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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders
Pages 17-90

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From page 17...
... The committee's mandate also includes assessing the broader significance for society of these immunization safety issues. In this fourth report in a series, the committee examines the hypothesis that the hepatitis B vaccine increases the risk for demyelinating disorders of the central or peripheral nervous systems, including multiple sclerosis (MS)
From page 18...
... · The scientif c assessment has two components: an examination of the epidemiological and clinical evidence regarding a possible causal relationship between the vaccine and the adverse event, and an examination of theory and experimental evidence from human or animal studies regarding biological mechanisms that might be relevant to the hypothesis. · The signif cance assessment addresses such considerations as the burden of the health risks associated with the vaccine-preventable disease and with the adverse event.
From page 19...
... For its evaluation of the hypothesis on hepatitis B vaccine and demyelinating neurological disorders, the committee first commissioned a background paper; its purposes were to review current understanding of the biological mechanisms thought to be involved in MS and other demyelinating disorders, and to analyze the relationship of those mechanisms to the putative role of hepatitis B vaccine in such disorders. The committee also held an open scientific meeting in March 2002 (see Appendix B)
From page 20...
... does or does not cause the adverse event in question. The weight of the available clinical and epidemiological evidence determines whether it is possible to shift from that neutral position to a finding for causality ("the evidence favors acceptance of a causal relationship")
From page 21...
... ~ of O a)
From page 22...
... under review in the case of this report, the effects of hepatitis B immunization on the risk for demyelinating neurological disorders. Epidemiological studies carry the most weight in a causality assessment; these studies measure health-related exposures and outcomes in a defined sample of subjects and make inferences about the nature and strength of associations between exposures and outcomes in the overall population from which the study sample was drawn.
From page 23...
... This committee, however, is often faced with a set of circumstances in which the epidemiological evidence is judged inadequate to accept or reject a causal association between a vaccine exposure and an adverse event of concern. It is then left with the task of examining proposed or conceivable biological mechanisms that might be operating if an epidemiologically sound association could be shown between vaccine exposure and an adverse event.
From page 24...
... , the committee will review evidence regarding "biological mechanisms" that might be consistent with the proposed relationship between a vaccine exposure and given adverse events. This assessment of the biological data is presented in a section of the report that is distinct from any argument regarding the causality of such relationships.
From page 25...
... Data from population-based studies of the effects of the vaccine administration on the occurrence of the adverse outcomes under review are considered not as evidence regarding the biological mechanisms but as evidence regarding causality. If the committee identifies evidence of biological mechanisms that could be operational, it will offer a summary judgment of that body of evidence as weak, moderate, or strong.
From page 26...
... Preventive Services Task Force, 1996~. However, the Immunization Safety Review Committee was convened specifically to assess topics that are often of immediate and intense concern.
From page 27...
... , optic neuritis, and transverse myelitis and the peripheral nervous system (PNS) demyelinating diseases of GBS and brachial neuritis.
From page 28...
... The Canonization Safety Review Committee, however, is neither equipped nor charged to conduct such a review. Adverse Neurological Events The adverse events considered in this report are all diseases involving demyelination of nerve cell axons in either the central or peripheral nervous systems.
From page 29...
... More than 80 percent of patients with MS initially experience a relapsing-remitting course, with clinical exacerbations of neurological symptoms that are followed by complete or partial recovery. Exacerbations can last from one day to several weeks.
From page 30...
... is the most sensitive of these paraclinical diagnostic tests, detecting lesions in 95 percent of patients (Waubant and Stuve, 2002~. Neuroirnaging studies may show disease activity that is not reflected in clinical symptoms and disability; only lesions of sufficient size give rise to neurological symptoms.
From page 31...
... At least three periventricular lesions Magnetic Resonance Imaging Criteria for Dissemination of Lesions in Time 1. If a first scan occurs 3 months or more after the onset of the clinical event, the presence of a gadolinium-enhancing lesion is sufficient to demonstrate dissemination in time, provided that it is not at the site implicated in the original clinical event.
From page 32...
... Nine or more T2 lesions in brain or 2) 2 or more lesions in spinal cord, or 3)
From page 33...
... . Acute Disseminated Encephalomyelitis ADEM, an inflammatory demyelinating disease of the CNS that can result in permanent and severe neurological disability, occurs most commonly in children and adolescents.
