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Immune-mediated myelitis following hepatitis B vaccination
Autoimmunity Reviews 12 (2012) 144–149
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Review
Immune-mediated myelitis following hepatitis B vaccination Joerg-Patrick Stübgen ⁎ Department of Neurology and Neuroscience, Weill Cornell Medical College/New York Presbyterian Hospital, USA
a r t i c l e
i n f o
Article history: Received 2 March 2012 Accepted 20 March 2012 Available online 1 April 2012 Keywords: Hepatitis B vaccine Post-vaccination Autoimmunity Myelitis
a b s t r a c t The hepatitis B virus (HBV) is an important international cause of infectious acute and chronic liver diseases. HBV vaccines were developed to combat the potential life-threatening effects of HBV infection. Published case histories, retrospective reviews and analyses of epidemiological data report on the onset of immunemediated myelitis after recombinant HBV vaccination, mostly in adults with a presumed genetic/ immunologic predisposition. However, HBV vaccination has not borne out to be a significant trigger of serious autoimmune events, including acute myelitis, in populations at large over prolonged observation periods after immunization. Published study methods lack the sensitivity to categorically establish a causal relationship between exposure to HBV vaccine components and immune mediated myelitis, but in practice the faint possibility of such a link should not be totally rejected. © 2012 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . Hepatitis B virus background . . . . . . . Hepatitis B vaccine background . . . . . . Hepatitis B virus vaccines and autoimmunity Hepatitis B virus vaccines and acute myelitis 5.1. Case reports . . . . . . . . . . . . 5.2. Retrospective reviews . . . . . . . 5.3. Epidemiological studies . . . . . . 6. Post-vaccination autoimmunity . . . . . . 7. Conclusion . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . .
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1. Introduction The transverse myelitis syndrome entails an immune-mediated attack against spinal cord structures; it is associated with a preceding infection or vaccination, an underlying systemic autoimmune disease or an acquired inflammatory demyelinating disease [1]. Between 15 and 30% of cases are deemed “idiopathic” because no cause can be established [2,3]. The annual incidence of post-infectious or idiopathic myelitis is estimated to be less than 5 cases per million of the population, with bimodal age peaks between 10 and 19 years, and 30 ⁎ Department of Neurology and Neuroscience, Weill Cornell Medical College/New York Presbyterian Hospital, 525 East 68th Street, NY 10065-4885, USA. Tel.: + 1 212 746 2334; fax: + 1 212 746 8742. E-mail address: [email protected]. 1568-9972/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2012.03.008
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and 39 years [4–7]. The rarity of acute transverse myelitis hinders study, and appropriate experimental or animal models have not been developed. Vaccines offer a major contribution to public health in the modern era [8]. Vaccination is a powerful immune system stimulus, and has the theoretical potential to induce or exacerbate immune disturbances that manifest as serological indices of immune system dysregulation or as clinically manifest autoimmune disease. Adverse autoimmune reactions to various vaccines have been reported, but a causative association has not been definitely established. Epidemiological studies and controlled studies that aimed to evaluate the role of viral vaccines in a variety of autoimmune diseases obtained negative results [9,10]. However, these types of studies lacked the statistical power to rule out the possibility of a rare causal relationship [9,11]. It seems not unreasonable to consider vaccines rare triggers of
J.-P. Stübgen / Autoimmunity Reviews 12 (2012) 144–149
autoimmune reactions in genetically or immunologically predisposed individuals [12]. However, there exists no “unequivocal and irrevocable” evidence of a causative link between immunization and autoimmunity [13]. The worldwide use of recombinant hepatitis B virus (HBV) vaccines has been shown to be an effective and safe method to combat the spread of HBV infections. However, these vaccines have been associated with diverse adverse events, and are the second most common vaccines reported to the US Vaccine Adverse Events Reporting System [VAERS] (www.hrsa.gov/ vaccinecompensation/index.html). In a recent multi-analysis review of literature case reports of acute myelitis following immunization, HBV vaccines were the most common vaccines associated with acute myelitis [14]. The aim of this article is to present in a single text a review of the relationship between HBV vaccination and acute (transverse) myelitis. A systematic search was conducted of relevant publications using data bases MEDLINE [PubMed], EMBASE and DynaMed (through December 2011) that included case reports and series, case–control studies, postmarketing surveillance programs, and published analyses of VAERS. Search terms included “myelitis”, “myelopathy”, “hepatitis B vaccine/ vaccination”, “post-vaccination”, and “autoimmunity”. Article bibliographies were checked to ensure all studies and reports were included. Publications were retrieved, cross-referenced, and analyzed. 2. Hepatitis B virus background Hepatitis B virus (HBV), a small DNA virus of the Hepadnaviridae family, is an important, worldwide cause of infectious acute and chronic liver diseases [15]. Before introduction of universal childhood vaccination programs in the US, an estimated 300,000 new HBV infections occurred yearly [16]. In the US these days, 97% of newly recognized HBV infections and about 75% of newly diagnosed HBV carriers involve adults [17]. HBV is transmitted by permucosal or percutaneous exposure to infected blood via sexual contact, contaminated needles or blood products [18]. The clinical incubation period ranges from 2 to 3 months. Around two-thirds of patients with acute HBV infection suffer a mild, asymptomatic and subclinical illness [19]. About 5 to 10% of infected adults cannot clear HBV, and become chronically infected [20]. Worldwide, about 400 million people suffer chronic HBV infection with a prevalence ranging from 0.5% (US and Europe) to 10% (eastern Asia) [21,22].
