9
Haemophilus influenzae Type b Vaccines

BACKGROUND AND HISTORY

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

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



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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 9 Haemophilus influenzae Type b Vaccines BACKGROUND AND HISTORY Prior to the introduction of Haemophilus influenzae type b (Hib) vaccines, Hib was the leading cause of bacterial meningitis in the United States among children younger than 4 years of age. Each year, an estimated 10,000 cases of Hib meningitis and 5,000 cases of other severe Hib infections occurred, including pneumonia, septic arthritis, epiglottitis, periorbital cellulitis, and facial cellulitis (Schlech et al., 1985; Todd and Bruhn, 1975). The cumulative incidence of invasive Hib disease in the first 5 years of life in the United States was estimated to be approximately 1 case per 200 children. The mortality rate for children with meningitis was 3 to 6 percent, and 20 to 30 percent of survivors had permanent sequelae, including hearing loss, mental retardation, and seizure disorders (Cochi et al., 1985). Nearly 75 percent of cases of Hib disease occurred in children younger than 2 years of age, and the susceptibility of young children to infection with Hib correlated with their lack of antibody to the type b capsular polysaccharide, polyribosylribitol phosphate (PRP) (Ward and Cochi, 1988). In the 1970s, a vaccine composed of purified PRP, the plain polysaccharide vaccine, was prepared and was found to be immunogenic in adults and older children. However, responsiveness to PRP was highly age dependent. The vaccine was without protective efficacy in children less than 18 months of age and was of variable efficacy even when given at 2 years of age (Black et al., 1988; Harrison et al., 1988; Osterholm et al., 1988; Peltola et al., 1984; Shapiro et al., 1988). In addition to variable estimates of vaccine

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality efficacy, several investigators noted a possible increased incidence of disease in the immediate postimmunization period (less than 7 days) (Black et al., 1988; Harrison et al., 1988; Osterholm et al., 1988; Shapiro et al., 1988). In the 1980s, several groups of investigators developed the first Hib polysaccharide-protein conjugate vaccines. Enhancement of the immunogenicity of carbohydrate antigens by chemical conjugation with proteins had been reported in 1929 by Avery and Goebel, but the idea had not been previously applied to the development of vaccines for human use. The Hib conjugate vaccines prepared by Schneerson et al. (1980), Gordon (1984), and Anderson (1983) showed enhanced immunogenicity and T-cell-dependent characteristics, that is, responses in immature animals, booster responses, predominance of immunoglobulin G (IgG) antibodies, and priming by prior carrier immunization. A series of Hib conjugate vaccines was developed, tested, and licensed in the late 1980s. These vaccines differ in the molecular size of the Hib polysaccharide, the protein used as the carrier, and the methods used to link the polysaccharide to the protein (Table 9-1). Thus, in consideration of the side effects of Hib conjugate vaccines, it is plausible that variations in the type or frequency of adverse effects may occur because of differences in the polysaccharide or protein components of the vaccines. Routine immunization of infants with Hib conjugate vaccine in a multiple-dose schedule is now recommended in the United States (American Academy of Pediatrics, Committee on Infectious Diseases, 1991b; Centers for Disease Control, 1991a). Because of the need to provide protective immunity during the high-risk period of infancy and for parental convenience, Hib conjugate vaccines are given simultaneously with diphtheria and tetanus toxoids and pertussis vaccine (DPT) and polio vaccines. The efficacies of these schedules on the basis of the results of prelicensure trials were estimated to be greater than 90 percent for PRP-outer membrane protein vaccine (PRP-OMP) in Navajo infants when given at 2 and 4 months of age (Santosham et al., 1992) and 100 percent after three doses of oligosaccharide conjugate Hib (HbOC) vaccine given at 2, 4, and 6 months of age (Black et al., 1992a). A new Hib conjugate vaccine, PRP conjugated to tetanus toxoid (PRP-T), was licensed on March 30, 1993 (Centers for Disease Control and Prevention, 1993). The immunogenicity of this vaccine in infants immunized at ages 2, 4, and 6 months is similar to that of previously licensed Hib conjugate vaccines (Decker et al., 1992). Although controlled trials of the efficacy of PRP-T in the United States had to be terminated because of licensure of other conjugate vaccines, no cases of invasive disease were detected in approximately 100,000 infants given two or more doses in these and other studies (Fritzell and Plotkin, 1992; Greenberg et al., 1991), and a controlled trial in the Oxford region of the United King-

