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2
Histories of Pertussis and Rubella Vaccines

PERTUSSIS VACCINES

Epidemiology of Whooping Cough
Clinical Description

Pertussis, or whooping cough,1 is a serious epidemic respiratory infection caused by Bordetella pertussis, a gram-negative bacillus. Pertussis is characterized by a paroxysmal, spasmodic cough that usually ends in a prolonged, high-pitched crowing inspiration or whoop (American Academy of Pediatrics, 1986; Berkow, 1987; Cherry et al., 1988; Mortimer, 1988). Children are most commonly affected, although there are current indications that the disease, in a milder form, may be more prevalent in adults than was previously believed (Aoyama et al., 1990; Farizo et al., 1990). In fact, evidence suggests that immunized2adults in developed nations are the most common source of pertussis infections in neonates and children (Nelson, 1978).

The first recorded description of a pertussis epidemic was made by a Parisian, Guillaume de Baillou, in 1578 (Holmes, 1940). His characterization of the disease is graphic.  

1 The terms pertussis and whooping cough are used interchangeably throughout this report.

2 The terms immunization and vaccination are used interchangeably throughout this report.



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Page 9 2 Histories of Pertussis and Rubella Vaccines PERTUSSIS VACCINES Epidemiology of Whooping Cough Clinical Description Pertussis, or whooping cough,1 is a serious epidemic respiratory infection caused by Bordetella pertussis, a gram-negative bacillus. Pertussis is characterized by a paroxysmal, spasmodic cough that usually ends in a prolonged, high-pitched crowing inspiration or whoop (American Academy of Pediatrics, 1986; Berkow, 1987; Cherry et al., 1988; Mortimer, 1988). Children are most commonly affected, although there are current indications that the disease, in a milder form, may be more prevalent in adults than was previously believed (Aoyama et al., 1990; Farizo et al., 1990). In fact, evidence suggests that immunized2adults in developed nations are the most common source of pertussis infections in neonates and children (Nelson, 1978). The first recorded description of a pertussis epidemic was made by a Parisian, Guillaume de Baillou, in 1578 (Holmes, 1940). His characterization of the disease is graphic.   1 The terms pertussis and whooping cough are used interchangeably throughout this report. 2 The terms immunization and vaccination are used interchangeably throughout this report.

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Page 10 The lung is so irritated by every attempt to expel that which is causing the trouble it neither admits the air nor again easily expels it. The patient is seen to swell up and as if strangled holds his breath tightly in the middle of his throat . . . For they are without the troublesome coughing for the space of four or five hours at a time, then this paroxysm of coughing returns, now so severe that blood is expelled with force through the nose and through the mouth. Most frequently an upset stomach follows. . . . For we have seen so many coughing in such a manner, in whom after a vain attempt semiputrid matter in an incredible quantity was ejected. Opinions differ as to why a clinically characteristic disease like pertussis was not described prior to de Baillou's description. Kloos and colleagues (1981) suggest that the absence of a clinical description of pertussis prior to the sixteenth century may reflect adaptation of a close genetic variant of B. pertussis to humans as recently as five centuries ago. Holmes (1940), in contrast, as noted by Mortimer (1988), attributed the lack of a prior description to an earlier preoccupation of physicians with other serious infections such as plague, smallpox, and typhus and to the possibility that they may have relegated the care of pertussis patients to ''old women." The incubation period of unmodified pertussis averages 7 to 14 days, with a maximum of 21 days (Berkow, 1987). Clinically, pertussis can be divided into three sequential stages: the catarrhal, paroxysmal, and convalescent stages (Cherry et al., 1988; Mortimer, 1988). The onset of illness in the early catarrhal stage is subtle and is generally indistinguishable from that of a minor upper-respiratory infection. Early symptoms include rhinorrhea, mild conjunctival injection, sneezing, anorexia, listlessness, and a hacking nocturnal cough that gradually becomes diurnal as well. Fever is usually absent. During this time, coughing continues to increase in frequency and intensity and, by 7 to 10 days after the onset of illness, becomes explosive and episodic, heralding the onset of the paroxysmal stage. The disease is most infectious during the catarrhal stage, after which infectivity gradually declines. The paroxysmal stage, which lasts 1 to 4 weeks, is dominated by severe episodes of coughing, which can occur 10 times or more in a 24-hour period. Each paroxysm is characterized by five or more rapid short coughs followed by a deep hurried inspiration. It is this hurried inspiration through a narrowed airway that produces the characteristic whoop. Paroxysms are thought to be caused by efforts to expel the thick mucus that characteristically accumulates in the tracheobronchial tree. During such episodes, copious amounts of this mucus are expelled, often causing vomiting and, in infants, choking spells and cyanosis. The child is often exhausted following a paroxysm, although he or she can appear happy and relatively normal between episodes. Multiple paroxysms tend to occur within

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Page 11 a short period of time. A variety of stimuli, including feeding, sucking, or crying, can trigger an attack. Very young infants tend to have apneic spells rather than paroxysms of cough. The convalescent stage, which usually begins 4 to 6 weeks after the onset of disease, is characterized by a gradually diminishing frequency and severity of paroxysms. The whoop soon disappears, although a nonparoxysmal cough may persist for several months. Diagnosis B. pertussis can be cultured by inoculation of nasopharyngeal mucus, obtained by swab, on special agar such as Bordet-Gengou with added methicillin or Regan-Lowe with added cephalexin. A positive culture is diagnostic. False-negative cultures are common, particularly in persons receiving antibiotics (Berkow, 1987). B. pertussis can also be detected by direct immunofluorescence, although the test has been hampered by relatively frequent false-positive and false-negative results (Wirsing von König et al., 1990). Serologic tests, including enzyme-linked immunosorbent assays, to detect antibody to filamentous hemagglutinin (FHA) and other B. pertussis components are being developed for diagnostic purposes (Berkow, 1987; Storsaeter et al., 1990; Wirsing von König et al., 1990). Probing for Bordetella DNA, either directly or after preliminary amplification by the polymerase chain reaction or culture, may provide another useful means of detection (Wirsing von König et al., 1990). Complications Minor complications of pertussis include subconjunctival hemorrhages and epistaxis secondary to the paroxysmal coughing. Suppurative otitis media is a frequent complication, especially in infants (Mortimer, 1988). Major complications of pertussis can be fatal. They are divided into three general categories: respiratory, central nervous system (CNS), and nutritional. The most common are respiratory, including asphyxia in infants. Other severe respiratory complications include bronchopneumonia, a frequent complication in elderly people, atelectasis, bronchiectasis, interstitial and subcutaneous emphysema, and pneumothorax. CNS complications following pertussis include acute encephalitis that can progress to convulsions, stupor, and coma. Pathologic findings reveal cerebral hemorrhage and edema (Dolgopol, 1941). Long-term sequelae include spastic paralysis, mental retardation, or other permanent neurologic disorders. Rates of CNS complications differ widely among studies. For example, 1.7 to 7 percent or more of pertussis cases in large series of hospitalized children developed CNS complications (Zellweger, 1959), whereas