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safe and well tolerated [23,27]. The CDC opined that there exists no firm scientific evidence that invokes HBV vaccines as a definite cause of chronic illness. Independent review committees of the US Institute of Medicine and the World Health Organization's Global Advisory Committee on Vaccine Safety concluded that no unequivocal link has been established between the HBV vaccines and chronic illness [28]. Moreover, non-live composite vaccines, including recombinant HBV vaccine, seem mostly immunogenic and safe in pediatric patients with rheumatic diseases [29] and in adults with underlying immunosuppression [30,31], including autoimmune inflammatory rheumatic diseases [32,33]. Nevertheless, evidence in the form of published case reports and analyses of the VAERS epidemiological database as well as biological plausibility theories hint at an association (mainly temporal) between a variety of acute and chronic autoimmune diseases and any of the components of recombinant HBV vaccines (i.e., crossreactive HBsAg epitopes, extraneous yeast antigens, aluminum adjuvant, thimerosal preservative) among probable genetically or immunologically predisposed adult vaccine recipients [23,27,34,35]. Manifestations of a disease may be considered “vaccine-related” within a post-vaccination period of 2–3 months according to the Viral Hepatitis Prevention Board (a WHO collaborating center for the prevention of viral hepatitis) (www.vhpb.org). The concept of a spectrum of immune-mediated diseases following the injection (e.g., vaccine adjuvant) or implanting of foreign matter [36,37], has recently attracted increasing attention and has been termed “Auto-inflammatory Syndrome induced by Adjuvants” (ASIA) or Shoenfeld's syndrome [38,39]. Adjuvant exposure is common, but clinically overt ASIA seems relatively rare, and may require additional risk factors such as genetic susceptibility or the coexposure to other environmental factors [38]. A recent study analyzed the common characteristics of 93 patients with autoimmunity following HBV vaccine as part of the spectrum of ASIA syndrome [40]; commonly reported manifestations included neuropsychiatric (70%), musculoskeletal (59%), gastrointestinal (50%) and fatigue (42%) complaints. 5. Hepatitis B virus vaccines and acute myelitis Case histories, retrospective reviews and post-marketing surveillance data report on the onset of acute myelitis following HBV vaccination.
3. Hepatitis B vaccine background 5.1. Case reports HBV vaccines were developed to combat the potential lifethreatening effects of HBV infection. The recombinant HBV vaccines, (available in the US since 1986) are highly purified, genetically engineered, single-antigen vaccines [23]. Manufacturers produce these vaccines by inserting the gene for HBsAg into a variety of yeast cells (or mammalian cell line) [24]; free HBsAg particles (20 nm size) are purified by biochemical and biophysical methods. Particles are adsorbed onto an adjuvant (aluminum hydroxide) with/without a preservative (thimerosal). In the US, licensed single-antigen HBV vaccines, Engerix R (GlaxoSmithKline) and Recombivax R (Merck), are given as a 3-dose series, and are recommended for use in national childhood vaccination programs and the high-risk adult population [15]. The seroconversion rate after required doses was 99% for infants up to 2 years, 96% for 13-year-old children, and 86% for adults up to 60 years of age [25,26]. Production of plasma-derived HBV vaccine was discontinued in the US in 1990, and is unavailable on this market. 4. Hepatitis B virus vaccines and autoimmunity There exists broad consensus among the medical and scientific communities that the benefits of HBV vaccination far outweigh any potential risks, and that single-antigen recombinant HBV vaccines are
Literature reports on new-onset central nervous system demyelination shortly after HBV vaccination included cases of acute (transverse) myelitis. A summary of published case histories of HBV vaccine-associated acute myelitis appears in Table 1 [41–49]. Two cases were excluded because patient demographic and clinical information was not supplied [50]. The pediatric cases occurred in children immunized at an age beyond the recommended US childhood immunization schedule (www.cdc.gov/vaccines/recs/ acip). The interval between vaccination and first manifestations of myelitis varied between 6 days and 6 weeks. Myelitis occurred after administration of either plasma-derived or recombinant HBV vaccines. Myelitis occurred after any of 3 recommended vaccine doses; one pediatric case occurred after a recombinant HBV vaccine booster shot. Spine MRI scans showed cord swelling, T2-weighted signal change with or without Gadolinium enhancement, and the longitudinal extent of lesions stretched up to 11 cord segments; the spinal cord was also reported normal. Head MRI scans were normal. In some cases, management entailed a short course of immunomodulatory therapy, and supported a hypothesis of a vaccine-associated immune attack against unidentified spinal cord antigens. Some patients improved or recovered spontaneously, so that a relatively short,
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Table 1 HBV vaccine-associated myelitis. Author
Age/sex
Interval/dose/type
CSF/MRI
Treatment
Outcome (follow-up)
Mahassin [41] Trevisani [42] Tartaglino [43] Senejoux [44] Song [45] Renard [46] Iñiguez [47] Karaali-Savrun [48]
56/M 11/F 40/M 64/F 31/M 16/F 15/F 42/F 33/M 40/F 42/F 3/M
3 weeks/#3/(rt) 3 weeks/#1/(pd) 2 weeks/#1/(rt) 6 days/#2/(rt) 2 weeks/#3/(pd) 8 hours/booster/(rt) 1 week/#1/(NR) 6 weeks/#2/(rt) 4 weeks/#3/(rt) 3 weeks/#1/(rt) 3 months/#3/(rt) 10 days/#1/(NR)
↑cells/N ↑protein/N NR/C6-T8 N/T2 N/C4-5 OCB/C2 N/C6-T2 NP/C2-3 N/C1-2 OCB/T9-10 OCB/C6 N/C4-T3
I.v. CS None NR None I.v. CS I.v. CS I.v. CS None I.v. CS P.o./i.v. CS NR I.v. CS/IVIG
Independent ambulation (6 months) Partial urinary retention (2.5 years) NR Resolving dysesthesia (6 months) Paresthesia (6 months) Recovered; (+) Lhermitte (4 months) Recovery (4 years) Recovery (3 months) Recovery (NR) Relapsing–remitting (18 months) NR (1 year) Ambulant (6 months)
Fonseca [49]
CS, corticosteroids; pd, plasma-derived; n, normal; NP, not performed; NR, not reported; OCB, oligoclonal bands; rt, recombinant.
