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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 8 Hepatitis B Vaccines BACKGROUND AND HISTORY Hepatitis B virus infection may result in a wide variety of acute or chronic hepatic and extrahepatic manifestations as well as a chronic carrier state. Following an incubation period of 4 weeks to 6 months, the patient develops anorexia, low-grade fever, and, in more severe cases, tender enlargement of the liver associated with jaundice. At least 80 percent of otherwise healthy adult patients and a larger percentage of children with acute hepatitis B virus infection recover completely from the infection with no sequelae. Fewer than 1 percent develop massive hepatic necrosis and then death. Of those who recover from acute hepatitis, up to 15 percent become chronic carriers, that is, have chronic hepatitis B virus infection. There are major differences between children and adults regarding the development of the chronic carrier state. Ninety percent of newborn infants infected with hepatitis B virus become chronic carriers; however, the risk of becoming a chronic carrier following primary infection decreases during early childhood, so that by the age of 4 years, only 10 percent of those infected become chronic carriers. An even smaller percentage of adults (1-4 percent) become chronic carriers. As a result, the infection of children at birth or soon thereafter results in a higher prevalence of chronic carriers, with the consequent higher risk of hepatocellular carcinoma and chronic liver disease and perpetuation of the risk through maternal-fetal transmission.
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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality The public health importance of hepatitis B infection in susceptible populations spurred the search for a vaccine against this virus. While studying serologic polymorphisms, Blumberg discovered an antibody that reacted with the blood from an Australian aborigine (Blumberg et al., 1969). The reactant became known as the Australia antigen (Au) and was the basis of the test used to screen blood for the presence of hepatitis B virus. This work earned B. S. Blumberg the Nobel Prize in 1976. This basic research also led to the development of a vaccine. Krugman and colleagues, in a classic series of studies in the early 1970s, further laid the groundwork for development of the vaccine. They worked with two strains of hepatitis B virus in human volunteer studies. One was labeled MS-1 and was later identified as hepatitis A virus. The other was labeled MS-2 and was later confirmed to be hepatitis B virus. Those investigators found that a 1:10 dilution of serum infected with hepatitis B virus boiled for 1 minute lost its infectivity but retained its antigenicity and prevented or modified hepatitis B virus infection in approximately 70 percent of vaccinated subjects later challenged with infective MS-2 serum (Krugman and Giles, 1973; Krugman et al., 1970, 1971). Krugman's principle was developed into a more sophisticated vaccine by several groups (Coutinho et al., 1983; Crosnier et al., 1981; McLean et al., 1983; Purcell and Gerin, 1975). The vaccines consisted of inactivated, alum-adsorbed, 22-nm hepatitis B virus surface antigen (HBsAg) particles that had been purified from the plasma of human chronic hepatitis B virus carriers. The method of purification was by a combination of biophysical (ultracentrifugation) and biochemical procedures. Inactivation was a threefold process with 8 M urea, pepsin at pH 2, and formalin at a 1:4,000 dilution. The plasma-derived hepatitis B vaccine was licensed by the U.S. Food and Drug Administration in late 1981. A belief among some prospective vaccinees that the plasma-derived vaccine might be contaminated with human blood pathogens (particularly human immunodeficiency virus [HIV]) was an important deterrent to the optimal utilization of the hepatitis B vaccine in high-risk individuals. The treatment steps described above were shown to inactivate representatives of various viruses found in human blood, including HIV (Francis et al., 1986). Hepatitis B vaccines derived from human plasma were subsequently developed in countries other than the United States, including countries in Europe and Asia. All of the plasma-derived vaccines were given safety tests in tissue culture systems, in animals, and then in humans. Trials of efficacy were done among infants born to carrier mothers, children, and various groups of adults, including homosexual men. Those trials demonstrated adequate antibody production after a three-dose schedule and a high rate of protection following immunization in populations with higher levels of exposure to the antigen than those populations currently receiving the
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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality vaccine in the United States (Beasley et al., 1983; McLean et al., 1983; Szmuness et al., 1980, 1982; Wong et al., 1984). The vaccines were used very widely, especially in Asia. Recombinant vaccines are produced by Saccharomyces cerevisiae (common baker's yeast), into which a plasmid containing the gene for HBsAg has been inserted. These were developed and licensed in the 1980s (Emini et al., 1986; Stephenne, 1990). Purified HBsAg is obtained by lysing the yeast cells and separating HBsAg from the yeast components by biochemical and biophysical techniques. These vaccines contain more than 95 percent HBsAg protein. Yeast-derived protein constitutes no more than 5 percent of the final product. Hepatitis B vaccines are packaged to contain 10-40 µg of HBsAg protein per ml and are absorbed with aluminum hydroxide (0.5 mg/ml). Thimerosal (1:20,000 concentration) is added as a preservative. In 1986, the first recombinant hepatitis B vaccine was licensed in the United States. Two recombinant vaccines, both