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality TABLE 9-1 Characteristics of Hib Vaccines Vaccine, (producer, trade name) Polysaccharide Protein Carrier Age of Administration (date of licensure) PRP       (Praxis, b Capsa 1; Lederle, HibImmune; Connaught, HibVAX) ''Native'' None >24 mo (4/85)a (>18 mo if high risk) PRP-D (Connaught, ProHiBit) Medium Diphtheria toxoid 18 mo (12/22/87)b 15 mo (12/89)c HbOC (Lederie-Praxis, Hib-TITER) Small CRM197 mutant of Corynebacterium diphtheriae protein 18 mo (12/22/88)d 15 mo (12/89)c 2 mo (10/4/90)e PRP-OMP (Merck Sharp & Dohme, PedvaxHIB) Medium Neisseria meningiditis outer membrane protein complex 15 mo (12/89)c 2 mo (12/13/90)f PRP-T, (Pasteur Merieux-Connaught Vaccins, ActHIB) Large Tetanus toxoid 2 mo (3/30/93)g a Centers for Disease Control (1985). b Centers for Disease Control (1988). c Centers for Disease Control (1990a). d Centers for Disease Control (1989). e Centers for Disease Control (1990b). f Centers for Disease Control (1990d). g Centers for Disease Control and Prevention (1993). dom demonstrated efficacy of the vaccine when given at ages 2, 3, and 4 months (Booy et al., 1992). Following the widespread distribution and administration of Hib conjugate vaccines, few cases of vaccine failure (a case of Hib disease occurring more than 14 days after the second or third doses) have been reported (Black et al., 1992a; Holmes et al., 1991; Santosham et al., 1992), and postlicensure studies have shown a marked decrease in the incidence of Hib disease in the United States (Adams et al., 1993; Black et al., 1992b; Broadhurst et al., 1993; Centers for Disease Control, 1990c; Murphy et al., 1993b). The American Academy of Pediatrics and the Advisory Committee on Immunization Practices recommend that conjugate Hib vaccines be administered as two to three doses beginning at age 2 months and then a booster at 12 to 15 months.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality BIOLOGIC EVENTS FOLLOWING IMMUNIZATION The Hib vaccines themselves contain no infective agents, just the organism's capsular polysaccharide; thus, there is no risk of developing Hib infection or clinical manifestations of Hib disease from any of the Hib vaccine components themselves (Granoff and Osterholm, 1987; Weinberg and Granoff, 1988). Occasionally, however, Hib disease is falsely diagnosed following immunization with both plain PRP and conjugated Hib vaccines, on the basis of the results of urine PRP antigen detection tests, because children excrete PRP in their urine for several days following immunization (Goepp et al., 1992; Jones et al., 1991; Spinola et al., 1986). The risk of developing a Hib infection within the first 7 days following immunization with Hib vaccines is discussed later in this chapter. Rates of local reactions to Hib vaccines, such as pain, tenderness, swelling, and erythema at the site of injection, have varied from study to study, but the overall reaction rates to plain PRP vaccines are lower than those to conjugate vaccines. Approximately 20 to 25 percent of children develop local pain or tenderness, and 5 to 15 percent have redness or swelling at the injection sites in the 24 to 72 hours following immunization. These reactions are almost always mild and transient. Low-grade fever has been reported in the first 24 to 72 hours postimmunization in from 1 to 20 percent of Hib vaccine recipients. Temperatures of 39ºC (102.2ºF) or greater have been reported in less than 2 percent of Hib vaccine recipients. Most investigators have reported irritability in 10 percent or fewer of plain PRP vaccine recipients and about 10 to 25 percent of conjugate vaccine recipients. These systemic reactions are short-lived and are not felt to be serious by parents or physicians (Ahonkhai et al., 1990, 1991; Barkin et al., 1987; Black et al., 1987, 1991b; Campbell et al., 1990; Claesson et al., 1988, 1989, 1991; Clements et al., 1990; Dashefsky et al., 1990; Decker et al., 1992; Eskola et al., 1990a; Ferreccio et al., 1991; Frayha et al., 1991; Fritzell and Plotkin, 1992; Granoff and Cates, 1985; Granoff and Osterholm, 1987; Greenberg et al., 1987; Hendley et al., 1987; Kayhty et al., 1988, 1989; Kovel et al., 1992; Lenoir et al., 1987; Lepow et al., 1984a, 1985, 1986, 1987; Milstien et al., 1987; Parke et al., 1991; Peltola et al., 1977; Popejoy et al., 1989; Rowe et al., 1990; Santosham et al., 1991a; Vadheim et al., 1990; Watemberg et al., 1991; Weinberg and Granoff, 1988). Rates of local and systemic reactions to Hib vaccines have usually been similar to or lower than those to injections with placebo or DPT, inactivated polio vaccine, or measles-mumps-rubella vaccine (MMR) alone or to those vaccines plus Hib vaccines (Ahonkhai et al., 1991; Black et al., 1991b; Campbell et al., 1990; Clements et al., 1990; Eskola et al., 1987; Lepow et al., 1984a, 1987; Vadheim et al., 1990; Watemberg et al., 1991). Exceptions include a study by Dashefsky et al. (1990), in which 71 percent of