From page 34...
... Optic neuritis can occur as an isolated monophasic disease, or it nary be a symptom of other demyelinating diseases such as ADEM or MS. Optic neuritis is frequently, though not always, followed by a diagnosis of MS.
From page 35...
... Because no known cure exists for transverse myelitis, treatment is primarily devoted to symptom management and alleviation through steroid treatment to control inflammation and through physical therapy to maintain muscle strength and mobility. Guillain-Barre Syndrome GBS is the most common acquired peripheral demyelinating disease in humans (Waubant and Stuve, 2002~.
From page 36...
... Symptoms of acute HBV infection include 3 Chronic infection is defined by having hepatitis B surface antigen (HBsAg) for more than six months (Maddrey, 2000)
From page 37...
... This vaccine used inactivated alum-adsorbed hepatitis B virus surface antigen (HBsAg) particles purified from human plasma Dom persons with chronic HBV infections.
From page 38...
... High-risk adults include, but are not limited to, health care workers and public-safety workers who have exposure toblood in the worl~lace, hemodialysis patients, household contacts and sex partners of HBV carriers, and adoptees from countries where HBV is endemic (CDC, 1991~. SCIENTIFIC ASSESSMENT Causality As has been specified, the committee's review focused on six possible adverse outcomes: multiple sclerosis, acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, Guillain-Barre syndrome, and brachial neuritis.
From page 39...
... None of the challenge-rechallenge cases provides the level of laboratory or diagnostic detail to be contributory to a causality argument. VAERS received several reports of demyelinating disease following hepatitis B vaccination from November 1, 1990 through December 31, 2001 (CDC, 2002~.
From page 40...
... Reports included 125 cases of MS, 15 cases of brachial neuritis, 83 cases of optic neuritis, 46 cases of peripheral neuritis, 91 cases of GBS, 30 cases of ADEM or demyelinating disease not otherwise specified, and 109 cases of myelitis. Most of these reports were included in only one outcome category, but some (73)
From page 41...
... Two risk intervals were analyzed: receipt of the first dose of hepatitis B vaccine within two years of the index date and receipt of at least one dose of the vaccine at any time before the index date. The analyses with the healthy controls showed a relative risk of MS of 0.7 (95% CI 0.3-1.7)
From page 42...
... Considering only subjects with documented hepatitis B vaccine exposure and cases with definite or probable incident MS, the adjusted odds ratio for a first CNS demyelinating episode within two months of hepatitis B vaccination was 1.6 (95% CI 0.~5.6~. (Results for all cases are discussed below in the section on
From page 43...
... At the committee's March 2002 meeting, DeStefano (2002) presented unpublished findings from a case-control study examining the relationship in adults between hepatitis B vaccination and the development of central nervous system demyelinating diseases, specifically MS and optic neuritis.
From page 44...
... VAERS. A total of 408 unique reports of demyelinating disease following hepatitis B vaccination were received from November 1, 1990 through December 31, 2001 (foreign reports were excluded)
From page 45...
... Study strengths included limited confounding by the nature of the casecrossover study design, high response rates and validation of vaccine exposures, limited recall bias through collection of exposure data without specific reference to the index relapse, and results that are unaffected by a change in length of effect periods. Causality Argument For risk of incident MS in adults, the committee reviewed three controlled studies, of which one was published (Ascherio et al., 2001)
From page 46...
... For other neurological conditions following hepatitis B vaccination among children in this age group, VAERS has received 1 report each of brachial neuritis and optic neuritis, 8 reports of GBS, 6 reports of myelitis, and none of peripheral neuritis. Although underreporting to VAERS is substantial and MS occurs so rarely in infants and children, the lack of VAERS reports of MS in infants and children might indicate that MS is not occurring subsequent to hepatitis B vaccination in infants and children.
From page 47...
... Information on vaccine exposure was obtained through telephone interviews and confused with vaccination certificates for 152 cases and 253 controls. A conditional logistic regression was used to calculate adjusted odds ratios for risk of a first episode of CNS demyelinating disorder following hepatitis B vaccination.
From page 50...
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From page 52...
... Hepatitis B vaccine exposure was determined on the basis of medical chart reviews and telephone interviews for those vaccinated outside the HMO. Odds ratios for the risk of incident demyelinating disease following hepatitis B vaccination were calculated using a conditional logistic regression stratified by matching variables and adjusted for family history, race and ethnicity, place of birth, Scandinavian ancestry, smoking, and marital status.