produced in yeasts, are currently licensed in the United States (by Merck Sharp & Dohme and SmithKline Biologicals). These recombinant vaccines are also used in many countries worldwide. An additional recombinant vaccine that is produced in mammalian cells (Pasteur-Merieux) is available in some countries in Europe (Hadler and Margolis, 1992). Recombinant vaccines are also produced in Japan and may become widely available in the future. Additional second-generation recombinant vaccines are currently under development. Plasma-derived vaccine is no longer being produced in the United States, although it is being produced inexpensively in other countries and has become the predominant form of vaccine in much of Asia, where it is being used in national programs to attempt to interrupt maternal-neonatal transmission. In 1991, hepatitis B vaccine was recommended by both the Centers for Disease Control and the American Academy of Pediatrics for universal administration to infants. The Advisory Committee on Immunization Practices and the American Academy of Pediatrics recommend that hepatitis B vaccine be given at birth and then again at ages 1 to 2 months and 6 to 18 months. The Advisory Committee on Immunization Practices also recommends an alternative to that schedule of administration, that is, at ages 1 to 2 months, 4 months, and 6 to 18 months. BIOLOGIC EVENTS FOLLOWING IMMUNIZATION The antibodies produced after infection with hepatitis B virus or after administration of plasma-derived vaccine or recombinant vaccine are alike in terms of their ability to elicit protective determinants that are active against all subtypes of the virus (Hauser et al., 1987). In the United States,
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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality hepatitis B recombinant vaccines are given as a three-dose series. This consists of two priming doses given 1 month apart; this is followed by a third dose given 6 months after the first one (Centers for Disease Control, 1990). An alternative schedule, consisting of three priming doses at 1-month intervals and then a fourth dose 12 months after the first one, is approved for one vaccine (SK-RIT). The priming doses induce detectable antibody to HBsAg in 70-85 percent of healthy adults and children, but they are of relatively low titer. The final dose induces adequate high-titer antibody in more than 90 percent of healthy adults under the age of 50 and 95 percent of children and infants (100-3,000 IU/liter in adults and >5,000 IU/liter in children). The immunogenicity and safety of hepatitis B vaccine in premature infants are less well defined (Lau et al., 1992). Studies show seroconversion rates similar to those observed with the plasma-derived vaccine licensed for use in the United States (Andre and Safary, 1989; McLean et al., 1983; Zajac et al., 1986). Factors affecting the antibody response to recombinant vaccine include vaccine type and handling, timing of doses, and site of injection. Freezing of the vaccine during shipment or excessive heat may reduce its potency. The deltoid muscle is the preferred site for vaccination, and it is now clear that gluteal injection may decrease the response to the vaccine by as much as 50 percent (Shaw et al, 1989). The anterolateral thigh is the preferred site of vaccine injection in infants. Recombinant vaccine has decreased immunogenicity compared with that of plasma-derived vaccine when the vaccine is administered by the intradermal route, so this route of administration is not recommended by the Centers for Disease Control and Prevention. Factors that do not affect the response include simultaneous administration with hepatitis B immune globulin and with other vaccines, including diphtheria and tetanus toxoids and pertussis vaccine (DPT) (Coursaget et al., 1986). Age is an important factor affecting the immune response (Andre, 1989; Shaw et al., 1989). The maximal response is in children (ages 2-19 years); this is followed by equivalent responses in young adults and infants (West et al, 1990). The poorest response is in older adults, beginning in the sixth decade of life, and only 50 to 70 percent of adults over age 60 have satisfactory antibody responses. The age-related decrease in immune response is significantly greater in men than in women. The response is diminished in persons with immunosuppressive illnesses, including renal failure and HIV infection. Both higher-titer vaccine and increased numbers of doses are required to achieve a 70 percent response in patients who are on hemodialysis (Centers for Disease Control, 1990). More than 50 trials of plasma-derived vaccine are reported in the literature. These trials were conducted in nearly half that number of countries and have included the vaccination of more than 100,000 individuals (Beasley
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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality et al., 1983; Chung et al., 1985; Francis et al., 1982; McLean et al., 1983; Szmuness et al., 1980). All trials dealt with plasma-derived vaccines that were very similar in composition. Although there were some differences in potency and effectiveness, the results were uniform in reporting a vaccine with minimal local side effects. In a double-blind, randomized controlled study, Szmuness and colleagues (1980) reported no significant differences in any response to the vaccine compared with that to placebo except for local pain. The minimal reactions reported in other studies have been local pain, myalgia, and low-grade and transient fever, usually within the first 24 hours. The frequency of such side effects is not cited in reports of many trials, and statements like ''reported untoward reactions to immunization were negligible'' are often made. When the frequency of side effects is cited, however, particularly in the initial trials, the