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Page 12 the incidence rates of encephalopathy3ranged from an estimated 0.08 per 1,000 cases in a case series collected from 1932 to 1946 in Brooklyn, New York (Litvak et al., 1948; Mortimer, 1988), to 0.8 per 1,000 cases in the National Childhood Encephalopathy Study (Alderslade, 1981). Current data from the Supplementary Pertussis Surveillance System (SPSS) of the U.S. Centers for Disease Control (CDC) indicate that of the 8,682 total cases reported to the CDC from 1986 to 1988, 0.7 percent were diagnosed with encephalopathy and 1.8 percent were diagnosed with seizures (Centers for Disease Control, 1990). The accuracy of these figures, however, is uncertain because the CDC estimates that only 5 to 10 percent of pertussis cases in the United States during this time period were captured by SPSS (Centers for Disease Control, 1990). Nutritional deficiencies seen with pertussis result directly from the inability of patients to retain feedings. Feeding precipitates paroxysms of coughing which in turn produces repeated vomiting (Mortimer, 1988). The combination of the disease and malnutrition can lead to death.  Descriptive Epidemiology Ecology of B. pertussis B. pertussis is transmitted by direct respiratory contact with infected persons in the catarrhal or early paroxysmal stage of disease (Berkow, 1987). Humans are the sole host. Indirect transmission by contact with the organism on fomites or on dust is rare (Mortimer, 1988). Pertussis is highly infectious; attack rates in nonimmunized populations have been reported to range from 25 to 50 percent in schools and from 70 to 100 percent in susceptible household contacts (Centers for Disease Control, 1985; Gordon and Hood, 1951; Kendrick, 1940; Linnemann, 1979). Epidemiologic and laboratory studies suggest that natural pertussis infection confers vigorous, long-lasting immunity (Gordon and Hood, 1951; Huang et al., 1962; Stallybrass, 1931). The chronic carrier state appears to be extremely rare and is not a factor in disease transmission (Cherry et al., 1988; Lambert, 1986; Linnemann et al., 1968). Pertussis is an epidemic disease, occurring every 2 to 5 years in endemic areas, with an average interval of 3.3 years (Cherry, 1984). No consistent seasonal pattern has 3 Encephalopathy as defined by Zellweger (1959) follows two clinical forms. "The first form begins suddenly with convulsions, followed by a state of unconsciousness or coma with varying neurological symptoms. In the second form, the onset is more insidious; the temperature rises within a few days to a high fever, even to hyperpyrexia, the patients become progressively somnolent, comatose and even unconscious. In this form convulsions, as well as other neurological symptoms, as paresis, hemiplegia, paraplegia, motor aphasia, and decerebrate rigidity may appear. Exceptionally pertussis encephalopathy imitates an acrodynia-like picture of a confused state" (Zellweger and Steinegger, 1950, pp. 381-382).

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Page 13 been identified (Friedlander, 1925; Kanai, 1980; Luttinger, 1916; Mortimer, 1988; Nelson, 1978). Distribution by Person Pertussis can occur at any age. Prior to mass immunization, an estimated 95 percent of people contracted pertussis during their lifetimes (Gordon and Hood, 1951), with 20 percent of cases seen in children under age 1 year and 60 percent occurring in children from ages 1 to 4 years (Luttinger, 1916). After the introduction of widespread immunization, age-specific attack rates shifted upward. The CDC's SPSS indicates that for the years 1986 to 1988, 46 percent of cases in the United States were reported in children less than age 1 year, with approximately 35 percent occurring in children less than age 6 months. Twenty-one percent of total cases were seen in children ages 1 to 4 years. Of the remaining cases, 16, 5, and 11 percent occurred in people ages 5 to 9, 10 to 14, and 15 years or older, respectively (Centers for Disease Control, 1990). It should be reiterated in reviewing these figures that the SPSS captures only an estimated 5 to 10 percent of pertussis cases in the United States (Centers for Disease Control, 1990). In light of the vagaries of pertussis detection and diagnosis, pertussis mortality and incidence rates worldwide substantially underestimate the true magnitude of the disease. Incidence rates of pertussis are consistently higher in females than they are in males across all geographic areas and ages, with the exception of children less that age 1 year. The excess of cases in females, which has been evident in both the pre- and postvaccination eras, differs from other communicable diseases of childhood, which tend to occur more frequently in males (Cherry, 1984; Gordon and Hood, 1951). With respect to race, incidence rates are similar in whites and nonwhites in the United States (Cherry et al., 1988). Mortality rates, like incidence rates, are highest in the first 6 months of life. The case fatality rate for infants less than age 6 months has been reported to be 0.5 percent (Centers for Disease Control, 1990). Case fatality rates, like attack rates, are reported to be higher in females than in males. The reasons for this are not clear (Cherry et al., 1988). Distribution by Place Pertussis continues to be a major cause of infant and child mortality in the developing world. World Health Organization (WHO) data collected in 1983 indicate that 600,000 of the 100 million children born annually in less developed countries die of pertussis or its complications (Grant, 1986). The following annual crude incidence rates were reported for 1982: 2 to 2,000 per 100,000 population in the WHO Africa region, <1 to 590 per 100,000 population in the Western Pacific region, and 0.25 to 85 per 100,000 population in the European region (Muller et al., 1986). The wide ranges in these statistics most likely reflect differ-

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Page 14 ences in reporting rates as well as in disease incidence. The crude incidence rate of pertussis in the United States in 1988 was estimated to be 1.4 per 100,000 population (Centers for Disease Control, 1990). Time Trends Mortality rates from pertussis in the industrialized world have declined significantly in the twentieth century. In Great Britain, at the turn of the century, approximately 1 in 1,000 children under age 15 years died of pertussis, with mortality rates being significantly higher among infants less than age 1 year. Rates then began to decline in the first few decades of the century and, by World War II, were approximately one-tenth of what they had been 40 years earlier (Department of Health and Social Security, 1976). Mortality rates declined even more rapidly in the postwar period, although epidemics of pertussis continued to occur (Department of Health and Social Security, 1981; Miller et al., 1982). Mortality from pertussis in the United States has also declined in the twentieth century. Mortality rates in the United States, like those in Great Britain, began to decline in the early decades of the century, declining more rapidly after World War II (Mortimer, 1980; Mortimer and Jones, 1979). Incidence rates also declined, leveling out in the early 1970s. Since then, age-adjusted incidence rates have fluctuated between 0.5 and 1.5 per 100,000 population (Centers for Disease Control, 1987). Nature of the Causative Organism, B. pertussis B. pertussis is a gram-negative pleomorphic bacillus. The genus Bordetella contains four species: B. pertussis, which is the agent responsible for human pertussis; B. parapertussis, which causes a mild pertussis-like syndrome in humans; B. bronchiseptica, which produces a respiratory illness in animals but can also infect humans; and B. avium, which causes a respiratory illness in birds (Kersters et al., 1984; Manclark and Cowell, 1984). Kloos and colleagues (1981) reported that the four species are genetically similar and may be more appropriately considered as biotypes of the same species. They further hypothesized that the lack of clinical description of pertussis prior to the sixteenth century may represent an adaptation of an earlier variant of B. pertussis from an animal to the human host (Kloos et al., 1981). B. pertussis contains many biologically active and antigenic factors (see Table 2-1). Although the effects of these various factors following natural infection or injection with killed B. pertussis bacilli have been examined in a number of studies in animals, understanding of the organism's biology and pathogenesis remains incomplete.