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality infants receiving the PRP-OMP vaccine plus MMR were reported to develop irritability compared with 35 percent for groups receiving either vaccine alone, and a study by Ferreccio et al. (1991), which found a 7 to 20 percent increase in fever in children who received PRP-T with DPT than in those who received DPT alone. Immunization with the first-generation Hib polysaccharide, or purified PRP, vaccine stimulates production of anti-PRP antibody in the same manner as natural infection (Granoff and Cares, 1985; Norden et al., 1976; Trollfors et al., 1992). This immune response is felt to be T-cell independent. In contrast, the immune responses to PRP conjugate vaccines appear to use T cells as well as B cells (Robbins and Schneerson, 1990; Steinhoff et al., 1991; Weinberg and Granoff, 1988). Antibodies produced in response to the intact organism, plain PRP vaccines, and conjugate vaccines have subtle differences, but all have been demonstrated to have in vitro opsonic and bactericidal activities and to be protective in animal models of Hib disease as well as in human trials (Adams, 1992; Anderson et al., 1972; Black, 1992; Black et al., 1988, 1991a,b; Cates, 1985; Cates et al., 1985; Eskola et al., 1987, 1990a,b, 1992; Fothergill and Wright, 1933; Fritzell and Plotkin, 1992; Gray, 1990; Kulhanjian, 1992; Loughlin et al., 1992; Musher et al., 1988; Newman et al., 1973; Peltola, 1992; Peltola et al., 1984; Robbins et al., 1973; Santosham et al., 1991b; Schneerson et al., 1971; Schreiber et al., 1986; Smith et al., 1989; Vadheim, 1992). The difference in reliance on T cells for antibody production results in differences in the age at which the antibody response occurs, the amount of antibody produced, and the ability to boost antibody production by revaccination or exposure to the organism. The conjugate vaccines stimulate anti-PRP antibody responses in young infants, whereas the plain PRP vaccines do not provide protective amounts of antibody in most individuals until after the age of 2 years. The conjugate vaccines also induce larger amounts of anti-PRP antibodies in vaccinees of all ages, and they induce an anti-PRP antibody response in many individuals who do not respond well to natural infection with Hib or to the plain PRP vaccine, including patients with Hib disease before the age of 2 years and those with splenectomy; sickle cell disease; malignancy; IgG2 deficiency; Navajo, Apache, and Alaskan natives; and allogeneic bone marrow recipients (Barra et al., 1992; Edwards et al., 1989; Feldman et al., 1990; Frank et al., 1988; Gigliotti et al., 1989, 1991; Granoff et al., 1989; Kafidi and Rotschafer, 1988; Kaplan et al., 1988; Marcinak et al., 1991; Rubin et al., 1989, 1992; Santosham et al., 1992; Siber et al., 1990; Steinhoff et al., 1991; Walter et al., 1990; Weinberg and Granoff, 1990; Weisman et al., 1987). It is evident that the different Hib vaccines produce not only different quantities of anti-PRP antibody but also that this antibody differs in such characteristics as IgG subclass, avidity, and affinity (Ambrosino et al., 1992;