estimates range from 0 to 45 percent, but in most studies, about 30 percent of adults have local reactions of sore arms and local induration. Fewer children have these side effects (less than 10 percent). Most of the trials have studied vaccination by the standard route, but some studies have evaluated the intradermal route, including the jet injection technique used in mass immunization campaigns such as in the military. Studies have been conducted in infants, children, adult health care workers, health profession students, patients on dialysis and with renal disease, homosexual or bisexual men, and mentally retarded individuals in institutions. The greatest number of studies have been conducted in infants. Most of these are of hepatitis B vaccine alone, but others have examined different combinations of the vaccine and hepatitis B immune globulin. From these studies, the optimal current recommendation for immunization of newborns of HBsAg-positive mothers was developed. The current recommendations incorporate administration of a combination of vaccine and immune globulin with the initial dose shortly after birth; this is followed by administration of vaccine alone at 1- and 6-month intervals. Trials of more than 12 separate recombinant vaccines have been conducted in more than 25 countries and have involved more than 100,000 recipients. As is the case for plasma-derived vaccines, however, it is important to note that individual trials usually involved a few hundred subjects per study (Andre, 1989). When larger vaccination programs were monitored, observations of adverse events were necessarily less detailed and less accurately reported. The results of the trials of recombinant vaccine are much the same as those of trials of plasma-derived vaccines (Andre, 1989). Local reactions of soreness were found in approximately one-third of recipients; generalized reactions of fatigue, headache, or fever were found in 10-15 percent of recipients. The frequencies of these side effects were less in infants and children. The trials are notable for the absence of any serious adverse reactions. The studies were not designed to assess serious, rare adverse
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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality events; the total number of recipients is too small and the follow-up generally too short to detect rare or delayed serious adverse reactions. Studies of the immunogenicity of the recombinant vaccine show that, by the third dose, over 95 percent of healthy children and adults have responded by producing antibody. Infants and older individuals produce less antibody than young children and adults, which is the usual case for many vaccines. GUILLAIN-BARRÉ SYNDROME Clinical Description Guillain-Barré syndrome (GBS) is characterized by the rapid onset of flaccid motor weakness with depression of tendon reflexes and inflammatory demyelination of peripheral nerves. The diagnostic criteria for GBS spelled out in Chapter 3 are those used in this chapter, although the data available from case reports in the literature or in reports of adverse events are often sparse and do not fulfill all diagnostic criteria. 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 The association of GBS and swine influenza vaccine has been an impetus for scrutinizing all new vaccines for neurologic sequelae. This was, no doubt, the impetus for the postmarketing surveillance study of Shaw et al. (1988). In addition, hepatitis B virus infection itself may have, on occasion, triggered GBS (Berger et al., 1981; Marti-Masso et al., 1979; Ng et al., 1975; Niermeijer et al., 1975; Penner et al., 1982; Tabor, 1987; Tsukada et al., 1987). Evidence for Association Biologic Plausibility Chapter 3 presents background information on the biologic plausibility of a causal relation between vaccines and demyelinating disease. The association with GBS has been reported from various countries and with various versions of both plasma-derived and recombinant hepatitis B vaccines. As already mentioned, GBS has on occasion been reported to occur following hepatitis B viral infection.
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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Case Reports, Case Series, and Uncontrolled Observational Studies Following the introduction of plasma-derived hepatitis B vaccine in 1982, a passive surveillance effort was initiated by the Centers for Disease Control (CDC) to monitor for all serious adverse events. A study of the neurologic adverse events reported in approximately 850,000 vaccinees during the first 3 years of surveillance was published in 1988 (Shaw et al., 1988). Nine cases of putative GBS occurring after administration of hepatitis B vaccine came to attention, all in adults. The clinical information for eight cases was reviewed independently by four academic neurologists. They expressed a wide range of opinions as to whether these cases represented GBS. Two of the nine cases were judged to be definite GBS by three of the four reviewers, two cases received two of four votes as definite GBS, one case was thought to be definite GBS by one of the four reviewers, and three cases were not thought to be definite GBS by any of the reviewers. Although the neurologists did not all agree that each of the nine cases was GBS, the authors used all nine cases in the analysis. Because no concurrent control populations were available, two population-based studies were used to calculate expected numbers of GBS cases for comparison purposes. One set of background incidence data came from a CDC study designed to evaluate the relation between GBS and swine flu vaccination, which presumably used case definition methods similar to those that led to the nine GBS cases in the study of Shaw et al. (1988). The second set of background incidence rates came from a linked medical records system