self-limited disease course implied a benign prognosis, and reflected the transient nature of the presumed immune perturbation [51]. Neurological outcome was favorable even in patients with severe initial deficits such as quadriplegia [49] or paraplegia [42] with urinary retention. No patient was re-exposed to HBV vaccine on the premise that vaccination triggered an immune attack against the spinal cord. However, a single patient developed relapsing–remitting demyelinating disease that eventually fulfilled criteria for a diagnosis of multiple sclerosis [48]. Conceivably, these reports underestimate the true number of HBV vaccine-associated myelitis cases worldwide. A dearth of recent publications may reflect negative reporting bias i.e., physicians are disinclined to report, and medical journals unwilling to publish, case histories that do not add significant or unique contributions to existing literature. Moreover, this literature search found no individual reports of acute myelitis in infants immunized according to the recommended pediatric HBV vaccination schedule (3rd vaccine dose administered by age 18 months). This phenomenon may hint at a relative inability of an immature immune system to launch clinical autoimmune disease in response to immunization (see later). Such a hypothesis gains some credence from a study that showed the same antibody profile in 6-year-old children immunized at birth with recombinant HBV vaccine compared to a matched control group [52]. In these reports, an association between myelitis and HBV vaccination seemed more than fortuitous based on a combination of observations [10,53]: (a) temporal association (reactions followed vaccination after a latent period compatible to the presumed immune-triggered mechanism of disease); (b) no alternative etiology was identified (however, an “idiopathic” or unidentified post-viral mechanism of disease may be impossible to disprove); (c) biological plausibility (see later); (d) stabilization and improvement of myelitis after interrupting exposure to HBV vaccine, the presumed inciting agent; (e) analogy i.e., cases of acute myelitis were reported after immunization with other vaccine types [14] as well as a spectrum of virus infections [7,54]; (f) specificity (similar cases of HBV vaccineassociated myelitis were reported from a wide geographic distribution). However, the criterion of “re-challenge” (i.e., recurrence or significant exacerbation of symptoms soon after re-exposure) was not met [35,55] because no patient was re-immunized after a presumed adverse vaccine response. The importance of case reports lies in the potential to provide “first line” evidence to generate a disease hypothesis [56,57]. Such reports identify a new disease or condition, generate information on the natural history of disease, offer fast and inexpensive study, and are frequently the first form of publication [58]. However, the anecdotal nature of reports creates a potential for selection bias, and provides only limited potential to establish causal effects. Therefore, these case reports of acute myelitis following administration of HBV vaccines should not be interpreted as proof of cause.
5.2. Retrospective reviews A recent systematic review of English-language journals published between 1970 and 2009 searched for, and analyzed, reported cases of transverse myelitis following vaccination in any age group [14]. HBV vaccines were the most common immunization associated with acute myelitis. The authors felt that the concept of vaccination-induced myelitis was not to be dismissed or ignored. This conclusion was based on the relatively close temporal association between the onset of myelitis and administration of various types of vaccine, and the possible mechanisms linking these phenomena. The association between acute myelitis and many different vaccines raised the question of a possible common denominator as culprit trigger for autoimmunity, such as a common adjuvant. This author reviewed the most notable retrospective case series of acute transverse myelitis in the pediatric population [59–63]. In the largest series (47 patients from a single center) only, a relatively high percentage of cases (28%) had received vaccines (a single HBV vaccine recipient) or allergy shots within 30 days of neurological symptom onset [63]. Although the study was primarily aimed to assess functional outcome at follow-up, the authors proposed that a potential causal link between vaccination and acute myelitis was weakened by the large fraction of younger children affected, the current recommended vaccination schedule for children, and the lack of any single vaccine association for the entire group. 5.3. Epidemiological studies Post-marketing surveillance by the US CDC, FDA and vaccine manufacturer (June 1982 to May 1985) for neurological events after plasma-derived HBV immunization included 4 voluntarily reported cases of acute transverse myelitis (out of about 850,000 vaccine recipients) [64]. The accepted interval between vaccination and onset of symptoms ranged from 2 weeks to as long as 27 weeks. In the final analysis, no conclusive epidemiologic association could be ascertained between any reported neurological adverse event and this type of vaccine. Plasma-derived HBV vaccine is no longer available in the US, and will not be discussed further. In 1990, the CDC and FDA established the VAERS program in response to the National Childhood Vaccine Injury Act. VAERS is a post-marketing, national vaccine safety surveillance program that collects information about adverse events after administration of licensed vaccines in the US (www.vaers.hhs.gov/index). It needs to be emphasized that the inclusion of any reported adverse event in VAERS data does not infer causality. It is also impossible to reliably estimate the incidence of vaccine-related adverse events because the data reported to VAERS consist of a collection of single case reports (without a case cohort control group) from an uncertain population
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sample size. VAERS is subject to the limitations of any voluntary, passive surveillance system, such as: (a) underestimation (under- or non-reporting); (b) differential reporting (reporting increases in the initial few years after vaccine licensure); (c) stimulated reporting (reporting increases after an alleged similar adverse events become known); (d) reporting of coincidental events (unknown type or duration of concomitant medical condition); (e) dubious data quality and completeness (varies between physicians or institutions), and (f) unknown differences between the post-marketing surveillance groups and the clinical trial-selected populations. In a study to assess the safety of recombinant HBV vaccines, the VAERS database was analyzed for the incidence (among adults) of adverse reactions after HBV vaccination (1997 to 2000) compared to vaccine (tetanus toxoid and tetanus–diphtheria) control groups (1991 to 2000) [34]. Analysis showed a statistically significant increase in the incidence of adverse reactions after immunization with HBV vaccines compared to the control vaccines (for myelitis, p = 0.01 and 0.05, respectively). The incidence of myelitis was determined at 0.56 cases per million HBV vaccine