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Page 15 TABLE 2-1 Biologically Active and Antigenic Components of B. pertussisa Factor Location and Structure Biologic Functions Agglutinogens Protein surface antigens; multiple serotypes, some located in fimbriae (pili) Provide serologic markers for study of epidemiologic characteristics of pertussis; may play a role in the attachment of bacteria to ciliated cells; antibody to agglutinogens may contribute to protection against infection Filamentous hemagglutinin (FHA) A cell surface protein that is a hemagglutinin; it is liberated into fluid of statically grown broth cultures Important mediator of attachment of bacteria to ciliated epithelial cells; antibody to FHA may protect against infection of ciliated cells Pertussis toxin (PT), also called lymphocytosis-promoting factor, leukocytosispromoting factor, histamine-sensitizing factor, islet-activating protein, and pertussigen An envelope protein that is a hemagglutinin; it is liberated into the fluid of static or submerged cultures; fivesubunit structure A toxin with many biologic functions in animal models, e.g., histamine sensitization, lymphocytosis promotion, enhancement of insulin secretion, and adjuvant activity; antibody to PT is protective in intracerebral mouse protection test; it is probably a major virulence factor Adenylate cyclase Enzyme that is liberated into culture supernatants Has potential to interfere with phagocyte function Heat-labile toxin, also called dermonecrotic toxin, lethal toxin, or lienotoxin Heat-labile protein toxin found in the cytoplasmic fraction of cell lysates Causes skin necrosis in mice, rabbits, and guinea pigs and is lethal in mice after intravenous administration Endotoxin, also called lipopolysaccharide Envelope toxin Activities similar to those of endotoxins of other gram-negative bacteria Tracheal cytotoxin Small glycopeptide found in culture supernatants Causes ciliostasis and cytopathology of hamster tracheal epithelial cells in organ culture Hemolysin Unknown Hemolysin-deficient mutant was shown to have reduced virulence in mice Outer membrane protein  respiratory infection Outer membrane of organism Antibodies to this protein protect mice against a Modified from Cherry et al. (1988) and Mortimer (1988). Reproduced by permission of Pediatrics.

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Page 16 B. pertussis Virulence Factors and Pathogenesis of Whooping Cough When B. pertussis invades susceptible humans, the organism adheres to ciliated epithelial cells of the respiratory tract and multiples there without invading the tissues (Lapin, 1943; Pittman, 1970). Yet, this colonization leads to profound changes in tissues that persist long after the responsible bacteria have been cleared. Such observations suggest that a toxin or toxins from the bacteria play an important part in the pathogenesis of the syndrome. Among the putative pertussis toxins, the secreted pertussis toxin (PT) is currently considered the best candidate as a major virulence factor (Cherry et al., 1988; Mortimer, 1988; Pittman, 1979, 1984; Weiss and Hewlett, 1986). PT is now believed to be responsible for many of the characteristic activities attributed in the past to "toxins" in culture filtrates or cell lysates of B. pertussis. These include lymphocytosis, which is often seen in patients with whooping cough, increased sensitivity to shock on injection of histamine into mice (histamine-sensitizing factor), and hyperinsulinemia and hypoglycemia (islet-activating protein) (Pittman, 1984). PT is a protein composed of five linked subunits (S1, S2, S3, S4, and S5). The subunits S2 to S5 form a nontoxic unit that binds to the cell membrane; toxicity is mediated by the subunit S 1, which acts as an enzyme (Pizza et al., 1989). The activity of subunit S1 inhibits a subclass of proteins (G proteins) that are essential for transmission of biochemical messages from receptors on the cell surface to the intracellular machinery that permits the cell to function. Genetic engineering has been used to replace one or two key amino acids within the enzymatically active S1 subunit, resulting in a stable nontoxic form of PT. Such an agent has the potential to be used as a safe immunogen (Pizza et al., 1989). Other toxins have been proposed, but there is less experimental evidence to support the participation of these other toxins in the pathogenesis of pertussis. Two forms of the enzyme adenylate cyclase, one of which is released into culture fluids and the other of which is intracellular, are associated with B. pertussis (Confer and Eaton, 1982; Hewlett and Wolff, 1976; Hewlett et al., 1976; Weiss et al., 1984). The latter can be internalized by phagocytic cells and inhibit their function through elevation of intracellular cyclic adenosine monophosphate (Confer and Eaton, 1982). There is a lipopolysaccharide that possesses all of the usual properties of enterobacterial endotoxins, except that it is less pyrogenic on a weight basis (Chaby et al., 1979). It is present in whole-cell vaccines (Cameron, 1988; Pittman, 1984). A dermonecrotic toxin (Livey and Wardlaw, 1984; Nakase and Endoh, 1986) and a tracheal cytotoxin (Goldman et al., 1982) have been purified and studied in tissue culture or animals. Adherence of B. pertussis to respiratory epithelium is required for the pathogenesis of whooping cough (Pittman, 1970). Adherence appears to involve a bacterial outer membrane

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Page 17 protein with a molecular mass of 69 kilodaltons, termed the 69-kD outer membrane protein (Charles et al., 1989; Shahin et al., 1990). Injection of this protein into mice elicits a protective antibody response in a respiratory model (Charles et al., 1989). Two other bacterial surface structures have been proposed to play a role in the pathogenesis of whooping cough through the promotion of adherence to respiratory cilia. These are FHA (Sato et al., 1983) and serotype-specific agglutinogens (Preston et al., 1982). Immunization with cellular vaccines raises antibody to both of these (Pittman, 1984). Major Milestones in the Development of Pertussis Vaccines Whole-Cell Vaccines When the description of the Bordet-Gengou technique for isolating the pertussis bacterium was published (Bordet and Gengou, 1906), numerous researchers began to experiment with vaccines from killed whole-cell B. pertussis. Such vaccines were developed, and used in children, by Bordet and Gengou in 1912, Nicolle of the Pasteur Institute in Tunis in 1913, and Madsen of the Danish State Serum Institute in 1914, among others (Chase, 1982). By 1914, pertussis vaccine was listed in New and Nonofficial Remedies, a publication of the American Medical Association (Council on Pharmacy and Chemistry, 1914, 1931). Kendrick, of the State of Michigan Health Department, further refined and used whole-cell pertussis vaccines in children (Kendrick, 1942, 1943; Kendrick and Eldering, 1936, 1939). In 1942, Kendrick and colleagues combined her improved killed vaccine with diphtheria and tetanus toxoids to produce the diphtheria-pertussis-tetanus (DPT)4combination vaccine. In 1944, the Committee on Infectious Diseases of the American Academy of Pediatrics suggested routine use of pertussis vaccine and, in 1947, recommended its use in the form of the DPT combination (American Academy of Pediatrics, 1944; Cherry, 1984). During the 1940s and 1950s, vaccination of U.S. children against pertussis became a routine procedure. By the mid-1960s, many states had passed laws requiring that all children be vaccinated with the DPT vaccine prior to entry into school (Coulter and Fisher, 1985). For additional information on the development of pertussis whole-cell vaccines, see Appendix B, Pertussis and Rubella Vaccines: A Brief Chronology. Acellular Vaccines Acellular pertussis vaccines were developed in Japan, prompted by ad 4 Throughout this report, the acronym DPT has been adopted for the triple vaccine because of its historic usage. It is synonymous with DTP.