conducted by the Mayo Clinic in Rochester, Minnesota, for Olmsted County, Minnesota. Relative risks for GBS following hepatitis B vaccination were calculated under a variety of assumptions, specifically, a 6- or 8-week at-risk interval and risk evenly distributed among three doses versus all risk associated with the first dose. Statistically significant increases in risk were found under all assumptions when the CDC data were used for comparison purposes, but only with a 6-week at-risk interval after the first vaccine dose when the Olmsted County data were used. Adjustments for age in the CDC data and age and sex in the Olmsted County data did not substantially change the results. The authors stated that "no conclusive epidemiologic association could be made between any neurologic adverse event and the vaccine" (Shaw et al., 1988, p. 337), presumably because their data derived from spontaneous reporting, they had no concurrent control information, and the diagnosis of GBS was sometimes suspect. A recent uncontrolled observational study of 43,618 Alaskan native vaccinees used a different strategy to investigate the relation between plasma-derived hepatitis B vaccine and GBS (McMahon et al., 1992). A computer search for all GBS cases in hospitals to which these individuals could be admitted disclosed 10 patients with GBS during the period in which hepati-
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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality tis B vaccine was administered. Of the 10 cases, 5 had been vaccinated with hepatitis B vaccine and 5 had not. Three of the vaccinees had experienced GBS prior to receiving hepatitis B vaccine, and two of the vaccinees had developed GBS long after vaccination (3 and 9 months, respectively). No relation between hepatitis B vaccination and GBS was demonstrated in that study. Five case reports could be culled from the literature (Lin et al., 1989; Morris and Butler, 1992; Ribera and Dutka, 1983; Tuohy, 1989). Of these, a single case report related to the plasma-derived vaccine licensed for use in the United States (Ribera and Dutka, 1983), and the others were from Taiwan (plasma-derived), New Zealand (two cases, both plasma-derived), and Australia (recombinant). The cases of GBS in Taiwan, New Zealand, and Australia were in children ages 3-7 years, whereas the case of GBS in the United States was in an adult. These age differences probably reflect the predominant ages of the vaccinees in the respective countries. The case from the United States did not qualify clinically as GBS, because no weakness was demonstrated and the only symptoms were fatigue and paresthesias. In the Monitoring System for Adverse Events Following Vaccination, three cases of GBS were reported as adverse events following hepatitis B vaccination from the time of the introduction of the vaccine until 1990. The Vaccine Adverse Event Reporting System (VAERS) contains 14 adverse reaction reports (submitted between November 1990 and July 1992) in which GBS is mentioned. Two of the reports are for the same patient; consequently, only 13 patients were reported. Of the 13 patients, 4 patients were described as having clinical syndromes that are incompatible with the diagnosis of GBS, and in 2 of these patients the latencies were 2 and 3 months, respectively. These four cases were considered to be other than GBS. An additional four reports contained virtually no information other than a listing of the diagnosis. For these cases, no conclusion regarding the diagnosis can be reached. Five cases appeared to be plausibly diagnosed as GBS, and the patients developed symptoms within 1 month of hepatitis B vaccination. All cases of GBS were in adults and all followed receipt of the recombinant vaccine. Controlled Observational Studies None. Controlled Clinical Trials None of the clinical trials reviewed by the committee contained information regarding hepatitis B vaccine and GBS.
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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Causality Argument There are reports of GBS following vaccination, but it is difficult to determine whether the frequency is greater than expected. There is some biologic plausibility for this association in terms of the occurrence of GBS following hepatitis B infection, the occurrence of demyelinating disease following vaccination in general (see Chapter 3), and the fact that cases have been reported in various countries and with various versions of both plasma-derived and recombinant vaccines. The episodes of GBS that occurred outside the United States are too rare to make any calculation of the incidence of GBS, and no value for the denominator is available. For New Zealand, a calculation of the incidence of GBS was made by using data from Olmsted County, Minnesota, for comparison. This seems inappropriate for geographic and demographic reasons. For the postmarketing surveillance data (Shaw et al., 1988), the authors assumed that the denominator was at least 850,000, which gives a crude rate of slightly greater than 1 case per 100,000 people receiving the vaccine. Shaw and colleagues examined the incidence rate of GBS in hepatitis B vaccine recipients in more depth using background rates from both Olmsted County and a national Centers for Disease Control study, and they also adjusted the data for age and sex. Some of the analyses of Shaw and colleagues, primarily those comparisons using the CDC data, reported a significant increase in the risk of GBS. However, the committee thought that the evidence was not conclusive for many of the same reasons Shaw and colleagues discussed in their report. Conclusion The evidence is inadequate to accept or reject a causal relation between hepatitis B vaccine and GBS. OTHER DEMYELINATING DISEASES Clinical Description Three central nervous system demyelinating diseases have been reported to occur following hepatitis B vaccination: a chronic demyelinating disease, multiple sclerosis, and two focal demyelinating lesions, optic neuritis and transverse myelitis. In patients with multiple sclerosis, demyelinating lesions occur in multiple locations and at different times. Transverse myelitis is characterized by the acute onset of signs of spinal cord disease, usually involving the descending motor tracts and the ascending sensory fibers, suggesting a lesion at one level of the spinal cord. On several occasions, it has been described as occurring after vaccination. The annual