doses administered. This number fell within the range of the background incidence of acute myelitis (post-infectious and idiopathic) in the general population. A re-review offered additional VAERS data on adverse reactions following administration of HBV vaccine compared to the tetanus–diphtheria vaccine control group [23]. The logic behind this analysis was a premise that the HBV and control vaccines were similarly affected by factors inherent to the database (null hypothesis). For the “myelitis” patient subgroup, analysis established the relative risk (6.8), attributable risk (5.6), and percentage association (87%) for a statistically significant p value b0.05. For “chronic myelitis” cases, analysis determined the relative risk (15.0), attributable risk (14.0), and percentage association (94%) for statistically significant p value b0.0001. In the HBV vaccine group, the mean age of myelitis patients was 29.1 (+/−9.9) years, and mean onset was 3.3 (+/−4.9) days. Without implying proof of a causal link, the statistical significance of analyzed data, nevertheless, revealed an apparent association between adult HBV vaccination and myelitis (among other adverse reactions). It seemed reasonable to conclude that adult HBV recipients were at increased risk to develop myelitis (and other adverse reactions), but only within a defined, close time frame following immunization. However, when entire adult populations were studied over extended periods (i.e., years) following immunization HBV vaccines were not a leading cause of serious autoimmune disorders (including acute myelitis) [23] or central nervous system demyelinating disease [65]. A retrospective examination of the VAERS database by the VAERS Working Group of the CDC found 120 reports of myelitis among other autoimmune conditions after HBV vaccination [35]. A summary of patient data included female to male ratio (2.2), median age (34 years), median interval between vaccination and onset of myelitis (22 days), and neurological outcome at 1 year (36% disabled). No cases of myelitis were found on a search of VAERS data for reports of positive re-challenge with HBV vaccines. Based on evidence such as biological plausibility, literature case reports (see above), and epidemiological (VAERS) data, the authors were inclined to at least consider a causal relationship between HBV vaccination and a variety of autoimmune diseases (including myelitis) in presumed genetically/immunologically susceptible adult vaccine recipients in a fairly close (days to weeks), defined period following immunization. Lastly, a case–control epidemiological study evaluated the potential risk of serious autoimmune adverse events that had been reported prospectively to VAERS following immunization with HBV vaccine compared to a tetanus-containing vaccine control group (recipients >7 years old during period 1. January 1990 to 25. May 2004) [27]. This study evaluated autoimmune conditions that had been previously identified on an a priori basis from case reports. Unfortunately, patients with acute myelitis were not included in this
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analysis because at least one “control” case was required for matching an “adverse event” case for the latter to be included in the study. 6. Post-vaccination autoimmunity The mechanisms of autoimmune phenomena after vaccination are extrapolated mainly from the known capacity of infectious agents (against which particular vaccines are directed) to induce autoimmunity [56], and from animal models and in vitro studies [12]. Biological plausibility is based on [66–71]: (a) molecular mimicry (structural homology between virus/vaccine and host antigenic components) [72,73]; (b) epitope spreading (a new immune response to dissimilar epitopes on the same or different antigens) [74,75]; (c) bystander effect (priming of virus/vaccine antigenspecific T cell in a permissive immune environment) [76,77]; (d) presentation of cryptic epitopes from self-tissue [78,79]; (e) reactivation of self-reactive memory T cells [80,81]; (f) superantigens (crosslinkage of T cell receptor and MHC molecule independent of specific antigen recognition) [82,83]; (g) formation of immune complexes [84,85]; (h) HLA class I antigen expression on non-immune cells (could lead to presentation of autoantigens and recognition by autoreactive T cells) [86,87], and (i) individual genetic susceptibility to autoimmunity [88]. These pathogenic mechanisms are not mutually exclusive, and any may be relevant depending on the stage of evolution of disease [89]. Any invoked mechanism depends also on the presumed pathogenesis of the specific immune disorder. Perhaps a common denominator, such as an aluminum-based adjuvant, plays a pathogenic part in the association between many different types of vaccine and acute myelitis [14] and other HBV vaccine-associated serious adverse events [19,23,40]. Adjuvants are administered simultaneously with vaccines to induce a more vigorous immune response to the vaccinated antigens [90–93]. There is growing appreciation of a direct link between adjuvant administration and “autoimmune”-like clinical syndromes (ASIA syndrome). Adjuvants may mimic specific sets of conserved molecules such as bacterial polysaccharides, endocytosed nucleic acids and unmethylated CpG-DNA that activate the innate immune response [14,90]. Adjuvants may exert immune-enhancing effects by: (a) translocation of antigens to lymph nodes which enhances antigen recognition by, and stimulation of, T cells; (b) antigen protection so that delivery and prolonged exposure to the immune system stimulates B and T cell production; (c) increase of local injection site reaction which enhances release of stimulatory chemokines by T cells and mast cells; (d) promoting release of inflammatory cytokines which recruit B and T cells to infection sites and increase translational events, or (e) interaction with pattern recognition receptors on leukocyte (accessory cell) surfaces [94–97]. The development and incorporation of safe and novel adjuvants into future vaccines should help motivate population compliance with recommended immunization programs worldwide. 7. Conclusion Case histories, retrospective reviews and epidemiological studies report on the occurrence of immune adverse events after HBV vaccination. These study methods lack sensitivity to categorically prove a causal relationship between vaccination and acute myelitis, but leave open to doubt a faint possibility of linkage. The concept of HBV vaccine-associated myelitis is difficult to ignore completely, and rests mainly on the temporal association of events and inference from the biological plausibility of vaccine-triggered autoimmune events. The rarity of acute transverse myelitis hinders study, but reviewed literature suggests that it is not unreasonable to at least consider a link between HBV vaccination and a variety of autoimmune diseases (including acute myelitis) in a close and defined period following immunization in presumed genetically/immunologically susceptible