From page 53...
... compared the number of observed cases of CNS demyelinating diseases with the number of cases expected under the hypothesis that no association exists between receipt of hepatitis B vaccine and risk of demyelinating disorder. An unpublished update was presented at the committee's March 2002 meeting (Fourrier and Begaud, 2002~.
From page 54...
... Based on an annual average MS incidence of two cases per 100,000 individuals, 917 cases of MS would have been expected among the vaccinated population during the 1989-1998 period. Noting that this number is almost five times greater than the number of reports actually received, the authors conclude that these findings provide no support for the hypothesis that receipt of GenHevac B vaccine increases the risk for onset of CNS demyelinating disorders.
From page 55...
... Therefore, the committee concludes that the evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and the first episode of a central nervous system demyelinating disorder. Acute Disseminated E?
From page 56...
... As described above, DeStefano (2002) presented to the committee, at its March 2002 meeting, unpublished f~ndings from a case-control study examining the relationship in adults between hepatitis B vaccination and the development of central nervous system demyelinating diseases, specifically MS and optic neuritis.
From page 57...
... Thus, the committee concludes that the evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and optic neuritis. Transverse Myelitis Other Studies: Passive Surveillance Data VAERS.
From page 58...
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From page 59...
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From page 60...
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From page 62...
... Thus, the committee concludes that the evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and brachial neuritis. Biological Mechanisms Although biological data do not provide an independent basis for evaluating causality, they can help validate epidemiologically based conclusions for or against causal associations.
From page 63...
... If the infectious agent was not detected, ongoing immune-mediated responses to that agent and the resulting injury of host tissues could be interpreted as autoimmunity, when in fact the immune response was directed against the foreign microbe and not against self. Major mechanisms proposed to account for the activation of self-reactive T and B cells and the induction of autoimmunity by infection include molecular mimicry, bystander activation, and non-specif~c or polyclonal activation of selfreactive T or B cells (Albert and Inman, 1999; Bach and Chatenoud, 2001; Benoist and Mathis, 2001; Davidson and Diamond, 2001; Marrack et al., 2001; Regner and Lambert, 2001; Rose, 2001; Singh, 2000; Wucherpfennig, 2001; Zinkernagel, 2001~.
From page 64...
... These nonspecific immune responses are usually self-limited, however, and resolve as the infection is cleared. If self-reactive T cells are activated by a nonspecific immune response, they could induce autoimmunity.
From page 65...
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From page 66...
... Nevertheless, the similarities of EAE to the human demyelinating diseases of MS and ADEM provide a strong indication that immunization with certain antigens can trigger autoimmune processes that produce demyelinating injuries. There is, however, no evidence that exposure to hepatitis B vaccine (which contains only one protein, HBsAg)
From page 67...
... Despite the usefulness of these animal virus models, the ability to extrapolate from them to human MS is limited. - Animal models for peripheral demyelinating disease also exist but are less well investigated than the models for CNS disease.
From page 68...
... are implicated as risk factors for both incident cases of MS and relapses, the hepatitis B virus is not prominent in the discussions of viral triggers. Known Effects of Other Vaccines Several vaccines are considered causally associated with demyelinating diseases of either the central or peripheral nervous system.
From page 69...
... There is no evidence that HBsAg is capable of bystander activation of a Thl-type response, is a superantigen, is a molecular mimic with a myelin-related antigen, or otherwise induces nonspecific polyclonal activation. Thus, the committee concludes that there is weak evidence for biological mechanisms by which hepatitis B vaccination could possibly influence an individual's risk of the central or peripheral nervous system disorders of MS, first episode of CDD, ADEM, optic neuritis, transverse myelitis, GBS, or brachial neuritis.
From page 70...
... In the present case, the committee considered the possibility that the exposure of adults and infants to the hepatitis B vaccine might increase the risk for demyelinating neurological disorders such as MS, GBS, and peripheral neuritis. This issue initially gained attention because of reports collected in the three years after the introduction of the plasma-derived vaccine, of demyelinating disease, particularly GBS, occurring after vaccination (Straw et al., 1988~.
From page 71...
