.5 million doses of Hib vaccine were distributed in the United States (a rough estimate based on 1991 data provided by the Centers for Disease Control). In one case, the thrombocytopenia occurred 7 days after receipt of DPT, OPV, and HbOC vaccine and was associated with high fever, diarrhea, weight loss, seizures, and renal failure, a symptom complex resembling hemolytic-uremic syndrome. The report stated

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

that there was a ''possibility of permanent renal dysfunction and possible brain damage,'' but no follow-up information was available. The other four cases occurred in children who had received MMR in addition to the Hib vaccines (two children received HbOC vaccine, one child received PRP-D vaccine, and one child received an unspecified Hib vaccine). Thrombocytopenia developed 5 to 13 days after immunization, and all four patients recovered. Two of the children had only petechiae and purpura in association with the thrombocytopenia, one child had a high fever and maculopapular rash in addition to petechiae, and one child had fever, a maculopapular rash, erythema multiforme, petechiae, and purpura.

Milstien and coworkers (1987) published a summary of the adverse reactions reported to the U.S. Food and Drug Administration (FDA) during the first year after marketing of the PRP vaccine (1985-1986). During that time, 4.5 million doses of vaccine were sold. Included in that summary was one report of petechiae (platelet count not given), one case of idiopathic thrombocytopenic purpura (ITP) (platelet count, 15,000/mm3) diagnosed 18 days after immunization, and one child who developed a low platelet count associated with hemolytic-uremic syndrome that began 2 days after receiving PRP vaccine.

Controlled Observational Studies

A study of the effect of two doses of PRP and PRP-D vaccines on hematologic indices was conducted in 61 adults (Lepow et al., 1984b). No effect of either vaccine on platelet count was observed.

Controlled Clinical Trials

In several large prospective trials of PRP and Hib conjugate vaccine efficacy and safety (Black et al., 1987, 1991b; Eskola et al., 1990a; Peltola et al., 1977; Santosham et al., 1991b; Vadheim et al., 1990), no subjects developed petechiae or purpura. Platelet counts were not measured, so the incidence of asymptomatic thrombocytopenia after immunization with Hib vaccines is unknown.

Causality Argument

The information concerning thrombocytopenia and Hib vaccines is limited. There is no biologic plausibility (data from animal models or experimental studies) to suggest a mechanism for thrombocytopenia following immunization for Hib. One case of thrombocytopenia without clinical illness occurred in a clinical trial study subject who had other possible risk factors that could have been responsible for the decline in platelet count

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

(Granoff et al., 1984). Four cases of thrombocytopenia have been reported through VAERS, and all subjects received other vaccines including a live viral vaccine, MMR. MMR is associated with thrombocytopenia (see Chapter 6). An additional report in VAERS described an event resembling hemolytic-uremic syndrome following immunization for Hib, diphtheria, tetanus, and pertussis (DPT), and polio (OPV). One case of ITP and one case of hemolytic-uremic syndrome were reported to the FDA following immunization with PRP vaccine (Milstien et al., 1987). No information regarding other medications or illnesses in the child with ITP was provided in the summary report. Most cases of hemolytic-uremic syndrome are now known to follow enteritis caused by intestinal pathogens that produce verotoxins (shigellalike toxins) (Centers for Disease Control, 1991b; Rowe et al., 1991). Both patients with hemolytic-uremic syndrome associated with Hib vaccine administration (noted above) presented with diarrhea. Thus, it is most likely that these were related to enteritis caused by verotoxin-producing Escherichia coli or Shigella dysenteriae rather than the Hib vaccines, which contain no toxins.

Conclusion

The evidence is inadequate to accept or reject a causal relation between Hib vaccines and thrombocytopenia.

EARLY SUSCEPTIBILITY TO H. INFLUENZAE TYPE b

Clinical Description

Early-onset Hib disease following immunization is defined as a case of serious systemic infection caused by Hib that occurs within the 7-day interval following immunization for Hib. The annual incidence of Hib has decreased dramatically with the introduction of Hib vaccines.