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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality incidence of transverse myelitis in Rochester, Minnesota, from 1970 to 1981 was 0.83 per 100,000 people (Beghi et al., 1982). Optic neuritis represents a lesion in the optic nerve behind the orbit but anterior to the optic chiasm. Well-documented cases of optic neuritis that occur following vaccination are even rarer than cases of transverse myelitis. No population-based incidence rates were identified. Chapter 3 contains a discussion of demyelinating diseases. Evidence for Association Biologic Plausibility Chapter 3 contains a discussion of the biologic plausibility of a causal relation between hepatitis B vaccine and demyelinating disease. The reports suggesting a relation between vaccination and multiple sclerosis have largely been associated with hepatitis B vaccine. It has been suggested that hepatitis B vaccine might have an inherent propensity to cause demyelinating disease, and a possible mechanism has been offered (Waisbren, 1992). There is a well-established sequence homology between a short sequence of the P antigen of the hepatitis B virus and the encephalitogenic portion of rabbit myelin basic protein. Using a synthesized amino acid sequence with adjuvant, Fujinami and Oldstone (1989) induced inflammatory encephalomyelitis in rabbits. Although molecular mimicry might induce disease in humans given some vaccines or in humans with certain infections, the relevance of this specific study to the hepatitis B vaccine is questionable, since the recombinant vaccine reported to be associated with the majority of the cases does not contain the P protein. In addition, the sequence of the myelin basic protein that is encephalitogenic for rabbits is not the same as the sequence that is encephalitogenic for primates, and the region implicated in monkeys is thought to be similar to the region implicated in humans. The initial or recurrent attacks of multiple sclerosis following a dose of hepatitis B vaccine may be a chance occurrence. This would be supported by the frequency of the disease, its onset in young adult life at the same time that the hepatitis B vaccine is often administered, the observation that the episodes have occurred at variable times (some as short as 24 hours and some as long as 6 weeks postvaccination), which would stretch the feasibility of a delayed-type hypersensitivity reaction, and the inconsistency of occurrence after any particular sequence of vaccinations. On the other hand, multiple sclerosis is thought to be an autoimmune disease that occurs in genetically susceptible individuals. Antigenic stimulation of any type in such people might precipitate either an exacerbation or even the first clinically evident attack of disease exacerbation.
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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Case Reports, Case Series, and Uncontrolled Observational Studies Two cases of multiple sclerosis were reported by Herroelen et al. (1991) in Belgium in two women (ages 26 and 28 years) 6 weeks after receiving recombinant hepatitis B vaccine. One patient had a prior diagnosis of multiple sclerosis and would have been considered to have had a relapse of multiple sclerosis; the onset of the relapse was 6 weeks after receipt of the third dose. The other patient had no history of neurologic disease; the onset of disease occurred 6 weeks after receipt of the first dose of recombinant vaccine. The vaccines administered to both women were licensed in the United States. In both cases, the diagnosis of multiple sclerosis was convincing. Two more cases of multiple sclerosis were reported to the Institute of Medicine (Waisbren, 1992). One occurred in a 37-year-old pediatric nurse 3 weeks following receipt of her third dose of plasma-derived vaccine. A second case was described in a 32-year-old nurse 2 weeks after receipt of her second dose of recombinant vaccine. Both cases were atypical of multiple sclerosis but were thought to be a form of demyelinating disease. The second patient appeared to have a clear-cut episode of optic neuritis in one eye. Three cases of transverse myelitis were reported by Shaw et al. (1988) in their postmarketing surveillance study of plasma-derived vaccine. The three cases were in adults, and transverse myelitis occurred 2 to 7 weeks after receipt of doses one to three. (A fourth case reported by Shaw et al. (1988) was not considered because it occurred 16 weeks after vaccination.) Five more cases of transverse myelitis that occurred after administration of recombinant vaccine were reported in VAERS (submitted between November 1990 and July 1992). Five cases of optic neuritis were reported by Shaw et al. (1988). They were in adults and occurred 1-6 weeks after receipt of doses one to three of plasma-derived vaccine. Fourteen more cases were reported in VAERS (submitted between November 1990 and July 1992). As is usual in VAERS reports, there was variable documentation of the cases. Controlled Observational Studies None. Controlled Clinical Trials None of the clinical trials reviewed by the committee contained information regarding hepatitis B vaccine and transverse myelitis, optic neuritis, multiple sclerosis, or other central demyelinating diseases.