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Decker et al., 1992; Granoff et al., 1988; Hetherington and Lepow, 1992; Holmes et al., 1991; Insel and Anderson, 1986; Parke et al., 1991; Schlesinger and Granoff, 1992; Shackelford and Granoff, 1988). These differences produce subtle functional differences in vitro, but the implications for protective activity in vivo are unknown (Amir et al., 1990a,b). Individuals who produce protective levels of antibody to Hib vaccines generally do so within 1 month of immunization (Kayhty et al., 1989; Peltola et al., 1977). Good immune responses to the conjugate vaccines have been demonstrated as soon as 1 week after immunization in older children and adults (Daum et al., 1989; Marchant et al., 1989). Unlike plain PRP vaccines, PRP conjugate vaccines stimulate memory B cells capable of generating booster responses to immunization with either plain PRP or PRP conjugate vaccines and, thus, presumably, to the intact Hib organism (Weinberg et al., 1987). PRP conjugate vaccines reduce the Hib oropharyngeal carrier state (Barbour, 1992; Mohle-Boetani, 1992; Murphy, 1991; Takala et al., 1991). TRANSVERSE MYELITIS Clinical Description Myelitis is inflammation of the spinal cord. Transverse myelitis is myelitis in which the inflammatory process principally involves one or more spinal cord segments, showing the manifestations of a transverse cord lesion that usually develops acutely. Initially, many cases of transverse myelitis are not complete. Early symptoms in some patients include sphincter paralysis associated with a total or partial loss of sensation below the level of the lesion. As the acute spinal shock resolves, the paraplegia becomes spastic. Acute multiple sclerosis and postinfective myelitis are among the commonest causes of this syndrome. The annual incidence of transverse myelitis in Rochester, Minnesota, from 1970 to 1980 was 0.83 per 100,000 people (Beghi et al., 1982). History of Suspected Association The history of a suspected association between Hib vaccines and transverse myelitis is based solely on three case reports in the Vaccine Adverse Event Reporting System (VAERS). There are no reports in the literature of an association between Hib vaccines and transverse myelitis.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Evidence for Association Biologic Plausibility A general discussion of transverse myelitis and vaccination can be found in Chapter 3. There are no data specifically bearing on the biologic plausibility of a causal relation between Hib vaccines and transverse myelitis. Case Reports, Case Series, and Uncontrolled Observational Studies There have been three cases reported in VAERS (submitted between November 1990 and July 1992) labeled as "transverse myelitis" following Hib vaccination. HbOC vaccine was the Hib vaccine used in all three cases. In one patient (there appeared to be two reports of this one case), the HbOC vaccine was administered alone, in the second the HbOC vaccine was administered with DPT and oral polio vaccine (OPV), and in the third HbOC vaccine was administered with DPT, OPV, and MMR. Only the third case provided sufficient evidence to establish a diagnosis of transverse myelitis. This child developed transverse myelitis 14 days after immunization with the HbOC, DPT, OPV, and MMR. She had a diffuse rash, diarrhea, and a fever 10 days after vaccination and 4 days prior to the onset of transverse myelitis. This case report was the only one to provide information on follow-up. At 4.5 months following vaccination, a magnetic resonance image (MRI) of the thoracic spine showed extensive atrophic change of the thoracic cord, extending from the seventh thoracic vertebra (T-7) through T-12. At 10 months postvaccination there was "persistent transverse myelitis" at the T-8 through T-10 level. Insufficient data were provided for the other two cases to determine whether the children actually had transverse myelitis. One of these children developed a temperature of 40.6ºC (105ºF) and "extreme floppiness and toxic appearance" 24 to 36 hours after immunization with the HbOC vaccine alone. He had a "multitude of lab tests and MRI" and was hospitalized for 30 days. The other baby was noted to be unable to crawl 12 days after immunization with the HbOC vaccine, DPT, and OPV. The mother reported that a neurologist felt that this child had possible transverse myelitis from polio vaccine. She reported that the lumbar puncture and brain scan were normal. The child was hospitalized for 2 days, and no further follow-up information was provided. There have been no cases of transverse myelitis reported in any case series or uncontrolled observational studies of Hib vaccines (Ahonkhai et al., 1990, 1991; Black et al., 1987; Claesson et al., 1991; Fritzell and Plotkin, 1992; Milstien et al., 1987; Parke et al., 1991; Popejoy et al., 1989; Rowe et al., 1990; Santosham et al., 1991a; Vadheim et al., 1990).