History of Suspected Association

In conducting vaccine efficacy trials for Hib vaccines, investigators expected to observe a number of vaccine "failures" (i.e., none of the Hib vaccines was likely to be 100 percent effective in the prevention of disease, particularly after administration of a single dose to young infants). For calculation of efficacy, "immunization" was usually defined as receipt of vaccine more than 14 days prior to the onset of disease; 14 days was considered a reasonable time period for development of a protective antibody response. In studies of vaccine efficacy for the unconjugated PRP vaccine, a wide range of estimates of vaccine efficacy was observed in various locations in the United States (Black et al., 1988; Harrison et al., 1988; Osterholm

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

et al., 1988; Shapiro et al., 1988). This observation was not easily explained by differences in study design or vaccine potency or by genetic differences among study populations. Furthermore, in several case-control studies there appeared to be an increased incidence of disease in the immediate postimmunization period (7 days or less) (Black et al., 1988; Harrison et al., 1988; Osterholm et al., 1988; Shapiro et al., 1988).

Evidence for Association

Biologic Plausibility

PRP vaccine contained only purified capsular polysaccharide, so the early-onset cases of Hib infection could not have been caused by infectious material in the vaccine itself. Several investigators postulated that the apparent increased susceptibility to infection in the immediate postimmunization period might be related to a transient decrease in preexisting antibody caused by the formation of complexes of antigen with antibody or by transient suppression of antibody synthesis (Marchant et al., 1989; Sood and Daum, 1990). Black and coworkers (1988) postulated that the clustering of early cases in the first week after immunization and the absence of cases in the second and third weeks after immunization observed in their study suggest that immunization may shorten the incubation period of Hib in children already destined to become ill. This mechanism implies that there is a redistribution of cases of disease to earlier in the time postimmunization rather than an actual increase in the rate of disease.

Observations of decreased immunity in the immediate postimmunization period were recorded as early as 1893 by Brieger and Ehrlich in a study of immunity in goat's milk after immunization with tetanus cultures. In 1896, Salomonsen and Madsen noted a decreased anti-diphtheria antibody content in the serum of horses early after immunization with diphtheria toxin, and those workers pointed out three phases of antitoxin response: (1) a fall, later called the "negative" phase, (2) a rise, and, after phase 2 reaches a maximum, (3) a fall. Madsen and coworkers (1937) studied the "negative" phase of the antitoxin curve in detail using rabbits immunized with diphtheria toxin. They were able to demonstrate that the negative phase in their experiments resulted from fixation between antigen and antitoxin in the bloodstream. Studies of individuals immunized for typhoid fever have suggested that immunization may transiently enhance susceptibility to infection both in epidemics of typhoid fever and in experimental murine infections (Raettig, 1959; Topley, 1938).

Using an infant rat model of Hib infection, Sood and colleagues (Sood and Daum, 1990; Sood et al., 1988) showed that the passive protection of animals provided by human immunoglobulin containing 5 µg of anti-PRP

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

antibody per ml was diminished by administration of a wide range of doses of PRP vaccine (25-250 ng). These doses of antibody and antigen were chosen to simulate clinically relevant amounts in children who receive a 25-µg dose of PRP in the vaccine. The magnitude but not the incidence of bacteremia varied with the dose of vaccine. Interestingly, small doses of vaccine that significantly affected the incidence and degree of bacteremia did not measurably affect antibody concentrations in the serum of rats, and thus, the relation between the decrease in the level of antibody and the occurrence of bacteremia in this model remains unclear. The conjugate vaccines varied in their ability to reverse passive immunity in rats, a phenomenon that may be related to variations in the binding of anti-capsular antibody to the different vaccine antigens (Sood and Daum, 1990).

The demonstration of detectable antigenuria in many children for as long as 7 days following immunization with PRP vaccine (Spinola et al., 1986) or with Hib conjugate vaccines (Jones et al., 1991; Sood and Daum, 1990) implies that children are antigenemic after immunization and, thus, that binding of free antibody and depression of the levels of free antibody can occur.

Anti-PRP antibody concentrations were sequentially measured in the serum of human subjects for 7 days following immunization with PRP (adults and children) or PRP-D (adults) vaccine. A decline was observed in most 2-year-old children immunized with PRP vaccine and in adults immunized with either vaccine (Daum et al., 1989). The nadir occurred on days 1 to 3, and the decrease averaged 25 percent for adults and 15 percent for children. Thus, it is theoretically possible that some Hib infections that occur early after immunization with vaccine are the result of this transient decrease in free antibody levels. However, in the same study, antibody levels were shown to rise rapidly after immunization and were greater than preimmunization levels in adults by day 7. In children, the distribution of antibody levels in sera obtained at 4 or 5 days postimmunization (with PRP vaccine) did not differ from that in preimmunization serum. In another study (Marchant et al., 1989), among 30 infants aged 18 to 21 months immunized with PRP-D vaccine, 9 had detectable preimmunization anti-PRP antibody concentrations (greater than 0.025 µg/ml). Although all nine of these children had depression of antibody on the second day after immunization, all achieved anti-PRP concentrations of greater than 0.15 µg/ml (a level thought to be protective against Hib challenge) by day 7. In that same study, 21 children were found to have undetectable antibody concentrations before immunization. All but 2 of these 21 children developed detectable antibody by day 7, and 67 percent of these children achieved protective levels by that time. The investigators concluded that although the small proportion of infants among previously unimmunized infants with preexisting antibody may develop a transient depression of antibody following immunization with Hib