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Page 18 verse experiences with the whole-cell vaccine. Japan made pertussis vaccination mandatory in 1948, but it was not until 1950 that nationwide immunization was undertaken, using whole-cell vaccine (Kanai, 1980). By the early 1970s, the incidence of pertussis in Japan had fallen so precipitously that some questioned the need for continued routine immunization against the disease, especially given the occasional reports of adverse events following immunization (Kanai, 1980; Public Health Service, 1986). Several jurisdictions, in fact, abandoned pertussis immunization at about that time (Public Health Service, 1986). A vaccine injury compensation system was established in 1970. Within a 2-month period in 1974-1975, two Japanese infants died less than 24 hours after receiving the DPT vaccine (Hinman and Onorato, 1987; Public Health Service, 1986; Sato et al., 1984). Although investigators concluded that the whole-cell pertussis component of DPT had not caused the deaths, vaccination policy was affected by the occurrences. Use of the pertussis vaccine was suspended temporarily during the investigation, and when its use was resumed, recommendations were made to raise the age of first administration from 3 months to 2 years. In addition, the Japanese Ministry of Health and Welfare established a Pertussis Vaccine Study Group to facilitate research on an improved vaccine. Clinical trials of acellular vaccines began in 1979; routine use of the new vaccines was initiated in 1981 (Public Health Service, 1986). Two types of acellular pertussis vaccines, the B type and the T type, are currently manufactured and distributed in Japan. The B type is made up of lymphocytosis-promoting factor (LPF) and FHA in approximately equal amounts; the T type (which is used more frequently) consists of significantly more FHA than LPF and includes agglutinogens (Hinman and Onorato, 1987). The vaccination series is begun at age 2 years and consists of three consecutive doses given at 1-month intervals and a fourth dose given 1 year later. The T-type vaccine has been evaluated in several preliminary studies of immunogenicity and toxicity in the United States (Anderson et al., 1985; Edwards et al., 1986; Lewis et al., 1986; Pichichero et al., 1987; Rodgers and Badgett, 1985). Trials of the Japanese vaccines have also been carried out in Sweden (Blackwelder et al., 1988; Hallander and Mollby, 1988; National Institutes of Health, 1988). Clinical trials of acellular pertussis vaccines are in progress in the United States. Brief History of the Controversy Pertaining to Adverse Events Following Pertussis Vaccination Madsen, of the State Serum Institute in Copenhagen, Denmark, was the first to describe the use of whole-cell pertussis vaccine on a large scale (Madsen, 1925, 1933). His vaccine successfully controlled two outbreaks in the Faroe Islands. His 1933 account reported two deaths within 48 hours

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Page 19 of immunization, the first published report of serious adverse effects after pertussis vaccination. In the same year, Sauer of Northwestern University Medical School in Chicago described minor reactions to a whole-cell pertussis vaccine being used in the United States (Sauer, 1933a,b). In the late 1940s, the first published reports of irreversible or chronic neurologic damage following vaccination against pertussis appeared (Brody and Sorley, 1947; Byers and Moll, 1948). Brody and Sorley reported only one case, but their report led to the first warnings that pertussis vaccine should not be administered to those with a known neurologic disorder. In Britain in 1974, questions about the safety of pertussis vaccines were widely publicized in the popular press after newspaper accounts of a study suggesting adverse reactions (Kulenkampff et al., 1974), and an Association of Parents of Vaccine Damaged Children was formed (Alderslade et al., 1981). Between 1974 and 1978, the proportion of British children vaccinated against pertussis fell from 80 to 30 percent, on average, dropping as low as 9 percent in some areas (British Medical Journal, 1981). An epidemic of pertussis subsequently occurred; between 1977 and 1979, more than 100,000 cases and 36 deaths were reported (Koplan and Hinman, 1987). The controversy over the safety of pertussis vaccines reached the U.S. public in 1982, when the television program, "DPT: Vaccine Roulette," was first broadcast by NBC affiliate WRC-TV in Washington, D.C. The program depicted children with severe injury allegedly caused by pertussis vaccines (Griffith, 1989; Koplan and Hinman, 1987). Following broadcast of that program, an advocacy group, Dissatisfied Parents Together, was formed in the United States. Its members called for research toward a safer pertussis vaccine and mandatory reporting of adverse reactions. Some members of the group called for a cessation of the use of whole-cell vaccines (Coulter and Fisher, 1985; Koplan and Hinman, 1987). For additional information on the controversy surrounding pertussis wholecell vaccines, see Appendix B, Pertussis and Rubella Vaccines: A Brief Chronology. RUBELLA VACCINES Epidemiology of the Disease Rubella Clinical Description Rubella is commonly a mild disease; it afflicts children and young adults. It is characterized by an erythematous, maculopapular, discrete rash; postauricular and suboccipital lymphadenopathy; and minimal fever (American Academy of Pediatrics, 1986). The disease is caused by an RNA virus belonging to the togavirus family. It can be transmitted transplacentally to the fetus, sometimes with devastating results (Berkow, 1987).

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Page 21 (Berkow, 1987; Schlossberg and Topolsky, 1977), serious complications are few and rare. Encephalitis, occasionally resulting in death, and thrombocytopenia have been reported (Morse et al., 1966; Sherman et al., 1965), as have chronic arthralgia, arthritis, and polyneuritis (Ogra and Herd, 1971; Ogra et al., 1975; Schaffner et al., 1974). The latter vary in frequency with age and sex, being greatest in adult females and least in prepubertal children. Complications of congenital rubella are numerous and profound (see the section Clinical Description). A rare late syndrome of congenital rubella is rubella panencephalitis (Townsend et al., 1975; Weil et al., 1975). Descriptive Epidemiology Ecology of the Rubella Virus Rubella virus is spread by airborne droplet nuclei or by close contact. Rubella does not appear to be as contagious as certain other common viral childhood diseases are, as indicated by seroepidemiologic studies showing that even after explosive outbreaks, 10 to 20 percent of young adults may remain susceptible (Plotkin, 1988). However, under crowded conditions where the proportion of susceptible individuals is high, rubella can be highly infective (Brody, 1966; Grayston et al., 1972; Halstead et al., 1969). Exposure to rubella disease is believed to confer life-long immunity (Berkow, 1987). Humans are the sole host of the rubella virus, and subclinical cases are common. Virus has been shown to be present in nasopharyngeal secretions from 7 days before to 14 days after onset of the rash in postnatal cases. Infants with congenital rubella can shed the virus in nasopharyngeal secretions and urine for a year or more after birth (Cooper et al., 1965; Scheie et al., 1967). Distribution by Person Age at the time of infection varies geographically for postnatal rubella. In areas where living conditions are crowded, rubella tends to occur at an early age; in areas that are less crowded or that are isolated, such as island nations, rubella tends to occur at a later age, with a significant number of people remaining seronegative into young adulthood (Ingalls, 1967). Congenital rubella affects more infants of younger mothers than infants of older mothers, perhaps because the former are more likely to be seronegative (Plotkin, 1988). Distribution by Place Rubella occurs worldwide (Assaad and LjungarsEsteves, 1985; Cockburn, 1969). The disease is probably more common in areas where living conditions are crowded, although accurate incidence rates are difficult to obtain in the absence of seroepidemiologic confirmation, because many childhood cases are asymptomatic and therefore go undetected (Plotkin, 1988).