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Controlled Observational Studies There have been no controlled observational studies investigating an association between Hib vaccines and transverse myelitis. Controlled Clinical Trials Transverse myelitis has not been reported in any of the controlled clinical trials of plain PRP or PRP conjugate vaccines that have been performed (Barkin et al., 1987; Black et al., 1991b; Campbell et al., 1990; Claesson et al., 1988, 1989; Clements et al., 1990; Dashefsky et al., 1990; Decker et al., 1992; Eskola et al., 1987, 1990a,b; Ferreccio et al., 1991; Frayha et al., 1991; Granoff and Osterholm, 1987; Greenberg et al., 1987; Hendley et al., 1987; Kayhty et al., 1988, 1989; Kovel et al., 1992; Lenoir et al., 1987; Lepow et al., 1984a,b, 1985, 1986, 1987; Peltola et al., 1977; Santosham et al., 1992; Watemberg et al., 1991). Causality Argument There is no animal model or other data supporting the association between Hib vaccines and transverse myelitis. There are three cases reported in VAERS labeled "transverse myelitis" in children aged 6, 9, and 15 months occurring following the administration of HbOC vaccine during a period when an estimated several million doses of HbOC vaccine were administered. One of these children received HbOC vaccine alone, and the interval between immunization and the development of neurologic symptoms in this child was brief (less than 48 hours). A second child also received DPT and OPV. The patient for whom sufficient documentation of transverse myelitis was provided also had received DPT, OPV, and MMR. No cases of transverse myelitis have been reported following administration of the other Hib vaccines, nor have any cases been reported in the literature. Conclusion The evidence is inadequate to accept or reject a causal relation between Hib vaccines and transverse myelitis. GUILLAIN-BARRÉ SYNDROME Clinical Description The Guillain-Barré syndrome (GBS) is an acute polyneuropathy that gives rise to muscular weakness, paralysis, and areflexia usually in an as-