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

vaccine, the more important determinant of susceptibility to early Hib disease in this age group is acquisition of protective antibody rather than depression of preexisting antibody levels. A recent study (Granoff et al., in press) demonstrated that PRP vaccine induces high antibody responses within 6 to 9 days after vaccination when given to 12-month-old infants who were previously vaccinated with Hib conjugate vaccine beginning at 2 months of age. Proof that transient suppression of preexisting antibody may be associated with increased susceptibility to Hib disease can come only from epidemiologic studies of recently immunized versus unimmunized populations.

Another possible mechanism of enhanced susceptibility to Hib disease in the early postimmunization period is the transient suppression of antibody synthesis. This alternative is unlikely on the basis of the observation that children with "early" cases of Hib disease after vaccination have excellent antibody responses to their disease (Murphy, 1987).

Case Reports, Case Series, and Uncontrolled Observational Studies (PRP)

LeMay (1986) presented the first report of a case of Hib infection occurring early after immunization. This case was in a 2.5-year-old child who developed epiglottitis with a blood culture positive for Hib within 24 hours after immunization with PRP vaccine. The child attended a day-care center but had not been in contact with individuals known to have Hib disease. The author emphasized the implication of using rifampin prophylaxis rather than reliance upon postexposure immunization for the prevention of disease following identification of an index case in a day-care center or household.

Hiner and Frasch (1988) examined the spectrum of Hib disease occurring in children immunized with PRP vaccine on the basis of reports received by the Food and Drug Administration between May 1985 and September 1987. At least some of these cases overlap with the cases described in the case-control studies outlined below. The purposes of the study were (1) to examine the types of Hib disease in vaccinated children compared with the types in unvaccinated children and (2) to determine whether there was any interval after immunization in which invasive disease was more likely to occur. Reports of 216 cases were analyzed. Vaccination did not alter the frequencies of the different clinical entities associated with invasive Hib disease except in the children who developed disease within 72 hours after immunization, when meningitis was less frequent and epiglottitis and cellulitis were relatively more frequent. In the 6-month interval after immunization, more cases (53 percent) occurred in the first 2 months than at later intervals. Of the 13 cases that occurred in the first 10-day interval, 10 occurred within 72 hours of vaccination. However, the authors noted that

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

the "data do not provide evidence for increased susceptibility immediately after immunization, because the frequency of cases by days to onset occurring within the first 60 days was random" (Hiner and Frasch, 1988, p. 346).

Controlled Observational Studies (PRP)

Four case-control studies, all of which were published in 1988 (Black et al., 1988; Harrison et al., 1988; Osterholm et al., 1988; Shapiro et al., 1988) and all of which used similar designs and methods of surveillance, bear on the question of the increased risk of early disease after receipt of PRP vaccine. The four studies are summarized in Table 9-2. The first, by Black et al. (1988), is from the Northern California Kaiser Permanente Medical Care Program. The studies by Harrison et al. (1988), Shapiro et al. (1988), and Osterholm et al. (1988) all appeared in a single issue of the Journal of the American Medical Association and were based on study populations throughout the United States. Although the studies of Harrison et al. (1988), Shapiro et al. (1988), and Osterholm et al. (1988) used a matched design in the primary analyses, the data on early disease were reported in an unmatched fashion.

All four of the case-control studies provided data bearing on the risk of early Hib disease within the first 7 days following vaccination. For the study by Black et al. (1988), the committee used only three of the four vaccinated (exposed) cases in the analysis, since one of the patients had requested vaccine because of contact with an individual with Hib disease (see below for the possibility of increased risk in this situation). Based on the method of Mantel and Haenszel (1959), the meta-analysis of all four studies yielded an odds ratio of 2.6 (95 percent confidence interval [CI], 1.1-7.50) for the association between PRP vaccine and the development of Hib disease within 7 days of vaccination.