... Hepatitis B Vaccine Safety Concerns in France The possibility that the hepatitis B vaccine may contribute to the development of MS and other autoimmune disorders provoked concerning France in the early 1990s after the publication of two case reports on CNS demyelination following hepatitis B vaccination (Herroelen et al., 1991~. The reports received strong media attention, and fears about the safety of the vaccine quickly spread throughout France and then to Europe and North America.
From page 72...
... Acute HBV infection can result in serious illness and some deaths, but chronic infection is a greater concern because of the increased risk of cirrhosis and hepatocellular carcinoma (HCC) in the infected person and the continuing risk for transmission of the virus to others.
From page 73...
... CDC has estimated that in 1991, prior to the recommendation for universal infant immunization, approximately 16,000 children between the ages of 0 to 9 years acquired nonperinatal HBV infections (Armstrong et al., 2001~. Slightly more than half of them were children of foreign-born mothers (See Table 4~.
From page 74...
... . TABLE 5 Estimated Number of Chronic Hepatitis B Infections and Related Deaths in 1998 Birth Cohort with No Immunization Program HBV- Chronic Infection # Chronic Death Rate # Deaths g Infected Rate Infections (HCC/Cirh)
From page 75...
... A perinatal prevention and infant immunization program would reduce the estimated lifetime risk of infection by at least 68 percent. Nevertheless, gaps continue to exist in the prevention of perinatal infection.
From page 76...
... However, a recent survey of pediatricians found that 11 percent of the respondents remained concerned about the safety of administering a vaccine to neonates (Cooper et al., 2001~. Nevertheless, the committee found little overall indication that safety concerns are a major barrier to acceptance of hepatitis B vaccination in the United States.
From page 77...
... For the first set of searches, the committee assumed that the concerned public would turn to standard search engines to locate appropriate information. Thus, the committee conducted keyword searches using Netscape, Lycos, Google, and Yahoo.
From page 78...
... For the second set of searches, We committee examined websites of five orga~ations, both within and outside government, to which parents and the concerned public would likely turn for answers to their vaccine-related questions. (see Table 7~.
From page 79...
... . Conclusions The committee's assessment of the significance of concerns about possible neurological disorders as a result of hepatitis B vaccination took several factors into account: the burden of hepatitis B infection in infants, in adults, and in the population; the burden of neurological conditions, particularly MS; and indica
From page 80...
... Policy Review The committee does not recommend a policy review of the hepatitis B vaccine by any of the national and federal vaccine advisory bodies, on the basis of concerns about demyelinating neurological disorders. Research Although the committee concluded that the epidemiological evidence is inadequate to accept or reject a causal relationship between the hepatitis B vaccine and most of the demyelinating disorders it reviewed, the committee found a
From page 81...
... Because the hepatitis B vaccine has been routinely administered to newborns and infants since 1991, surveillance of this exposed and aging group provides an opportunity to study its incidence of MS. The incidence of other central and peripheral nervous system disorders, such as optic neuritis, ADEM, GBS, brachial neuritis, and transverse myelitis should also be examined in this group.
From page 82...
... The Immunization Safety Review Committee reviewed the evidence regarding the hypothesis that the hepatitis B
From page 83...
... BOX 2 Committee Conclusions and Reco~endations SCIENTIFIC ASSESSMENT Causality Conclusions The committee concludes that the evidence favors rejection of a causal relationship between hepatitis B vaccine administered to adults and incident multiple sclerosis. The committee also concludes that the evidence favors rejection of a causal relationship between hepatitis B vaccine administered to adults and multiple sclerosis relapse.
From page 84...
... The committee concludes that the evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and GBS. The committee concludes that the evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and brachial neuritis.
From page 85...
... 2002. Descriptive summary of VAERS reports indicating possible demyelinating disease following hepatitis-B vaccination, all ages, 1999-2001.
From page 86...
... Presentation to Immunization Safety Review Committee. Herroelen L, de Keyser J
From page 87...
... 2002. Immunization Safety Review: Multiple Immunizations and Immune Dysfunction.
From page 88...
... Optic neuritis. Curr Opin Ophthalmol 9(6)
From page 89...
... 2000. Translated from [Central nervous system demyelinating disease following hepatitis B vaccination with GenHevae B
From page 90...
... 1999. No increase in demyelinating diseases after hepatitis B vaccination.


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