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality cending pattern. About one-third of patients with GBS require assisted ventilation, but rarely is the condition fatal. In most patients there is spontaneous improvement after weeks or months, usually leading to complete recovery. The annual incidence of GBS appears to be approximately 1 per 100,000 for adults. The data are not definitive, but the annual incidence of GBS in children under age 5 years appears to be approximately the same. The annual incidence of GBS in children over age 5 years and teenagers appears to be lower. Chapter 3 contains a detailed discussion of GBS. History of Suspected Association In 1989, D'Cruz and coworkers reported three cases of GBS following immunization with the Hib conjugate vaccine PRP-diphtheria toxoid (PRP-D). Two children received the PRP-D vaccine alone, but the third child received DPT and OPV as well. The onset of symptoms in this child occurred 1 day following immunization. One day is too short a period of time, as described in Chapter 3, to support the notion that the GBS attack was plausibly related to the vaccination. Evidence for Association Biologic Plausibility A general discussion of GBS and vaccination can be found in Chapter 3. There are no data specifically bearing on the biologic plausibility of a causal relation between Hib vaccines and GBS. Case Reports, Case Series, and Uncontrolled Observational Studies A total of seven cases labeled GBS have been described following immunization with the three Hib conjugate vaccines that are currently licensed for use in the United States. The three cases following administration of the PRP-D vaccine noted above occurred during a period when approximately 6.2 million doses of PRP-D vaccine were distributed (D'Cruz et al., 1989). None of these children were noted to have an antecedent infection. A different lot of PRP-D vaccine was used in each child. A fourth case of GBS following vaccination with PRP-D vaccine was reported recently by Gervaix and colleagues (1993). A 4-year-old girl developed signs of GBS (progressive weakness in legs with hypotonia and complete loss of tendon reflexes, difficulty in swallowing, and bilateral facial weakness) 10 days after receiving PRP-D Hib vaccine. The report documented decreased nerve conduction velocities and prolonged distal latencies. Serological tests were negative for cytomegalovirus, herpesvirus, Epstein-Barr virus, Borrelia burgdorferi, and Campylobacter species. IgM

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality antibodies to PRP in plasma were high 15 days after immunization. The child responded to intravenous immunoglobulin therapy. The other three reports of GBS following the administration of Hib conjugate vaccines were detected by VAERS (submitted between November 1990 and July 1992). Two of the three children developed an infection between the time of immunization and the onset of the neurologic symptoms. These two children developed GBS (within the time frame described by the committee as plausible) following immunization with HbOC vaccine. One of these children also had received MMR, and the other child had received DPT and OPV at the time of the HbOC immunization. The former developed GBS 12 days following immunization and 6 days following the onset of otitis media and bronchospasm. The latter developed GBS 6 days after immunization and was noted to be on amoxicillin, but the indication for antibiotic therapy was not specified. The third VAERS report described a child who was immunized as part of a PRP-OMP vaccine safety trial and was not noted to have received any other vaccine. This child developed an unsteady gait and decreased deep tendon reflexes 44 days after immunization and had otitis media, an upper respiratory tract infection, and a rash about 1 month following receipt of Hib vaccine and 2 weeks prior to the onset of neurologic symptoms. The child's discharge diagnosis was GBS. Although the latency is close to the window specified by the committee as reasonable (see Chapter 2), the other antecedent events (infection and rash) also suggest that if this child had GBS, it was far more likely related to these antecedent events. In one of the PRP-D vaccine recipients (D'Cruz et al., 1989) and one of the HbOC vaccine recipients reported by VAERS, OPV was given concurrently. An increased incidence of GBS was reported to have coincided with a national OPV immunization campaign in Finland, as discussed in Chapter 8 (Farkkila et al., 1991; Kinnunen et al., 1989; Uhari et al., 1989). The time of onset of symptoms following Hib vaccine administration ranged from 1 day (D'Cruz et al., 1989) to 44 days (a report from VAERS) in seven patients, with the onset of symptoms in five of the patients beginning 6 to 12 days after vaccination. The cases beginning 1 and 44 days after vaccination are not considered likely to be related to vaccination (see Chapter 3). The ages of the patients whose GBS began 6 to 12 days after vaccination were 15, 19, 20, and 33 months and 4 years. The symptoms of GBS resolved in three of these patients, and the outcomes for the others were not reported. There have been no cases of GBS reported in any case series or uncontrolled observational studies of Hib vaccines (Ahonkhai et al., 1990, 1991; Black et al., 1987; Claesson et al., 1991; Fritzell and Plotkin, 1992; Milstien et al., 1987; Parke et al., 1991; Popejoy et al., 1989; Rowe et al., 1990; Santosham et al., 1991a; Vadheim et al., 1990).