Controlled Clinical Trials (PRP)

A large, randomized trial to test the efficacy of the PRP (unconjugated) vaccine was carried out by Peltola and coworkers, and the results of long-term follow-up were reported in 1984 (Peltola et al., 1984). In that study, protective efficacy was observed only in those children immunized at 18 months of age or older. Among children immunized at 18-71 months of age, no cases of Hib disease were observed within the 7-day interval following immunization. Among 37,393 children immunized with Hib vaccine, 2 developed bacteremic Hib infection (20 and 21 months after receiving vaccine, respectively). Among 38,431 controls of the same age who

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

TABLE 9-2 Epidemiologic Studies of Early Hib Disease with Unconjugated (PRP only) Hib Vaccine

References

Location

Design

No. Exposeda/No. of Hib Cases

No. Exposeda/No. of Controls

OR (95% CI)b

Black et al., 1988

Northern

Case-control California

3/30

61/2,774

4.9 ( 1.2-17.7)

Harrison et al., 1988

Los Angeles, Missouri, New Jersey, Oklahoma, Tennessee, Washington

Case-control

3/104

5/207

1.2 (0.2-5.9)

Shapiro et al., 1988

Pennsylvania, Texas, Connecticut

Case-control

1/76

1/152

2.0 (0-74.8)

Osterholm et al., 1988

Minnesota

Case-control

3/88

1/176

6.2 (0.6-156.4)

Pooled (Mantel-Haenszel) estimate

 

 

 

 

2.6 (1.1-7.5)

a Exposed to vaccine within preceding 7 days.

b OR, odds ratio; CI, confidence interval.

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

were immunized with group A meningococcal capsular polysaccharide vaccine, 20 developed Hib infections (1 to 42 months after receiving vaccine).

Case Reports (Hib Conjugate Vaccines)

Ten cases of early Hib disease following immunization were reported through VAERS between November 1990 and July 1992. Nine cases occurred in children who received HbOC vaccine and one in a child who received PRP-D vaccine, presumably reflecting the distribution of Hib vaccine types during that period. Five of the nine cases occurred after the administration of one dose each to infants ages 2, 2, 3, and 4.5 months and 2 years. Two infants aged 4 months developed disease after receiving two doses of vaccine, one infant aged 8 months developed disease after receiving the third dose, and one infant aged 6 months developed disease after an unspecified number of doses. The child who received PRP-D vaccine was 2 years of age. Information regarding his previous vaccine history was not available. All cases occurred within 5 days of immunization. There were eight cases of meningitis, one case of periorbital cellulitis, and one case of septicemia with disseminated intravascular coagulation and shock that occurred less than 24 hours after receiving Hib vaccine. All cases were documented by a positive culture of blood or cerebrospinal fluid, but the serotype was specified as type b in only four instances. Serotype data are crucial, because in the post-Hib vaccine era, the proportion of cases of invasive disease caused by nontype b strains may increase, reflecting the dramatic decline in type b isolates (Adams et al., 1993; Black et al., 1992b; Broadhurst et al., 1993; Centers for Disease Control, 1990c; Murphy et al., 1993).

Uncontrolled Observational Studies, Controlled Observational Studies, and Controlled Clinical Trials (Hib Conjugate Vaccines)

Studies that bear on the risk of early Hib disease in recipients of the more recently developed Hib conjugate vaccines (first dose only) are summarized in Table 9-3. All are based on cohort designs. Two studies (Eskola et al., 1990a; Santosham et al., 1991b) were randomized trials, one was a controlled observational cohort study (Black et al., 1991b), and the others were all based on follow-up of vaccine recipients only. Several differences among the studies are worthy of note. The studies by Black et al. (1991b, 1992b) were based on HbOC vaccine, that of Santosham et al. (1991b) was based on PRP-OMP vaccine, and those of Eskola et al. (1990a), Vadheim et al. (1990), and Scheifele (1989) used PRP-D vaccine. The studies of Eskola et al. (1990a), Black et al. (1991b), and Santosham et al. (1991b) were based on the first dose administered to young infants (6 weeks to 6 months

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

of age), who are currently the largest group of recipients of the conjugate vaccine. The studies of both Vadheim et al. (1990) and Scheifele (1989) were based on a single dose administered to children 18 months to 60 months of age, that is, those who were formerly immunized with the unconjugated vaccine (PRP) (see studies above). In the study of Eskola et al. (1990a), the control children received one dose of PRP-D vaccine at 24 months of age.