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Page 22 Little is known about the geographic distribution of congenital rubella in much of the developing world (Mingle, 1985; Seth et al., 1985), although incidence rates tend to vary at a given time according to the number of susceptible (seronegative) adult women and the presence of the virus (Plotkin, 1988). In the United States, prior to widespread vaccination, incidence rates of congenital rubella syndrome in nonepidemic years averaged 4 to 8 per 10,000 pregnancies (Williams and Preblud, 1984). A similar rate of 4.6 per 10,000 births was observed in the United Kingdom (Peckham, 1985). Time Trends Prior to mass immunization, rubella was both an endemic and an epidemic disease in the United States. The disease occurred year-round, but tended to peak in the spring.  Epidemics occurred at 7-year intervals (Witte et al., 1969). With the advent of mass immunization, rubella incidence rates declined by more than 95 percent compared with those in the prevaccination era, although isolated epidemics in susceptible groups have continued to occur (Cherry et al., 1988). Nature of the Rubella Virus The initial realization of the teratogenic potential of maternal rubella in the early 1940s spurred attempts to isolate and characterize the responsible agent. It was not until 1962, however, that Weller and Neva (1962) and Parkman and colleagues (1962) independently isolated the rubella virus; the latter group used the technique of interference with the growth of enteroviruses in African green monkey kidney tissue culture that was to become a standard method for virus isolation (Plotkin, 1988). The rubella virus was subsequently found to be a cubical, medium-sized, lipid-enveloped virus, ultimately classified in the togavirus family. The virus, in addition to its lipid envelope, is composed of three proteins, two in the envelope and one in the core (Pettersson et al., 1985). Upon infection, it replicates in the nasopharynx, from which it spreads to the local lymph nodes. During viremia, the placenta can be infected, leading to introduction of the virus into the fetal bloodstream and to the subsequent disruption of organogenesis (Alford et al., 1964; Naeye and Blanc, 1965; Plotkin et al., 1965a; Tondury and Smith, 1965). The exact pathologic mechanisms underlying the disruption of organogenesis are unclear (Plotkin, 1988), but they may, in part, involve inhibition of fetal cell mitosis by a soluble protein inhibitor (Naeye and Blanc, 1965; Plotkin and Vaheri, 1967; Plotkin et al., 1965a). Major Milestones in the Development of Rubella Vaccines In 1938, Hiro and Tasaka succeeded in transmitting rubella by inoculating healthy nonimmune children with filtrates taken from children with

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Page 23 active cases of rubella. The causative agent remained unidentified (Chase, 1982). By 1948, Burnet and colleagues were using gamma globulin from patients with rubella to confer short-term passive immunity on pregnant women recently exposed to rubella (Chase, 1982). The practice became common in a number of industrialized countries. In the early 1960s, the rubella virus was isolated by Weller and colleagues at the Harvard School of Public Health (Weller and Neva, 1962) and by Parkman and colleagues at the Walter Reed Army Institute of Research (Parkman et al., 1962). The rubella epidemic in Europe and the United States between 1962 and 1965 led to thousands of cases of congenital rubella syndrome and lent impetus to the search for a vaccine (Chase, 1982; Plotkin, 1988). Between 1965 and 1967, several vaccines made from attenuated rubella strains were developed and tested in clinical trials (Plotkin, 1988). Three rubella vaccines were licensed in the United States in 1969-1970 and became widely used: HPV-77 (high passage virus) grown in dog kidney, HPV-77 grown in duck embryo, and Cendehill grown in rabbit kidney (Plotkin, 1988). A human diploid fibroblast vaccine, RA 27/3, also developed in the United States in the 1960s, was first licensed in Europe and came to be used extensively in the United Kingdom, France, Switzerland, and Italy. It was not licensed in the United States until 1979. By that time, the manufacturers of the dog kidney and Cendehill strains had left the U.S. market. In 1979, Merck Sharp & Dohme, the only remaining manufacturer of the duck embryo vaccine in the United States, began making and selling RA 27/3 instead. It has been the only rubella vaccine manufactured or distributed in the United States since that time. Although the rates of rubella and congenital rubella syndrome dropped dramatically after the introduction of rubella vaccines, medical policymakers in the United States became convinced by the late 1970s that to eradicate rubella and congenital rubella syndrome entirely, it would be advisable to vaccinate women of childbearing years as well as young children (Preblud, 1985; Tingle, 1990). Recommendations were made that women be vaccinated for rubella postpartum, and that female medical and health-care workers be vaccinated. Some institutions began to require such immunization for female health-care professionals; some universities also started to require immunization for female students. For additional information on the development of rubella vaccines, see Appendix B, Pertussis and Rubella Vaccines: A Brief Chronology. Brief History of the Controversy Pertaining to Adverse Events Following Rubella Vaccination Two types of adverse events after rubella immunization have primarily been reported. Postvaccination neuropathies were observed in children early in the experience with the vaccine. Between 1970 and 1974, a number of