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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality For purposes of analyses, these case reports can be divided into two reasonably distinct groups. One group consists of 17 individuals in whom arthritis involving multiple joints occurred within 3 weeks after vaccination and the arthritis was associated with fever. The second group includes 40 individuals who developed arthritis not associated with documented fever in one or more joints within 2 months after hepatitis B vaccination. An associated transient rash was observed in 9 of the 17 patients with polyarticular arthritis and fever. Fifteen of these 17 patients recovered from the arthritis rapidly (with resolution within 3 days to 2 months), whereas 2 individuals developed a more chronic arthritis that persisted for at least 1 year. Nine episodes of arthritis occurred after the first vaccine dose, seven after the second, and one after the third. Among these individuals, 16 were women and 1 was a man. The mean age of the 17 individuals was 43 years. The two individuals who developed a more chronic arthritis were both women, aged 38 and 50 years. The associated skin rashes were transient in all patients; detailed descriptions of the rashes were lacking. All individuals in this group had arthritis in more than one joint; however, a symmetrical polyarthritis of the type typical of a serum sickness-like reaction was described in only three individuals. For completeness, it should be noted that of the 17 patients with acute onset of arthritis and fever, 1 had associated erythema nodosum. At least three other cases of erythema nodosum have been reported following hepatitis B vaccination (DiGuisto and Bernhard, 1986; Goolsby, 1989; Rogerson and Nye, 1990). Although the rashes in the nine individuals in whom they occurred were not defined, there are reports in the literature of erythema multiforme following hepatitis B vaccination (Feldshon and Sampliner, 1984; Milstien and Kuritsky, 1986; Wakeel and White, 1992). Although both erythema multiforme and erythema nodosum may represent hypersensitivity reactions, neither has been observed sufficiently frequently to support a causal relation with the hepatitis B vaccine. The more severe, potentially fatal variant of erythema multiforme (Stevens-Johnson syndrome) has not been reported in association with hepatitis B vaccines. The larger group of 40 individuals who developed arthritis, without documentation of associated fever, within 2 months after receiving hepatitis B vaccine presented with a more heterogeneous clinical picture. In these individuals, involvement of a single joint was common, and the predominance in women was less striking than that in individuals with the more acute onset of arthritis with fever (11 men, 29 women). In this group, the mean age was 46 years (range, 21-92 years). Six of the 40 individuals in this group had antecedent rheumatoid arthritis, and the acute arthritis following vaccination was described as a flare-up of rheumatoid arthritis. The arthritis in the 40 individuals was of widely varying duration, persisting for up to 2 years in one instance.
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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Two large uncontrolled population-based studies provide relevant information on hepatitis B vaccination and arthritis. The largest is the summary of results of a vaccination program involving 166,757 children in New Zealand; each child received at least one injection of plasma-derived hepatitis B vaccine prepared by a U.S. pharmaceutical firm (Morris and Butler, 1992). In this large group of vaccinees, arthralgias or arthritis occurred on 12 occasions in 10 individuals, giving an incidence of less than 1 episode of arthralgia or arthritis in 10,000 vaccinees. Of these 12 episodes, five were reported after receipt of the first vaccine injection, six after the second, and one after the third. One of these patients was hospitalized for 1 day. In none of these individuals were there any chronic sequelae of the arthralgia or arthritis. The second large observational study described the frequency of adverse reactions to hepatitis B vaccine in 43,618 Alaskan natives who received 101,360 doses of hepatitis B vaccine (McMahon et al., 1989). In that study myalgias or arthralgias lasting for more than 3 days occurred in 12 individuals, an incidence of less than 1 episode in 3,000 vaccinees. The authors felt that the arthralgias were coincidental to the hepatitis B vaccines. since 5 of the 12 patients had negative skin tests to the vaccine. These five patients as well as four others who did not undergo skin testing received additional doses of hepatitis B vaccine without an adverse event. One of the 12 patients did have an Arthus-type reaction, with transient polyarthritis and a positive skin test to the hepatitis B vaccine. Controlled Observational Studies None. Controlled Clinical Trials No controlled clinical trials reviewed by the committee contained information regarding hepatitis B vaccine and arthritis. Causality Argument On the basis of the two largest available observational studies, arthropathy appears to be unusual following vaccination against hepatitis B virus. On the basis of VAERS reports, the possibility exists that a hypersensitivity arthritis occurred in the 17 individuals who developed acute arthritis associated with fever with or without an associated rash. In the absence of a denominator, however, it is not clear that these episodes represented more than coincidental occurrences. The 1988 National Health Survey indicated that approximately 13 percent of adults surveyed reported having ''arthritis or any kind of rheuma-
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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality tism'' at the time of the survey (National Center for Health Statistics, 1989). This provides background data against which the VAERS reports of arthritis without fever can be considered. Since the arthritis that occurs in patients with acute hepatitis B virus infection appears to occur only during the period of antigen excess, it is almost invariably self-limited and appears to subside as the level of antibody increases. It is therefore difficult to relate arthropathy following receipt of the hepatitis B vaccine to the same sort of serum sickness-like antigen-antibody reaction. The quantity of HBsAg (10-40 µg) in recombinant hepatitis B vaccine preparations is very small relative to the amount of HBsAg produced in the acute phase of hepatitis B virus infection; it is therefore unlikely that enough free antigen would be available to produce a serum sickness-like reaction several days or weeks after the vaccine injection. Therefore, the biologic plausibility of such a reaction occurring after receipt of hepatitis B vaccine appears slim. It seems