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adult vaccine recipients. Clinicians are encouraged to approach patient care according to the dictum “absence of proof does not equate proof of absence”. Take-home messages • HBV vaccination of children and at-risk adults reduced rate of new infections. • Recombinant HBV vaccines are effective, safe and well tolerated. • HBV vaccination has been associated with various autoimmune phenomena. • The concept of HBV vaccine-associated myelitis is difficult to ignore completely. • Post-vaccination myelitis is presumably immune-mediated. • Post-vaccination myelitis may benefit from immunomodulatory therapy. References [1] Frohman EM, Wingerchuk DM. Transverse myelitis. N Engl J Med 2010;263: 564–72. [2] De Seze J, Stojkovic T, Breteau G, Lucas C, Michon-Pasturel U, Gauvrit JY, et al. Acute myelopathies: clinical, laboratory and outcome profiles in 79 cases. Brain 2001;124:1509–21. [3] De Seze J, Lanctin C, Lebrun C, Malikova I, Papeix C, Wiertlewski S, et al. Idiopathic acute transverse myelitis: application of recent diagnostic criteria. Neurology 2005;65:1950–3. [4] Berman M, Feldman S, Alter M, Zilber N, Kahana E. Acute transverse myelitis: incidence and etiologic considerations. Neurology 1982;31:966–71. [5] Christensen PB, Wermuth L, Hinge HH, Bomers K. Clinical course and long-term prognosis of acute transverse myelopathy. Acta Neurol Scand 1990;81:431–5. [6] Jeffrey DR, Mandler RN, Davis LE. Transverse myelitis. Retrospective analysis of 33 cases, with differentiation of cases associated with multiple sclerosis and parainfectious events. Arch Neurol 1993;50:532–5. [7] Bhat A, Naguwa S, Cheema G, Gershwin ME. The epidemiology of transverse myelitis. Autoimmun Rev 2010;9:A395–9. [8] Maldonaldo YA. Current controversies in vaccination. Vaccine 2002;288:3155–8. [9] Chen RT, Pless R, DeStefano F. Epidemiology of autoimmune reactions induced by vaccination. J Autoimmun 2001;16:309–18. [10] Schattner A. Consequence or coincidence? The occurrence, pathogenesis and significance of autoimmune manifestations after viral vaccines. Vaccine 2005;23: 3876–86. [11] Stratton KR, Howe CJ, Johnston Jr RB. Adverse events associated with childhood vaccines other than pertussis and rubella. Summary of a report from the Institute of Medicine. JAMA 1994;271:1602–5. [12] Salemi S, D'Amelio R. Could autoimmunity be induced by vaccination? Int Rev Immunol 2010;29:247–9. [13] Shoenfeld Y, Aron-Maor A. Vaccination and autoimmunity — ‘vaccinosis’: a dangerous liaison? J Autoimmun 2000;14:1–10. [14] Agmon-Levin N, Kivity S, Szyper-Kravitz M, Shoenfeld Y. Transverse myelitis and vaccines: a multi-analysis. Lupus 2009;18:1198–204. [15] Centers for Disease Control, Prevention. Protection against viral hepatitis. Recommendations of the immunization practices advisory committee (ACIP). MMWR 1990;39:1–26. [16] Centers for Disease Control and Prevention. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: recommendations of the immunization practices advisory committee (ACIP). MMWR 1991;40:1–19. [17] Wasley A, Grytdal S, Gallagher K. Centers for Disease Control and Prevention (CDC). Surveillance for acute viral hepatitis — United States, 2006. MMWR Surveill Summ 2008;57:1–24. [18] Francis DP, Favero MS, Maynard JE. Transmission of hepatitis B virus. Semin Liver Dis 1981;1:27–32. [19] McMahon BJ, Helminiak C, Wainwright RB, Bulkow L, Trimble BA, Wainwright K. Frequency of adverse reactions to hepatitis B vaccine in 43,618 persons. Am J Med 1992;92:254–6. [20] Liang TJ. Hepatitis B: the virus and disease. Hepatology 2009;49(Suppl.):S13–21. [21] Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337:1733–45. [22] Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2001;34:1225–41. [23] Geier MR, Geier DA, Zahalsky AC. A review of hepatitis B vaccination. Expert Opin Drug Saf 2003;2:113–22. [24] Tron F, Degos F, Bréchot C, Couroucé AM, Goudeau A, Marie FN, et al. Randomized dose range study of a recombinant hepatitis B vaccine produced in mammalian cells and containing the S2 and preS2 sequences. J Infect Dis 1989;160:199–204. [25] Da Villa G, Picciottoc L, Elia S, Peluso F, Montanaro F, Maisto T. Hepatitis B vaccination: universal vaccination in newborn babies and children at 12 years of age versus high risk groups. A comparison in the field. Vaccine 1995;13:1240–2. [26] Shouval D. Hepatitis B vaccines. J Hepatol 2003;39(Suppl. 1):S70–6. [27] Geier DA, Geier MR. A case–control study of serious autoimmune adverse events following hepatitis B immunization. Autoimmunity 2005;38:295–301.
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[50] Isoda H, Ramsey RG. MR imaging of acute transverse myelitis (myelopathy). Radiat Med 1998;16:179–86. [51] Maillefert JF, Sibilia J, Toussirot E, Vignon E, Eschard JP, Lorcerie B, et al. Rheumatic disorders developed after hepatitis B vaccination. Rheumatology 1999;38: 978–83. [52] DeStefano F, Mulloolly JP, Okoro CA, Chen TR, Marcy SM, Ward JI, et al. Childhood vaccinations, vaccination timing, and risk of type 1 diabetes mellitus. Pediatrics 2001;108:E112. [53] Miller FW, Hess EV, Clauw DJ, Hertzman PA, Pincus T, Silver RM, et al. Approaches to identifying and defining environmentally associated rheumatic disorders. Arthritis Rheum 2000;43:243–9. [54] Kinkaid O, Lipton HL. Viral myelitis: an update. Curr Neurol Neurosci Rep 2006;6: 469–74. [55] Konstantinou D, Paschalis C, Maraziotis T, Dimopoulos P, Bassaris H, Skoutelis A. Two episodes of leukoencephalitis associated with recombinant hepatitis B vaccination in a single patient. Clin Infect Dis 2001;33:1772–3. 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Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
Review
Immune-mediated myelitis following hepatitis B vaccination Joerg-Patrick Stübgen ⁎ Department of Neurology and Neuroscience, Weill Cornell Medical College/New York Presbyterian Hospital, USA
a r t i c l e
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Article history: Received 2 March 2012 Accepted 20 March 2012 Available online 1 April 2012 Keywords: Hepatitis B vaccine Post-vaccination Autoimmunity Myelitis
a b s t r a c t The hepatitis B virus (HBV) is an important international cause of infectious acute and chronic liver diseases. HBV vaccines were developed to combat the potential life-threatening effects of HBV infection. Published case histories, retrospective reviews and analyses of epidemiological data report on the onset of immunemediated myelitis after recombinant HBV vaccination, mostly in adults with a presumed genetic/ immunologic predisposition. However, HBV vaccination has not borne out to be a significant trigger of serious autoimmune events, including acute myelitis, in populations at large over prolonged observation periods after immunization. Published study methods lack the sensitivity to categorically establish a causal relationship between exposure to HBV vaccine components and immune mediated myelitis, but in practice the faint possibility of such a link should not be totally rejected. © 2012 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . Hepatitis B virus background . . . . . . . Hepatitis B vaccine background . . . . . . Hepatitis B virus vaccines and autoimmunity Hepatitis B virus vaccines and acute myelitis 5.1. Case reports . . . . . . . . . . . . 5.2. Retrospective reviews . . . . . . . 5.3. Epidemiological studies . . . . . . 6. Post-vaccination autoimmunity . . . . . . 7. Conclusion . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . .