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Page 24 reports described two temporary conditions that came to be known as the "arm syndrome" and the "leg syndrome" (or the "catcher's crouch syndrome") (Gilmartin et al., 1972; Kilroy et al., 1970; Schaffner et al., 1974). Evidence indicated that these events were especially likely to occur with the dog kidney vaccine (e.g., Grand et al., 1972; Kilroy et al., 1970). Such reports contributed to the decision to license RA 27/3 in the United States and to the withdrawal of the other vaccine strains from distribution in the United States and a number of other countries (Plotkin, 1988). Acute arthralgia and arthritis following vaccination were also reported in the earliest studies of rubella vaccines (American Journal of Diseases of Children, 1969; Barnes et al., 1972; Horstmann et al., 1970; Lerman et al., 1971; Spruance and Smith, 1971). All rubella vaccine strains have been associated, to some extent, with reactions in the joints. Again, the HPV-77 dog kidney vaccine appeared to be most often associated with such events (Barnes et al., 1972; Spruance and Smith, 1971), but other strains, including RA 27/3, have been implicated as well (Fox et al., 1976; Freestone et al., 1971; Horstmann et al., 1970; Lerman et al., 1971; Rowlands and Freestone, 1971; Swartz et al., 1971; Tingle et al., 1979, 1985, 1986; Weibel et al., 1972). It has been reported that arthritis, arthralgia, and other joint disorders are observed with greater frequency after natural rubella infection than after administration of rubella vaccine (Tingle, 1990). The incidence of arthritis and arthralgia following rubella vaccination, as is the case with natural rubella infection, is low in infants and young children, but is higher and more severe in adults (Best et al., 1974; Dudgeon et al., 1969; Polk et al., 1982). There are reports of chronic, severe arthritis and related conditions in postadolescent women who have received the vaccine (Tingle et al., 1979, 1985, 1986). Some have charged that results of prelicensure clinical trials carried out primarily in children were improperly generalized to adults, leading to the assumption that the vaccine is safe for adults as well (Hatem, 1990; Tingle, 1990). A randomized, double-blind, placebo-controlled trial of rubella vaccine and chronic arthritis is currently in progress in Vancouver, British Columbia, Canada (A. Tingle, British Columbia Children's Hospital, personal communication, 1991).   In addition, as of April 1991, the CDC is considering issuing a request for proposals for a study of chronic arthritis following rubella vaccination that would include detailed laboratory studies of participants. REFERENCES Alderslade R, Bellman MH, Rawson NSB, Ross EM, Miller DL. 1981. The National Childhood Encephalopathy Study: a report on 1000 cases of serious neurological disorders in infants and young children from the NCES research team. In: Whooping Cough: Reports from the Committee on the Safety of Medicines and the Joint Committee on Vaccination

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Page 25 and Immunisation. Department of Health and Social Security. London: Her Majesty's Stationery Office. Alford CA, Griffiths PD. 1983. Rubella. In: Remington JS, Klein JE, eds. Infectious Diseases of the Fetus and Newborn Infant. Philadelphia: W.B. Saunders Co. Alford CA, Neva, FA, Weller TH. 1964. Virologic and serologic studies on human products of conception after maternal rubella. New England Journal of Medicine 271:1275-1281. American Academy of Pediatrics. 1944. Report of the Committee on Infectious Diseases: Pertussis. Evanston, IL: American Academy of Pediatrics. American Academy of Pediatrics. 1986. The Red Book. Report of the Committee on Infectious Diseases, 20th edition. Peter G, ed. Elk Grove Village, IL: American Academy of Pediatrics. American Journal of Diseases of Children. 1969. International conference on rubella immunization. 118:1-410. Anderson EL, Belshe RB, Bartram J. 1985. Clinical evaluation of acellular pertussis DT vaccine in young children. Abstract E27. Presented at the 85th Annual Meeting of the American Society for Microbiology, Las Vegas. Aoyama T, Goto R, Iwai H, Murase Y, Iwata T. 1990. Pertussis in the adult. In: Manclark CR, ed. Sixth International Symposium on Pertussis, Abstracts. DHHS Publication No. (FDA) 90-1162. Bethesda, MD: Public Health Service, U.S. Department of Health and Human Services. Assaad F, Ljungars-Esteves L. 1985. Rubella—world impact. Reviews of Infectious Diseases 7:S29-S36. Barnes EK, Altman R, Austin SM, Dougherty WJ. 1972. Joint reactions in children vaccinated against rubella: comparison of three vaccines. American Journal of Epidemiology 95:59-66. Berkow R, ed. 1987. Pertussis. Merck Manual of Diagnosis and Therapy, 15th edition. Rahway, NJ: Merck Sharpe & Dohme Research Laboratories. Best JM, Banatvala JE, Bowen JM. 1974. New Japanese rubella vaccine: comparative trials. British Medical Journal 3:221-224. Blackwelder W, Olin P, Storsaeter J. 1988. Efficacy trial in Sweden: design and results. Presented at NIAID/FDA/CDC/USAID Status of Acellular Pertussis Vaccines—Swedish Trial Update, Bethesda, MD, February 8-9, 1988. Bordet J, Gengou O. 1906. Le microbe de la coqueluche. Annales Institut Pasteur 20:731-741. British Medical Journal. 1981. Pertussis vaccine (editorial). 282:1563-1564. Brody JA. 1966. The infectiousness of rubella and the possibility of reinfection. American Journal of Public Health 56:1082-1087. Brody M, Sorley RG. 1947. Neurologic complications following administration of pertussis vaccine. New York State Journal of Medicine 47:1016-1017. Byers RK, Moll FC. 1948. Encephalopathies following prophylactic pertussis vaccination. Pediatrics 1:437-457. Cameron J. 1988. Evolution of control testing of pertussis vaccines. In: Wardlaw AC, Parton R, eds. Pathogenesis and Immunity in Pertussis. New York: John Wiley & Sons. Centers for Disease Control. 1985. Diphtheria, tetanus and pertussis: guidelines for vaccine prophylaxis and other preventive measures. Morbidity and Mortality Weekly Report 34:405-414, 419-426. Centers for Disease Control. 1987. Pertussis. Morbidity and Mortality Weekly Report 36:168-171. Centers for Disease Control. 1990. Pertussis surveillance—United States, 1986-1988. Morbidity and Mortality Weekly Report 39:57-65. Chaby R, Ayme G, Caroff M, Donikian R, Haeffner-Cavaillon N, Le Dur A, Moreau M, Mynard MC, Roumiantzeff M, Szabo L. 1979. Structural features and separation of some of

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Page 26 the biological activities of the Bordetella pertussis endotoxin by chemical fractionation. In: Manclark CR, Hill JC. International Symposium on Pertussis. U.S. Department of Health, Education, and Welfare Publication No. (NIH) 79-1830. Washington, DC: U.S. Government Printing Office. Charles IG, Dougan G, Pickard D, Chatfield S, Smith M, Novotny P, Morrissey P, Fairweather NF. 1989. Molecular cloning and characterization of protective outer membrane protein P69 from Bordetella pertussis. Proceedings of the National Academy of Sciences 86:3554-3558. Chase A. 1982. Magic Shots: A Human and Scientific Account of the Long and Continuing Struggle to Eradicate Infectious Diseases by Vaccination. New York: William Morrow and Co., Inc. Cherry JD. 1984. The epidemiology of pertussis and pertussis immunization in the United Kingdom and the United States: a comparative study. Current Problems in Pediatrics 14:1-78. Cherry JD, Brunell PA, Golden GS, Karzon DT. 1988. Report of the task force on pertussis and pertussis immunization—1988. Pediatrics 81(6, part 2):939-984. Cockburn WC. 1969. World aspects of the epidemiology of rubella. American Journal of Diseases of Children 118:112-122. Confer DL, Eaton JW. 1982. Phagocytic impotence by an invasive bacterial adenylate cyclase. Science 217:948-950. Cooper LZ, Green TH, Krugman S, Giles JP, Mirick GS. 1965. Neonatal thrombocytopenic purpura and other manifestations of rubella contracted in utero. American Journal of Diseases of Children 110:416-428. Cooper LZ, Ziring PR, Ockerse AB, Fedun BA, Kiely B, Krugman S. 1969. Rubella: clinical manifestations and management. American Journal of Diseases of Children 118:18-29. Coulter HL, Fisher BL. 1985. DPT: A Shot in the Dark. San Diego: Harcourt Brace Jovanovich. Council on Pharmacy and Chemistry. 1914. New and Nonofficial Remedies. Chicago: American Medical Association. Council on Pharmacy and Chemistry. 1931. Pertussis vaccines omitted from N.N.R. Journal of the American Medical Association 96:613. Department of Health and Social Security. 1976. Prevention and Health: Everybody's Business. London: Her Majesty's Stationery Office. Department of Health and Social Security. 1981. Whooping Cough: Reports from the Committee on Safety of Medicines and the Joint Committee on Vaccination and Immunisation. London: Her Majesty's Stationery Office. Dolgopol VB. 1941. Changes in the brain in pertussis with convulsions. Archives of Neurolology and Psychiatry 46:477-503. Dudgeon JA, Marshall WC, Peckham CS. 1969. Rubella vaccine trials in adults and children. American Journal of Diseases of Children 118:237-242. Edwards KM, Lawrence EM, Wright PF. 1986. Diphtheria, tetanus, and pertussis vaccine: a comparison of the immune response and adverse reactions to conventional and acellular pertussis components. American Journal of Diseases of Children 140:867-871. Farizo KM, Cochi SL, Zell R, Patriarca PA, Wassilak S, Brink EW. 1990. Perspectives on the epidemiology of pertussis in the United States, 1980-88. In: Manclark CR, ed. Sixth International Symposium on Pertussis, Abstracts. DHHS Publication No. (FDA) 90-1162. Bethesda, MD: Public Health Service, U.S. Department of Health and Human Services. Fox JP, Rainey HS, Hall CE, Ray CG, Patterson MJ. 1976. Rubella vaccine in postpubertal women: experience in western Washington state. Journal of the American Medical Association 236:837-843. Freestone DS, Prydic J, Hamilton-Smith SG, Laurence G. 1971. Vaccination of adults with Wistar RA27/3 rubella vaccine. Journal of Hygiene 69:471-477. Friedlander A. 1925. Whooping cough. In: Abt IA, ed. Pediatrics. Philadelphia: W.B. Saunders Co.

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Page 27 Gilmartin RC, Jabbour JT, Duenas DA. 1972. Rubella vaccine myeloradiculoneuritis. Journal of Pediatrics 80:406-412. Goldman WE, Klapper DG, Baseman JB. 1982. Detection, isolation, and analysis of a released Bordetella pertussis product toxic to cultured tracheal cells. Infection and Immunity 36:782-794. Gordon JE, Hood RI. 1951. Whooping cough and its epidemiological anomalies. American Journal of Medical Science 222:333-361. Grand MG, Wyll SA, Gehlbach SH, Landrigan PJ, Judelsohn RG, Zendel SA, Witte JJ. 1972. Clinical reactions following rubella vaccination. Journal of the American Medical Association 220:1569-1572. Grant JP. 1986. Immunization leads the way. In: State of the World's Children 1986. UNICEF. Oxford: Oxford University Press. Grayston JT, Gale JL, Watten RH. 1972. The epidemiology of rubella on Taiwan: introduction and description of the 1957-1958 epidemic. International Journal of Epidemiology 1:245-265. Greenberg M, Pellitteri O, Barton J. 1957. Frequency of defects in infants whose mothers had rubella during pregnancy. Journal of the American Medical Association 165:675-678. Gregg NM. 1941. Congenital cataract following German measles in the mother. Transactions of the Ophthalmological Society of Australia 3:35-46. Griffith AH. 1989. Permanent brain damage and pertussis vaccination: is the end of the saga in sight? Vaccine 7:199-210. Hallander H, Mollby R. 1988. Serologic results from efficacy trial. Presented at the NIAID/ FDA/CDC/USAID Workshop on the Status of Acellular Pertussis Vaccines—Swedish Trial Update, Bethesda, MD, February 8-9, 1988. Halstead SB, Diwan AR, Oda AI. 1969. Susceptibility to rubella among adolescents and adults in Hawaii. Journal of the American Medical Association 210:1881-1883. Hatem J. 1990. Review of prelicensing studies of RA27/3 vaccine. Unpublished. Hewlett E, Wolff J. 1976. Soluble adenylate cyclase from culture medium of Bordetella pertussis: purification and characterization. Journal of Bacteriology 127:890-898. Hewlett EL, Urban MA, Manclark CR, Wolff J. 1976. Extracytoplasmic adenylate cyclase of Bordetella pertussis. Proceedings of the National Academy of Sciences 73:1926-1930. Hinman AR, Onorato IM. 1987. Acellular pertussis vaccines. Pediatric Infectious Disease Journal 6:341-343. Holmes WH. 1940. Bacillary and Rickettsial Infections. New York: The Macmillan Co. Horstmann DM, Liebhaber H, Kohorn EI. 1970. Post-partum vaccination of rubella-susceptible women. Lancet 2:1003-1006. Huang CC, Chen PM, Kuo JK, Chiu WH, Lin ST, Lin HS, Lin YC. 1962. Experimental whooping cough. New England Journal of Medicine 266:105-111. Ingalls TH. 1967. The epidemiology of rubella. American Journal of Medical Science 253:349-356. Kanai K. 1980. Japan's experience in pertussis epidemiology and vaccination in the past thirty years. Japanese Journal of Medical Science and Biology 33:107-143. Kendrick P. 1940. Secondary familial attack rates from pertussis in vaccinated and unvaccinated children. American Journal of Hygiene 32:89-91. Kendrick P. 1942. Use of alum-treated pertussis vaccine, and of alum-precipitated combined pertussis vaccine and diphtheria toxoid, for active immunization. American Journal of Public Health 32:615-626. Kendrick P. 1943. A field study of alum-precipitated combined pertussis vaccine and diphtheria toxoid for active immunization. American Journal of Hygiene 38:193-202. Kendrick P, Eldering G. 1936. Progress report on pertussis immunization. American Journal of Public Health 26:8-12.

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Page 28 Kendrick P, Eldering G. 1939. A study in active immunization against pertussis. American Journal of Hygiene 29:133-153. Kersters K, Hinz KH, Hertle A, Segers P, Lievens A, Siegmann O, de Ley J. 1984. Bordetella avium sp. nov., isolated from the respiratory tracts of turkeys and other birds. International Journal of Systematic Bacteriology 34:56-70. Kilroy AW, Schaffner W, Fleet WF, Lefkowitz LB, Karzon DT, Fenichel GM. 1970. Two syndromes following rubella immunization: clinical observations and epidemiological studies. Journal of the American Medical Association 214:2287-2292. Kloos WE, Mohapatra N, Dobrogosz WJ, Ezzell JW, Manclark CR. 1981. Deoxyribonucleotide sequence relationships among Bordetella species. International Journal of Systematic Bacteriology 31:173-176. Koplan JP, Hinman AH. 1987. Decision analysis, public policy, and pertussis: are they compatible? Medical Decision Making 7:72-73. Kulenkampff M, Schwartzman JS, Wilson J. 1974. Neurological complications of pertussis inoculation. Archives of Disease in Childhood 49:46-49. Lambert HP. 1986. The carrier state: Bordetella pertussis. Journal of Antimicrobial Chemotherapy 18(Suppl. A):13-16. Lapin JH. 1943. Whooping Cough. Springfield, IL: Charles C Thomas. Lerman SJ, Nankervis GA, Heggie AJ, Gold E. 1971. Immunologic response, virus excretion and joint reactions with rubella vaccine. Annals of Internal Medicine 74:67-73. Lewis K, Cherry JD, Holroyd J, Baker LR, Dudenhoeffer FE, Robinson RG. 1986. A doubleblind study comparing an acellular pertussis-component DTP vaccine in 18-month old children. American Journal of Diseases of Children 140:872-876. Linnemann CC Jr. 1979. Host-parasite interactions in pertussis. In: Manclark CR, Hill JC, eds. International Symposium on Pertussis. U.S. Department of Health, Education, and Welfare Publication No. (NIH) 79-1830. Washington, DC: U.S. Government Printing Office. Linnemann CC, Bass JW, Smith MHD. 1968. The carrier state of pertussis. American Journal of Epidemiology 88:422-427. Litvak AM, Gibel H, Rosenthal SE, Rosenblatt P. 1948. Cerebral complications in pertussis. Journal of Pediatrics 32:357-379. Livey I, Wardlaw AC. 1984. Production and properties of Bordetella pertussis heat-labile toxin. Journal of Medical Microbiology 17:91-103. Lundstrom R. 1962. Rubella during pregnancy: a follow-up study of children born after an epidemic of rubella in Sweden, 1951, with additional investigations on prophylaxis and treatment of maternal rubella. Acta Paediatrica Scandinavica 133(Suppl.):1-110. Luttinger P. 1916. The epidemiology of pertussis. American Journal of Diseases of Children 12:290-315. Madsen T. 1925. Whooping cough: its bacteriology, diagnosis, prevention, and treatment. Boston Medical and Surgical Journal 192:50-60. Madsen T. 1933. Vaccination against whooping cough. Journal of the American Medical Association 101:187-188. Manclark CR, Cowell JL. 1984. Pertussis. In: Germanier R, ed. Bacterial Vaccines. New York: Academic Press. Manson MM, Logan WPD, Loy RM. 1960. Rubella and other virus infections during pregnancy. Ministry of Health, Report on Public Health and Mechanical Subjects, No. 101. London: Her Majesty's Stationery Office. Miller DL, Alderslade R, Ross EM. 1982. Whooping cough and whooping cough vaccine: the risks and benefits debate. Epidemiologic Reviews 4:1-24. Mingle JAA. 1985. Frequency of rubella antibodies in the population of some tropical African countries. Reviews of Infectious Diseases 7:S68-S71. Morse EE, Zinkham WH, Jackson DP. 1966. Thrombocytopenic purpura following rubella infection in children and adults. Archives of Internal Medicine 117:573-579.

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Page 29 Mortimer EA. 1980. Pertussis immunization. Problems, perspectives, prospects. Hospital Practice 15:103-118. Mortimer EA. 1988. Pertussis vaccine. In: Plotkin SA, Mortimer EA, eds. Vaccines. Philadelphia: W.B. Saunders Co. Mortimer EA, Jones PK. 1979. An evaluation of pertussis vaccine. Reviews of Infectious Diseases 1:927-934. Muller AS, Leeuwenburg J, Pratt DS. 1986. Pertussis: epidemiology and control. Bulletin of the World Health Organization 64:321-331. Naeye RL, Blanc W. 1965. Pathogenesis of congenital rubella. Journal of the American Medical Association 194:1277-1283. Nakase Y, Endoh M. 1986. Bordetella heat-labile toxin: further purification, characterization and its mode of action. Proceedings of the Fourth International Symposium on Pertussis, Geneva, 1984. Developments in Biological Standardization 61:93-102. National Institutes of Health. 1988. Status of Acellular Pertussis Vaccines & Swedish Trial Update: Transcript of a Workshop. Bethesda, MD, February 8-9, 1988. Nelson JD. 1978. The changing epidemiology of pertussis in young infants: the role of adults as reservoirs of infection. American Journal of Diseases of Children 132:371-373. Ogra PL, Herd JK. 1971. Arthritis associated with induced rubella infection. Journal of Immunology 107:810-813. Ogra PL, Chiba Y, Ogra SS, Dzierba JL. 1975. Rubella-virus infection in juvenile rheumatoid arthritis. Lancet 1:1157-1161. Parkman PD, Beuscher EL, Artenstein MS. 1962. Recovery of rubella virus from army recruits. Proceedings of the Society of Experimental Biology and Medicine 11 1:225-230. Peckham C. 1985. Congenital rubella in the United Kingdom before 1970: the prevaccine era. Reviews of Infectious Diseases 7:S11-S16. Pettersson RF, Oker-Blom C, Kalkkinen N, Kallio A, Ulmanen I, Kaariainen L, Partenen P, Vaheri A. 1985. Molecular and antigenic characteristics and synthesis of rubella virus structural proteins. Reviews of Infectious Diseases 7:S140-S149. Pichichero ME, Badgett JT, Rodgers GC, McLinn S, Trevino-Scatterday B, Nelson JD. 1987. Acellular pertussis vaccine: immunogenicity and safety of an acellular pertussis vs. a whole cell pertussis vaccine combined with diphtheria and tetanus toxoids as a boster in 18- to 24-month old children. Pediatric Infectious Disease Journal 6:352-363. Pitt D, Keir EH. 1965. Results of rubella in pregnancy. Medical Journal of Australia 2:647-651. Pittman M. 1970. Bordetella pertussis—bacterial and host factors in the pathogenesis and prevention of whooping cough. In: Mudd S, ed. Infectious Agents and Host Reactions. Philadelphia: W.B. Saunders Co. Pittman M. 1979. Pertussis toxin: the cause of the harmful effects and prolonged immunity of whooping cough: a hypothesis. Reviews of Infectious Diseases 1:401-412. Pittman, M. 1984. The concept of pertussis as a toxin-mediated disease. Pediatric Infectious Diseases 3:467-486. Pizza M, Covacci A, Bartoloni A, Perugini M, Nencioni L, De Magistris MT, Villa L, Nucci D, Manetti R, Bugnoli M, Giovannoni F, Olivieri R, Barbieri JT, Sato H, Rappuoli R. 1989. Mutants of pertussis toxin suitable for vaccine development. Science 246:497-500. Plotkin SA. 1988. Rubella vaccine. In: Plotkin SA, Mortimer EA, eds. Vaccines. Philadelphia: W.B. Saunders Co. Plotkin SA, Vaheri A. 1967. Human fibroblasts infected with rubella virus produce a growth inhibitor. Science 156:659-661. Plotkin SA, Boue A, Boue JG. 1965a. The in vitro growth of rubella virus in human embryo cells. American Journal of Epidemiology 81:71-85. Plotkin SA, Oski FA, Hartnett EM, Hervada AR, Friedman S, Gowing J. 1965b. Some recently recognized manifestations of the rubella syndrome. Journal of Pediatrics 67:182-191.

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