unlikely that arthritis occurred more commonly in those individuals who developed arthritis without fever than in unvaccinated individuals in the same age group. The incidence of acute arthritis following vaccination appears small relative to the prevalence of arthritis in the population from which the vaccinees were drawn (National Center for Health Statistics, 1989). Again, the lack of a denominator precludes a definite conclusion in this regard. Polyarteritis nodosa with associated acute arthritis has been observed following hepatitis B vaccination (Le Goff et al., 1988, 1991; McMahon et al., 1989). Yet, the vascular lesions observed in patients with chronic arthritis associated with polyarteritis nodosa appear to demand the continued presence of HBsAg over periods of months to years. It does not seem biologically plausible that chronic antigenic stimulation of this nature would occur after receipt of the relatively small amount of HBsAg contained in each dose of recombinant hepatitis B vaccine. Therefore, the likelihood of a causal relation between hepatitis B vaccination and chronic arthropathy secondary to vasculitis appears small. The reported flare-up of rheumatoid arthritis within 2 months after receiving hepatitis B vaccine raises the possibility that the vaccine may have precipitated an acute exacerbation of rheumatoid arthritis. However, the prevalence of rheumatoid arthritis in the age group that received the vaccines (0.1 to 1.0 percent) and the lack of a denominator make it impossible to assess causality. Conclusion The evidence is inadequate to accept or reject a causal relation between hepatitis B vaccine and either acute or chronic arthropathy.
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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality ANAPHYLAXIS Clinical Description The term anaphylaxis refers to the rapid onset (within 4 hours after vaccine administration) of a potentially life-threatening illness in which mortality is related either to cardiovascular collapse or to airway obstruction caused by either bronchospasm or laryngospasm. These life-threatening pathophysiologic events are often associated with cutaneous manifestations (hives, angioedema) and arthritis or arthralgias. Chapter 4 contains in-depth discussions of anaphylaxis and other adverse immunologic reactions, for example, the Arthus reaction and serum sickness, to vaccination. History of Suspected Association No infants or adults have been reported to have died of anaphylaxis after vaccination with either plasma-derived or recombinant hepatitis B vaccine. However, several cases of anaphylaxis following receipt of recombinant hepatitis B vaccines have been reported in adults. Of the groups of adults in industrialized countries for whom hepatitis B vaccine has been recommended, health care workers make up the great majority of vaccinees (Alter et al., 1988). As a consequence, most anaphylactic reactions have been observed in adult health care workers, of whom over 2 million have now been vaccinated against hepatitis B virus. Most of the documented cases of anaphylaxis occurred in women. This does not, however, justify a conclusion that women are more susceptible than men to anaphylaxis caused by hepatitis B vaccine, because women represent the majority of health care professionals for whom hepatitis B vaccine has been recommended. Evidence for Association Biologic Plausibility The possibility of a causal relation between hepatitis B vaccination and anaphylaxis is supported by biologic plausibility, by the temporal sequence of observed events following vaccination, and by the observation of a spectrum of host responses to the hepatitis B vaccine that follow a logical biologic gradient from true anaphylaxis to milder hypersensitivity reactions. Biologic plausibility derives from the knowledge that injection of foreign protein into humans can be expected to elicit, in some percentage of recipients, immunoglobulin E (IgE)-mediated responses that present as anaphylaxis. No specific inciting antigen has been demonstrated, and it is not known
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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality whether specific antibody of the IgE class is required for such events to occur after hepatitis B immunization. No data from experiments in animals clarify the immunologic events leading to anaphylaxis after hepatitis B vaccination. Case Reports, Case Series, and Uncontrolled Observational Studies The largest number of documented cases of anaphylaxis have been reported in VAERS (submitted between November 1990 and July 1992). Those reports include five well-documented cases of anaphylaxis in response to recombinant hepatitis B vaccine, none of which were fatal. Three of the cases of anaphylaxis occurred after the first dose of vaccine, whereas two occurred after the second dose. One of the five cases has been published as a case report (Hudson et al., 1991). There were five additional VAERS reports of apparent anaphylaxis following hepatitis B vaccination that did not meet the strict criteria applied in this report since a low blood pressure was not recorded. In each of these cases the patient received either intramuscular epinephrine (four cases) or diphenhydramine hydrochloride (Benadryl; one case), with excellent clinical responses. An additional eight cases of anaphylactic-type reactions (cardiovascular collapse associated with wheezing) are described in the VAERS reports, but the time interval following vaccination either was greater than 4 hours or was not defined in the VAERS report. Less severe manifestations of immediate hypersensitivity that do not fulfill the definition of anaphylaxis occur more commonly (Hudson et al., 1991; Lohiya, 1987; numerous VAERS reports). These are usually characterized by urticaria, wheezing, and sometimes, facial edema. Cardiovascular collapse does not occur, however, either because the reactions are inherently less severe or because they are aborted by intervention, usually with epinephrine. A possible explanation for the occurrence of anaphylaxis after the first vaccine injection is that the patients were sensitized to thimerosal or yeast protein, both of which are components of recombinant vaccines (Kirkland, 1990). An equally tenable hypothesis is that the three patients had previously been exposed to antigens similar to those present in the recombinant hepatitis B vaccine. Anaphylaxis was not observed in the 166,757 children vaccinated with a plasma-derived vaccine in New Zealand (Morris and Butler, 1992), nor was it observed in 43,618 Alaskan natives who received plasma-derived vaccine (McMahon et al., 1992). The postmarketing surveillance study discussed above (Shaw et al., 1988) investigated only specific adverse neurologic outcomes following receipt of hepatitis B vaccine and provided no data regarding anaphylaxis.