The randomized, prospective field trial of PRP-D vaccine in 114,000 infants in Finland (Eskola et al., 1990a) showed a vaccine efficacy of 94 percent (95 percent CI, 83-98 percent) when given at 3, 4, 6, and 14-18 months of age. Eight cases of Hib disease occurred in 58,000 vaccinated children, but no cases of early Hib disease occurred following immunization. Four cases occurred after one to two doses (interval after immunization, 25 days-2.5 years) (J. Eskola, National Public Health Institute, Helsinki, Finland, personal communication, 1993), and four cases occurred after three doses (days 55-173 after immunization) (Eskola et al., 1990a). The control children received PRP-D vaccine at 24 months of age, and one child in this group developed epiglottitis with Hib bacteremia at 24 months of age on the same day that she received PRP-D vaccine and DPT.

Although control groups were studied by Eskola et al. (1990a), Black et al. (1991b), and Santosham et al. (1991b), no relative risk estimate for early disease can be calculated, since no cases of Hib were observed within 7 days of vaccination in either the vaccinated or unvaccinated groups in any of those studies.

Because the studies of Vadheim et al. (1990) and Scheifele (1989) and the small immunogenicity studies did not include control groups, metaanalysis could not be used to estimate the relative risk of early Hib disease following receipt of the conjugate vaccines. Nonetheless, a pooled relative risk can be estimated from the ratio of the total number of observed cases among vaccine recipients in all of the studies combined (i.e., ignoring the control groups of Black et al. [1991b] and Santosham et al. [1991b]) to the total number of expected cases. The number of cases of early Hib disease in each study can be treated as having a Poisson distribution. The expected number of cases for each study is estimated from the age-specific annual incidence rates reported from the prevaccine era, that is, an external comparison group (Ward and Cochi, 1988), and was considered to be a constant. The results are shown in Table 9-3. No statistically significant increase in the risk of early disease is apparent with the conjugate vaccines. It should be noted that recent studies have demonstrated that immunization with Hib conjugate vaccines decreases colonization rates in immunized subjects and may decrease the level of transmission of Hib to their contacts (Murphy et al., 1993; Takala et al., 1991), thus potentially decreasing the risk of disease both in unimmunized and in recently immunized children. This argues for

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

TABLE 9-3

Epidemiologic Studies of Early Hib Disease After First Dose of Hib Conjugate Vaccines (Vaccine Recipients Only)

Reference

Location

Vaccine

Ages

No.

Cases of Hib Disease Within 7 Days of Vaccination

Observed

Expecteda

Scheifele, 1989

British Columbia

PRP-D

18-60 mo

5,263

1

0.04

Eskola, 1990a, and personal communication

Finland

PRP-D

3 mo

58,000

0

1.65

 

Finland

PRP-D

24 mo

56,000

1

0.77

Vadheim et al., 1990

Southern California

PRP-D

18-60 mo

29,309

1

0.23

Black et al., 1991b

Northern California

HbOC

6 wk-6 mo

30,400

0

0.85

Santosham et al., 1991b

Arizona

PRC-OMP

6 wk-4 mo

2,588

0

0.07

b

 

HbOC

1-6 mo

664

0

.02

 

 

 

15-23 mo

268

0

.01

c

 

PRP-D

7-14 mo

678

0

.03

 

 

 

15-24 mo

300

0

.01

d

 

PRP-OMP

1-6 mo

918

0

.03

 

 

 

7-11 mo

300

0

.02

 

 

 

12-17 mo

476

0

.02

 

 

 

18-23 mo

249

0

.00

 

 

 

24-71 mo

361

0

.00

e

 

PRP-T

2-3 mo

269

0

.01

 

 

 

18-23 mo

55

0

.00

Black et al., 1992b, and personal communication

Northern California

HbOC

6 wk-6 mo

53,000

0

1.48

 

 

 

15-18 mo

22,000

1

0.68

 

 

 

 

Total

4

5.92

 

 

 

 

9.5% CIf(1.09-10.24)

 

 

 

 

RRg (95% CI)

 

.68 (0.18-1.73)

 

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

a Expected based on age-specific annual incidence figures in Ward and Cocchi (1988).

b HbOC studies: Madore at al., 1990a,b; Rowe et al., 1990; Tudor-Williams et al., 1989; Anderson et al., 1987.

c PRP-D studies: Berkowitz et al., 1987; Lepow et al., 1987.

d PRP-OMP studies: Ahonkai et al., 1990; Campbell et al., 1990.

e PRP-T studies: Claesson et al., 1988, 1989; Parke et al., 1991; Booy et al., 1992.

f CI, confidence interval.

g RR, relative risk.