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1. Introduction The transverse myelitis syndrome entails an immune-mediated attack against spinal cord structures; it is associated with a preceding infection or vaccination, an underlying systemic autoimmune disease or an acquired inflammatory demyelinating disease [1]. Between 15 and 30% of cases are deemed “idiopathic” because no cause can be established [2,3]. The annual incidence of post-infectious or idiopathic myelitis is estimated to be less than 5 cases per million of the population, with bimodal age peaks between 10 and 19 years, and 30 ⁎ Department of Neurology and Neuroscience, Weill Cornell Medical College/New York Presbyterian Hospital, 525 East 68th Street, NY 10065-4885, USA. Tel.: + 1 212 746 2334; fax: + 1 212 746 8742. E-mail address: [email protected]. 1568-9972/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2012.03.008
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and 39 years [4–7]. The rarity of acute transverse myelitis hinders study, and appropriate experimental or animal models have not been developed. Vaccines offer a major contribution to public health in the modern era [8]. Vaccination is a powerful immune system stimulus, and has the theoretical potential to induce or exacerbate immune disturbances that manifest as serological indices of immune system dysregulation or as clinically manifest autoimmune disease. Adverse autoimmune reactions to various vaccines have been reported, but a causative association has not been definitely established. Epidemiological studies and controlled studies that aimed to evaluate the role of viral vaccines in a variety of autoimmune diseases obtained negative results [9,10]. However, these types of studies lacked the statistical power to rule out the possibility of a rare causal relationship [9,11]. It seems not unreasonable to consider vaccines rare triggers of
J.-P. Stübgen / Autoimmunity Reviews 12 (2012) 144–149
autoimmune reactions in genetically or immunologically predisposed individuals [12]. However, there exists no “unequivocal and irrevocable” evidence of a causative link between immunization and autoimmunity [13]. The worldwide use of recombinant hepatitis B virus (HBV) vaccines has been shown to be an effective and safe method to combat the spread of HBV infections. However, these vaccines have been associated with diverse adverse events, and are the second most common vaccines reported to the US Vaccine Adverse Events Reporting System [VAERS] (www.hrsa.gov/ vaccinecompensation/index.html). In a recent multi-analysis review of literature case reports of acute myelitis following immunization, HBV vaccines were the most common vaccines associated with acute myelitis [14]. The aim of this article is to present in a single text a review of the relationship between HBV vaccination and acute (transverse) myelitis. A systematic search was conducted of relevant publications using data bases MEDLINE [PubMed], EMBASE and DynaMed (through December 2011) that included case reports and series, case–control studies, postmarketing surveillance programs, and published analyses of VAERS. Search terms included “myelitis”, “myelopathy”, “hepatitis B vaccine/ vaccination”, “post-vaccination”, and “autoimmunity”. Article bibliographies were checked to ensure all studies and reports were included. Publications were retrieved, cross-referenced, and analyzed. 2. Hepatitis B virus background Hepatitis B virus (HBV), a small DNA virus of the Hepadnaviridae family, is an important, worldwide cause of infectious acute and chronic liver diseases [15]. Before introduction of universal childhood vaccination programs in the US, an estimated 300,000 new HBV infections occurred yearly [16]. In the US these days, 97% of newly recognized HBV infections and about 75% of newly diagnosed HBV carriers involve adults [17]. HBV is transmitted by permucosal or percutaneous exposure to infected blood via sexual contact, contaminated needles or blood products [18]. The clinical incubation period ranges from 2 to 3 months. Around two-thirds of patients with acute HBV infection suffer a mild, asymptomatic and subclinical illness [19]. About 5 to 10% of infected adults cannot clear HBV, and become chronically infected [20]. Worldwide, about 400 million people suffer chronic HBV infection with a prevalence ranging from 0.5% (US and Europe) to 10% (eastern Asia) [21,22].
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safe and well tolerated [23,27]. The CDC opined that there exists no firm scientific evidence that invokes HBV vaccines as a definite cause of chronic illness. Independent review committees of the US Institute of Medicine and the World Health Organization's Global Advisory Committee on Vaccine Safety concluded that no unequivocal link has been established between the HBV vaccines and chronic illness [28]. Moreover, non-live composite vaccines, including recombinant HBV vaccine, seem mostly immunogenic and safe in pediatric patients with rheumatic diseases [29] and in adults with underlying immunosuppression [30,31], including autoimmune inflammatory rheumatic diseases [32,33]. Nevertheless, evidence in the form of published case reports and analyses of the VAERS epidemiological database as well as biological plausibility theories hint at an association (mainly temporal) between a variety of acute and chronic autoimmune diseases and any of the components of recombinant HBV vaccines (i.e., crossreactive HBsAg epitopes, extraneous yeast antigens, aluminum adjuvant, thimerosal preservative) among probable genetically or immunologically predisposed adult vaccine recipients [23,27,34,35]. Manifestations of a disease may be considered “vaccine-related” within a post-vaccination period of 2–3 months according to the Viral Hepatitis Prevention Board (a WHO collaborating center for the prevention of viral hepatitis) (www.vhpb.org). The concept of a spectrum of immune-mediated diseases following the injection (e.g., vaccine adjuvant) or implanting of foreign matter [36,37], has recently attracted increasing attention and has been termed “Auto-inflammatory Syndrome induced by Adjuvants” (ASIA) or Shoenfeld's syndrome [38,39]. Adjuvant exposure is common, but clinically overt ASIA seems relatively rare, and may require additional risk factors such as genetic susceptibility or the coexposure to other environmental factors [38]. A recent study analyzed the common characteristics of 93 patients with autoimmunity following HBV vaccine as part of the spectrum of ASIA syndrome [40]; commonly reported manifestations included neuropsychiatric (70%), musculoskeletal (59%), gastrointestinal (50%) and fatigue (42%) complaints. 5. Hepatitis B virus vaccines and acute myelitis Case histories, retrospective reviews and post-marketing surveillance data report on the onset of acute myelitis following HBV vaccination.