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Controlled Observational Studies There have been no controlled observational studies investigating an association between Hib vaccines and GBS. Controlled Clinical Trials GBS has not been reported in any of the controlled clinical trials of plain PRP or PRP conjugate vaccines that have been performed (Barkin et al., 1987; Black et al., 1991b; Campbell et al., 1990; Claesson et al., 1988, 1989; Clements et al., 1990; Dashefsky et al., 1990; Decker et al., 1992; Eskola et al., 1987, 1990a,b; Ferreccio et al., 1991; Frayha et al., 1991; Granoff and Osterholm, 1987; Greenberg et al., 1987; Hendley et al., 1987; Kayhty et al., 1988, 1989; Kovel et al., 1992; Lenoir et al., 1987; Lepow et al., 1984a,b, 1985, 1986, 1987; Peltola et al., 1977; Santosham et al., 1992; Watemberg et al., 1991). Causality Argument There are no animal models of GBS following immunization for Hib; however, Chapter 3 presents evidence that GBS is biologically plausible as a consequence of vaccines in general. Data bearing on causality are limited to case reports. Seven cases labeled as GBS were reported to occur following immunization with three different Hib conjugate vaccines over a period when an estimated several million doses of Hib conjugate vaccines were distributed. Five of these cases fit the criteria for possible vaccine-related GBS discussed in Chapter 3. Hib conjugate vaccine administration was the only potential predisposing factor cited for the development of GBS in three of the five children who fit the case definition of GBS following immunization for Hib. Gervaix and colleagues (1993) speculated that the anti-PRP IgM antibodies detected in the plasma of the patient they described might have cross-reacted with glycoproteins of peripheral nerve myelin, leading to GBS. Two of the five children who developed GBS following immunization with Hib vaccine had possible predisposing factors (infections, OPV immunization) other than Hib immunization. Conclusion The evidence is inadequate to accept or reject a causal relation between Hib vaccines and GBS.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality cines would be more likely than any other foreign protein, including other vaccines, to cause anaphylaxis. There are few cases of anaphylaxis following Hib vaccination in the literature. Insufficient details are provided by Mäkelä and colleagues (1977) to determine whether the responses represented anaphylaxis. The symptoms described in the paper by Milstien et al. (1987) are suggestive but not conclusive of anaphylaxis, but the administration of epinephrine might have aborted development of enough signs of anaphylaxis to be convincing. Conclusion The evidence is inadequate to accept or reject a causal relation between Hib vaccines and anaphylaxis. DEATH A detailed discussion of the evidence regarding death following immunization can be found in Chapter 10. Conclusion The evidence favors acceptance of a causal relation between PRP vaccine and death from early-onset Hib disease in children 18 months of age or older who receive their first Hib immunization with unconjugated PRP vaccine. There is no direct evidence for this; the conclusion is based on the potential for Hib disease to be fatal. The risk would appear to be extraordinarily low. The evidence favors rejection of a causal relation between conjugated Hib vaccines and death from early-onset Hib disease. The evidence is inadequate to accept or reject a causal relation between Hib vaccines and sudden infant death syndrome. The evidence is inadequate to accept or reject a causal relation between Hib vaccine and death from causes other than those listed above. REFERENCES Adams J. Program Abstracts of the 32nd Interscience Conference on Antimicrobial Agents and Chemotherapy. Abstract 974, p. 273. Washington, DC: American Society for Microbiology; 1992. Adams WG, Deaver KA, Cochi SL. Decline of childhood Haemophilus influenzae type b (Hib) disease in the Hib vaccine era. Journal of the American Medical Association 1993;269:221-226. Ahonkhai VI, Lukacs LJ, Jonas LC, Matthews H, Vella PP, Ellis RW, et al. Haemophilus influenzae type b conjugate vaccine (meningococcal protein conjugate) (PedvaxHIB): clinical evaluation. Pediatrics 1990;85(4 Pt 2) :676-681.

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