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

caution in comparing observed rates among recent vaccinees with historical (expected) rates in children from the prevaccine era.

Causality Argument

The biologic plausibility of a causal relation is provided by studies in human subjects and experimental animals that demonstrate a transient decrease in protective antibody levels following immunization with the unconjugated PRP vaccine. Both individually and by meta-analysis, data from four case-control trials suggest that immunization of children over 18 months of age who receive their first Hib immunization with unconjugated PRP vaccine is associated with an increased risk of disease in the 7-day interval following immunization. Because these were not controlled clinical trials, it is theoretically possible that the results are confounded (biased) by indication for receipt of the vaccine. For example, children in the immunized group may have been at greater risk for early-onset disease if they were immunized because of day-care center attendance or exposure to an individual with Hib disease.

The epidemiologic evidence from prospective observational studies favors rejection of a causal relation between immunization with Hib conjugate vaccines and an increased risk of disease in the early postvaccination interval. Although these vaccines also appear to be capable of causing a transient decline in serum antibody levels following immunization, conjugate vaccines produce a rapid and more predictable rise in protective antibody levels, and thus, the interval of increased risk, if any, is very short. In addition, conjugate vaccines are given to young infants, who generally have little preexisting protective antibody to be decreased, and thus, it is highly likely that the vaccine will provide protection rather than suppression of antibody (and increased risk of disease).

There are no epidemiologic data regarding the risk of Hib disease in the early period following immunization with PRP vaccine in individuals who have previously received one or more doses of Hib conjugate vaccine. However, the immunologic data showing rapid development of high antibody levels in previously immunized children given PRP vaccine at 12 months of age suggest that these children, like unimmunized children receiving Hib conjugate vaccine, would not be at increased risk of Hib disease in the early postvaccination interval.

Conclusion

The evidence favors acceptance of a causal relation between unconjugated PRP vaccine and early-onset Hib disease in children over 18 months of age who receive their first Hib immunization with unconjugated PRP vaccine.

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
×

On the basis of the incidence in the prevaccine era (Ward and Cochi, 1988) for the 24- to 35-month age group (presumably, the main age group previously immunized with PRP vaccine) of 1.0 per 100,000 per week (i.e., the annual rate divided by 52) and the Mantel-Haenszel odds ratio for the metaanalysis of 2.62, the attributable incidence is 2.62 - 1.0 = 1.62 cases of early-onset (within 7 days of vaccination) Hib disease per 100,000 vaccinees. It should be stated, however, that the above figures may not be valid, since today the 7-day incidence of disease is probably less than the 1.0 per 100,000 from the prevaccine era owing to decreased colonization and transmission of disease.

The evidence favors rejection of a causal relation between immunization with Hib conjugate vaccines and early-onset Hib disease.

The evidence is inadequate to accept or reject a causal relation between PRP vaccine and early-onset disease in individuals who previously received one or more doses of Hib conjugate vaccine.

Risk-Modifying Factors

Because immunization with Hib vaccines may lead to a transient decrease in protective antibody levels, unimmunized children at increased risk of colonization (household or day-care contact with individuals with recent cases of Hib infection) may require special measures (see the recommendations of the American Academy of Pediatrics, Committee on Infectious Diseases [1991a]). A number of studies have demonstrated the safety and efficacy of Hib conjugate vaccines in high-risk groups such as adults with human immunodeficiency virus infection (Steinhoff et al., 1991) and children with sickle cell anemia (Frank et al., 1988; Rubin et al., 1992), cancer (Feldman et al., 1990), and asplenia (Jakacki et al., 1990), although in the latter two groups the antibody responses to vaccine were lower than normal.

ANAPHYLAXIS

Clinical Description

Anaphylaxis and anaphylactic shock refer to an acute, severe, and potentially lethal systemic allergic reaction. Signs and symptoms begin within minutes to a few hours after exposure. Death, if it occurs, usually results from airway obstruction caused by laryngeal edema or bronchospasm and may be associated with cardiovascular collapse. Most cases resolve without sequelae, and early treatment with alpha-adrenergic drugs can abort the full expression of the syndrome. A general discussion of anaphylaxis can be found in Chapter 4.

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
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Evidence for Association

Biologic Plausibility

The biologic plausibility for a causal relation between Hib vaccines and anaphylaxis derives from the knowledge that injection of foreign protein into humans can be expected to elicit, in some percentage of recipients, IgE-mediated responses that present as anaphylaxis.

Case Reports, Case Series, and Uncontrolled Observational Studies

A study of efficacy and reactions to vaccination against either Hib or Neisseria meningitidis reported two cases of apparent anaphylactic reactions (Mäkelä et al., 1977). One child had received unconjugated Hib vaccine. There had been a total of 48,977 people vaccinated against Hib. Both children responded to epinephrine. No other details were provided. A summary of adverse reaction reports submitted to FDA for a 1-year period beginning in April 1985 lists two cases of what the authors termed anaphylactoid-like reactions (Milstien et al., 1987). A 3-year-old boy became pale, started wheezing, and exhibited hypotension 5 minutes after vaccination. A 4-year-old boy became nauseated, pale, bradycardic, and cyanotic 20 minutes after vaccination. Both children responded to epinephrine.

There are no published case reports. The reports in VAERS (submitted between November 1990 and July 1992) include one case of an immediate reaction to Hib vaccine alone and three cases of a response to a combination of vaccines that included a Hib conjugate vaccine. The first of these probably does not represent true anaphylaxis and may have been a severe breath-holding spell. The last three all received a combination of Hib vaccine, DPT, and OPV. One of these, in which a 6-month-old child developed acute flushing and edema 10 minutes after immunization, may have represented an anaphylactic reaction that was aborted by the early use of epinephrine.

Controlled Observational Studies and Controlled Clinical Trials

None of the controlled studies identified by the committee contained reports of anaphylaxis in association with the administration of any Hib vaccine.

Causality Argument

There is biologic plausibility that Hib vaccines, like all foreign proteins, could cause anaphylaxis. There are no data to suggest that Hib vac-

Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
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cines would be more likely than any other foreign protein, including other vaccines, to cause anaphylaxis. There are few cases of anaphylaxis following Hib vaccination in the literature. Insufficient details are provided by Mäkelä and colleagues (1977) to determine whether the responses represented anaphylaxis. The symptoms described in the paper by Milstien et al. (1987) are suggestive but not conclusive of anaphylaxis, but the administration of epinephrine might have aborted development of enough signs of anaphylaxis to be convincing.

Conclusion

The evidence is inadequate to accept or reject a causal relation between Hib vaccines and anaphylaxis.

DEATH

A detailed discussion of the evidence regarding death following immunization can be found in Chapter 10.

Conclusion

The evidence favors acceptance of a causal relation between PRP vaccine and death from early-onset Hib disease in children 18 months of age or older who receive their first Hib immunization with unconjugated PRP vaccine. There is no direct evidence for this; the conclusion is based on the potential for Hib disease to be fatal. The risk would appear to be extraordinarily low.

The evidence favors rejection of a causal relation between conjugated Hib vaccines and death from early-onset Hib disease.

The evidence is inadequate to accept or reject a causal relation between Hib vaccines and sudden infant death syndrome.

The evidence is inadequate to accept or reject a causal relation between Hib vaccine and death from causes other than those listed above.

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×

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Suggested Citation:"9 Haemophilus influenzae Type b Vaccines ." Institute of Medicine. 1994. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. doi: 10.17226/2138.
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Childhood immunization is one of the major public health measures of the 20th century and is now receiving special attention from the Clinton administration. At the same time, some parents and health professionals are questioning the safety of vaccines because of the occurrence of rare adverse events after immunization.

This volume provides the most thorough literature review available about links between common childhood vaccines--tetanus, diphtheria, measles, mumps, polio, Haemophilus influenzae b, and hepatitis B--and specific types of disorders or death.

The authors discuss approaches to evidence and causality and examine the consequences--neurologic and immunologic disorders and death--linked with immunization. Discussion also includes background information on the development of the vaccines and details about the case reports, clinical trials, and other evidence associating each vaccine with specific disorders.

This comprehensive volume will be an important resource to anyone concerned about the immunization controversy: public health officials, pediatricians, attorneys, researchers, and parents.

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