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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Controlled Observational Studies None. Controlled Clinical Trials None of the clinical trials reviewed by the committee contained information regarding hepatitis B vaccine and anaphylaxis. Causality Argument The possibility of a causal relation between hepatitis B vaccination and anaphylaxis is supported by biologic plausibility, by the temporal sequence of observed events following vaccination, and by the observation of a spectrum of host responses to the hepatitis B vaccine that follow a logical biologic gradient from true anaphylaxis to milder hypersensitivity reactions. Biologic plausibility derives from the knowledge that injection of foreign protein into humans can be expected to elicit, in some percentage of recipients, IgE-mediated responses that present as anaphylaxis. Chapter 4 provides the criteria for accepting the diagnosis of anaphylaxis, including cardiovascular collapse and documented hypotension occurring within 4 hours after injection of the vaccine. Only cases meeting these criteria were included as cases of hepatitis B virus-associated anaphylaxis in this report. In the VAERS reports of suspected anaphylactic reactions, however, a logical biologic gradient can be observed, in that, in addition to the five well-documented reports of anaphylaxis following administration of hepatitis B vaccine, five additional cases of apparent anaphylaxis following hepatitis B vaccination that did not meet the strict criteria applied in this report and an additional eight cases of anaphylactic-type reactions (cardiovascular collapse associated with wheezing) were described. The evidence concerning a possible relation between hepatitis B vaccination and anaphylaxis is based on VAERS reports. On the basis of these reports, the evidence indicates that anaphylaxis can occur after vaccination against hepatitis B virus and that such an occurrence is an exceedingly rare event. Nonetheless the timing and the unmistakable classic presentation of anaphylaxis, together with the spectrum of host responses that follow a logical biologic gradient from mild to severe following hepatitis B vaccination, indicate that hepatitis B vaccines can cause anaphylaxis. Conclusion The evidence establishes a causal relation between hepatitis B vaccine and anaphylaxis. Because the conclusion is not based on controlled studies,
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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality no estimate of incidence or relative risk is available. It would seem to be low. Risk-Modifying Factors Anaphylaxis may occur, albeit rarely, following hepatitis B vaccination, and there are no known risk factors that predict the likelihood of anaphylaxis after hepatitis B vaccination. Although prior sensitization to thimerosal or yeast protein may predict greater local swelling at the site of vaccination, such sensitization has not been documented to predict anaphylaxis. DEATH A detailed discussion of the evidence regarding death following immunization can be found in Chapter 10. Only the causality argument and conclusions follow. See Chapter 10 for details. Causality Argument The evidence establishes a causal relation between hepatitis B vaccine and anaphylaxis. Anaphylaxis can be fatal. Although there is no direct evidence of fatal anaphylaxis following hepatitis B vaccination, in the committee's judgment hepatitis B vaccine could cause fatal anaphylaxis. There is no evidence or reason to believe that the case fatality rate for vaccine-associated anaphylaxis would differ from the case fatality rate for anaphylaxis associated with any other cause. Hepatitis B vaccine has only recently begun to be administered to the age group that is affected by sudden infant death syndrome (SIDS). There are no published studies of a possible causal relation between hepatitis B vaccine and SIDS. There are reports in VAERS of SIDS following immunization with hepatitis B vaccine given in conjunction with other vaccines. Conclusion The evidence establishes a causal relation between hepatitis B vaccine and fatal anaphylaxis. There is no direct evidence for this; the conclusion is based on the potential for anaphylaxis to be fatal. The risk would appear to be extraordinarily low. The evidence is inadequate to accept or reject a causal relation between hepatitis B vaccine and SIDS. The evidence is inadequate to accept or reject a causal relation between hepatitis B vaccine and death from any cause other than those listed above.
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Representative terms from entire chapter: