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Adverse Effects of Pertussis and Rubella Vaccines (1991)

Chapter: 2 Histories of Pertussis and Rubella Vaccines

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Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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.

Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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

Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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

Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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).

Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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-

Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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.

Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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.

Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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

Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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.

Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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

Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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).

Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Rubella was first clinically differentiated from other exanthematous illnesses by German physicians in the late eighteenth century, hence its popular name, German measles. The Latin term rubella, or ''little red," was coined by a British physician who reported on an epidemic of the disease among schoolboys in India in 1841 (Veale, 1866). Rubella subsequently evoked little interest in the medical community until 1941, when a report appeared associating congenital cataracts with maternal exposure to the disease during pregnancy (Gregg, 1941). A flurry of subsequent reports confirmed this association and further noted increased risks of congenital heart disease and deafness following maternal exposure to the disease, thus establishing the classical congenital rubella triad (Greenberg et al., 1957; Lundstrom, 1962; Manson et al., 1960; Pitt and Keir, 1965). Intrauterine rubella exposure is now known to be associated with a wide variety of abnormalities, including, for example, encephalitis, mental retardation, glaucoma, thrombocytopenic purpura, hypoplastic right heart, and diabetes (Alford and Griffiths, 1983; Cooper et al., 1969; Plotkin et al., 1965b).

The incubation period of rubella is 14 to 21 days, with the characteristic rash appearing within 14 to 17 days after exposure. The patient is usually asymptomatic in the first week after exposure.  By early in the second week, lymphadenopathy becomes apparent and rubella virus can usually be cultured from nasopharyngeal secretions. By the end of the second week, virus is detectable in the blood. After the 14- to 21-day incubation period, a 1- to 5-day prodromal illness consisting of malaise, low-grade fever, mild conjunctivitis, and, occasionally, arthralgia can occur, but it may be minimal or absent. The rash, in most cases, appears at this time, beginning on the face and neck and spreading quickly to the trunk and extremities. It usually lasts for about 5 days (Cherry et al., 1988; Plotkin, 1988).

Diagnosis

Diagnosis of rubella can be made in several ways. Virus can be most consistently isolated by inoculation of appropriate tissue culture media with nasal secretions. Virus can also be isolated from the throat, blood, urine, and cerebrospinal fluid, particularly in congenitally infected infants. Serologic testing of acute- and convalescent-phase serum is also useful in diagnosis, with seroconversion indicating infection. Diagnosis based on history of German measles or on clinical findings is unreliable without laboratory confirmation, because other viral exanthems mimic rubella.

Complications

Although a number of acute, transient sequelae of postnatal rubella, including polyarthralgia, polyarthritis, and testicular pain, have been noted

Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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(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).

Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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

Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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

Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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.

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Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page 21
Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Page 22
Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page 23
Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page 24
Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page 25
Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page 26
Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page 27
Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page 28
Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page 29
Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page 30
Suggested Citation:"2 Histories of Pertussis and Rubella Vaccines." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Next: 3 Methodologic Considerations in Evaluating the Evidence »
Adverse Effects of Pertussis and Rubella Vaccines Get This Book
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Parents have come to depend on vaccines to protect their children from a variety of diseases. Some evidence suggests, however, that vaccination against pertussis (whooping cough) and rubella (German measles) is, in a small number of cases, associated with increased risk of serious illness.

This book examines the controversy over the evidence and offers a comprehensively documented assessment of the risk of illness following immunization with vaccines against pertussis and rubella. Based on extensive review of the evidence from epidemiologic studies, case histories, studies in animals, and other sources of information, the book examines:

  • The relation of pertussis vaccines to a number of serious adverse events, including encephalopathy and other central nervous system disorders, sudden infant death syndrome, autism, Guillain-Barre syndrome, learning disabilities, and Reye syndrome.
  • The relation of rubella vaccines to arthritis, various neuropathies, and thrombocytopenic purpura.

The volume, which includes a description of the committee's methods for evaluating evidence and directions for future research, will be important reading for public health officials, pediatricians, researchers, and concerned parents.

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