3. Hepatitis B vaccine background 5.1. Case reports HBV vaccines were developed to combat the potential lifethreatening effects of HBV infection. The recombinant HBV vaccines, (available in the US since 1986) are highly purified, genetically engineered, single-antigen vaccines [23]. Manufacturers produce these vaccines by inserting the gene for HBsAg into a variety of yeast cells (or mammalian cell line) [24]; free HBsAg particles (20 nm size) are purified by biochemical and biophysical methods. Particles are adsorbed onto an adjuvant (aluminum hydroxide) with/without a preservative (thimerosal). In the US, licensed single-antigen HBV vaccines, Engerix R (GlaxoSmithKline) and Recombivax R (Merck), are given as a 3-dose series, and are recommended for use in national childhood vaccination programs and the high-risk adult population [15]. The seroconversion rate after required doses was 99% for infants up to 2 years, 96% for 13-year-old children, and 86% for adults up to 60 years of age [25,26]. Production of plasma-derived HBV vaccine was discontinued in the US in 1990, and is unavailable on this market. 4. Hepatitis B virus vaccines and autoimmunity There exists broad consensus among the medical and scientific communities that the benefits of HBV vaccination far outweigh any potential risks, and that single-antigen recombinant HBV vaccines are
Literature reports on new-onset central nervous system demyelination shortly after HBV vaccination included cases of acute (transverse) myelitis. A summary of published case histories of HBV vaccine-associated acute myelitis appears in Table 1 [41–49]. Two cases were excluded because patient demographic and clinical information was not supplied [50]. The pediatric cases occurred in children immunized at an age beyond the recommended US childhood immunization schedule (www.cdc.gov/vaccines/recs/ acip). The interval between vaccination and first manifestations of myelitis varied between 6 days and 6 weeks. Myelitis occurred after administration of either plasma-derived or recombinant HBV vaccines. Myelitis occurred after any of 3 recommended vaccine doses; one pediatric case occurred after a recombinant HBV vaccine booster shot. Spine MRI scans showed cord swelling, T2-weighted signal change with or without Gadolinium enhancement, and the longitudinal extent of lesions stretched up to 11 cord segments; the spinal cord was also reported normal. Head MRI scans were normal. In some cases, management entailed a short course of immunomodulatory therapy, and supported a hypothesis of a vaccine-associated immune attack against unidentified spinal cord antigens. Some patients improved or recovered spontaneously, so that a relatively short,
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Table 1 HBV vaccine-associated myelitis. Author
Age/sex
Interval/dose/type
CSF/MRI
Treatment
Outcome (follow-up)
Mahassin [41] Trevisani [42] Tartaglino [43] Senejoux [44] Song [45] Renard [46] Iñiguez [47] Karaali-Savrun [48]
56/M 11/F 40/M 64/F 31/M 16/F 15/F 42/F 33/M 40/F 42/F 3/M
3 weeks/#3/(rt) 3 weeks/#1/(pd) 2 weeks/#1/(rt) 6 days/#2/(rt) 2 weeks/#3/(pd) 8 hours/booster/(rt) 1 week/#1/(NR) 6 weeks/#2/(rt) 4 weeks/#3/(rt) 3 weeks/#1/(rt) 3 months/#3/(rt) 10 days/#1/(NR)
↑cells/N ↑protein/N NR/C6-T8 N/T2 N/C4-5 OCB/C2 N/C6-T2 NP/C2-3 N/C1-2 OCB/T9-10 OCB/C6 N/C4-T3
I.v. CS None NR None I.v. CS I.v. CS I.v. CS None I.v. CS P.o./i.v. CS NR I.v. CS/IVIG
Independent ambulation (6 months) Partial urinary retention (2.5 years) NR Resolving dysesthesia (6 months) Paresthesia (6 months) Recovered; (+) Lhermitte (4 months) Recovery (4 years) Recovery (3 months) Recovery (NR) Relapsing–remitting (18 months) NR (1 year) Ambulant (6 months)
Fonseca [49]
CS, corticosteroids; pd, plasma-derived; n, normal; NP, not performed; NR, not reported; OCB, oligoclonal bands; rt, recombinant.
self-limited disease course implied a benign prognosis, and reflected the transient nature of the presumed immune perturbation [51]. Neurological outcome was favorable even in patients with severe initial deficits such as quadriplegia [49] or paraplegia [42] with urinary retention. No patient was re-exposed to HBV vaccine on the premise that vaccination triggered an immune attack against the spinal cord. However, a single patient developed relapsing–remitting demyelinating disease that eventually fulfilled criteria for a diagnosis of multiple sclerosis [48]. Conceivably, these reports underestimate the true number of HBV vaccine-associated myelitis cases worldwide. A dearth of recent publications may reflect negative reporting bias i.e., physicians are disinclined to report, and medical journals unwilling to publish, case histories that do not add significant or unique contributions to existing literature. Moreover, this literature search found no individual reports of acute myelitis in infants immunized according to the recommended pediatric HBV vaccination schedule (3rd vaccine dose administered by age 18 months). This phenomenon may hint at a relative inability of an immature immune system to launch clinical autoimmune disease in response to immunization (see later). Such a hypothesis gains some credence from a study that showed the same antibody profile in 6-year-old children immunized at birth with recombinant HBV vaccine compared to a matched control group [52]. In these reports, an association between myelitis and HBV vaccination seemed more than fortuitous based on a combination of observations [10,53]: (a) temporal association (reactions followed vaccination after a latent period compatible to the presumed immune-triggered mechanism of disease); (b) no alternative etiology was identified (however, an “idiopathic” or unidentified post-viral mechanism of disease may be impossible to disprove); (c) biological plausibility (see later); (d) stabilization and improvement of myelitis after interrupting exposure to HBV vaccine, the presumed inciting agent; (e) analogy i.e., cases of acute myelitis were reported after immunization with other vaccine types [14] as well as a spectrum of virus infections [7,54]; (f) specificity (similar cases of HBV vaccineassociated myelitis were reported from a wide geographic distribution). However, the criterion of “re-challenge” (i.e., recurrence or significant exacerbation of symptoms soon after re-exposure) was not met [35,55] because no patient was re-immunized after a presumed adverse vaccine response. The importance of case reports lies in the potential to provide “first line” evidence to generate a disease hypothesis [56,57]. Such reports identify a new disease or condition, generate information on the natural history of disease, offer fast and inexpensive study, and are frequently the first form of publication [58]. However, the anecdotal nature of reports creates a potential for selection bias, and provides only limited potential to establish causal effects. Therefore, these case reports of acute myelitis following administration of HBV vaccines should not be interpreted as proof of cause.
5.2. Retrospective reviews A recent systematic review of English-language journals published between 1970 and 2009 searched for, and analyzed, reported cases of transverse myelitis following vaccination in any age group [14]. HBV vaccines were the most common immunization associated with acute myelitis. The authors felt that the concept of vaccination-induced myelitis was not to be dismissed or ignored. This conclusion was based on the relatively close temporal association between the onset of myelitis and administration of various types of vaccine, and the possible mechanisms linking these phenomena. The association between acute myelitis and many different vaccines raised the question of a possible common denominator as culprit trigger for autoimmunity, such as a common adjuvant. This author reviewed the most notable retrospective case series of acute transverse myelitis in the pediatric population [59–63]. In the largest series (47 patients from a single center) only, a relatively high percentage of cases (28%) had received vaccines (a single HBV vaccine recipient) or allergy shots within 30 days of neurological symptom onset [63]. Although the study was primarily aimed to assess functional outcome at follow-up, the authors proposed that a potential causal link between vaccination and acute myelitis was weakened by the large fraction of younger children affected, the current recommended vaccination schedule for children, and the lack of any single vaccine association for the entire group. 5.3. Epidemiological studies Post-marketing surveillance by the US CDC, FDA and vaccine manufacturer (June 1982 to May 1985) for neurological events after plasma-derived HBV immunization included 4 voluntarily reported cases of acute transverse myelitis (out of about 850,000 vaccine recipients) [64]. The accepted interval between vaccination and onset of symptoms ranged from 2 weeks to as long as 27 weeks. In the final analysis, no conclusive epidemiologic association could be ascertained between any reported neurological adverse event and this type of vaccine. Plasma-derived HBV vaccine is no longer available in the US, and will not be discussed further. In 1990, the CDC and FDA established the VAERS program in response to the National Childhood Vaccine Injury Act. VAERS is a post-marketing, national vaccine safety surveillance program that collects information about adverse events after administration of licensed vaccines in the US (www.vaers.hhs.gov/index). It needs to be emphasized that the inclusion of any reported adverse event in VAERS data does not infer causality. It is also impossible to reliably estimate the incidence of vaccine-related adverse events because the data reported to VAERS consist of a collection of single case reports (without a case cohort control group) from an uncertain population
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sample size. VAERS is subject to the limitations of any voluntary, passive surveillance system, such as: (a) underestimation (under- or non-reporting); (b) differential reporting (reporting increases in the initial few years after vaccine licensure); (c) stimulated reporting (reporting increases after an alleged similar adverse events become known); (d) reporting of coincidental events (unknown type or duration of concomitant medical condition); (e) dubious data quality and completeness (varies between physicians or institutions), and (f) unknown differences between the post-marketing surveillance groups and the clinical trial-selected populations. In a study to assess the safety of recombinant HBV vaccines, the VAERS database was analyzed for the incidence (among adults) of adverse reactions after HBV vaccination (1997 to 2000) compared to vaccine (tetanus toxoid and tetanus–diphtheria) control groups (1991 to 2000) [34]. Analysis showed a statistically significant increase in the incidence of adverse reactions after immunization with HBV vaccines compared to the control vaccines (for myelitis, p = 0.01 and 0.05, respectively). The incidence of myelitis was determined at 0.56 cases per million HBV vaccine doses administered. This number fell within the range of the background incidence of acute myelitis (post-infectious and idiopathic) in the general population. A re-review offered additional VAERS data on adverse reactions following administration of HBV vaccine compared to the tetanus–diphtheria vaccine control group [23]. The logic behind this analysis was a premise that the HBV and control vaccines were similarly affected by factors inherent to the database (null hypothesis). For the “myelitis” patient subgroup, analysis established the relative risk (6.8), attributable risk (5.6), and percentage association (87%) for a statistically significant p value b0.05. For “chronic myelitis” cases, analysis determined the relative risk (15.0), attributable risk (14.0), and percentage association (94%) for statistically significant p value b0.0001. In the HBV vaccine group, the mean age of myelitis patients was 29.1 (+/−9.9) years, and mean onset was 3.3 (+/−4.9) days. Without implying proof of a causal link, the statistical significance of analyzed data, nevertheless, revealed an apparent association between adult HBV vaccination and myelitis (among other adverse reactions). It seemed reasonable to conclude that adult HBV recipients were at increased risk to develop myelitis (and other adverse reactions), but only within a defined, close time frame following immunization. However, when entire adult populations were studied over extended periods (i.e., years) following immunization HBV vaccines were not a leading cause of serious autoimmune disorders (including acute myelitis) [23] or central nervous system demyelinating disease [65]. A retrospective examination of the VAERS database by the VAERS Working Group of the CDC found 120 reports of myelitis among other autoimmune conditions after HBV vaccination [35]. A summary of patient data included female to male ratio (2.2), median age (34 years), median interval between vaccination and onset of myelitis (22 days), and neurological outcome at 1 year (36% disabled). No cases of myelitis were found on a search of VAERS data for reports of positive re-challenge with HBV vaccines. Based on evidence such as biological plausibility, literature case reports (see above), and epidemiological (VAERS) data, the authors were inclined to at least consider a causal relationship between HBV vaccination and a variety of autoimmune diseases (including myelitis) in presumed genetically/immunologically susceptible adult vaccine recipients in a fairly close (days to weeks), defined period following immunization. Lastly, a case–control epidemiological study evaluated the potential risk of serious autoimmune adverse events that had been reported prospectively to VAERS following immunization with HBV vaccine compared to a tetanus-containing vaccine control group (recipients >7 years old during period 1. January 1990 to 25. May 2004) [27]. This study evaluated autoimmune conditions that had been previously identified on an a priori basis from case reports. Unfortunately, patients with acute myelitis were not included in this
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analysis because at least one “control” case was required for matching an “adverse event” case for the latter to be included in the study. 6. Post-vaccination autoimmunity The mechanisms of autoimmune phenomena after vaccination are extrapolated mainly from the known capacity of infectious agents (against which particular vaccines are directed) to induce autoimmunity [56], and from animal models and in vitro studies [12]. Biological plausibility is based on [66–71]: (a) molecular mimicry (structural homology between virus/vaccine and host antigenic components) [72,73]; (b) epitope spreading (a new immune response to dissimilar epitopes on the same or different antigens) [74,75]; (c) bystander effect (priming of virus/vaccine antigenspecific T cell in a permissive immune environment) [76,77]; (d) presentation of cryptic epitopes from self-tissue [78,79]; (e) reactivation of self-reactive memory T cells [80,81]; (f) superantigens (crosslinkage of T cell receptor and MHC molecule independent of specific antigen recognition) [82,83]; (g) formation of immune complexes [84,85]; (h) HLA class I antigen expression on non-immune cells (could lead to presentation of autoantigens and recognition by autoreactive T cells) [86,87], and (i) individual genetic susceptibility to autoimmunity [88]. These pathogenic mechanisms are not mutually exclusive, and any may be relevant depending on the stage of evolution of disease [89]. Any invoked mechanism depends also on the presumed pathogenesis of the specific immune disorder. Perhaps a common denominator, such as an aluminum-based adjuvant, plays a pathogenic part in the association between many different types of vaccine and acute myelitis [14] and other HBV vaccine-associated serious adverse events [19,23,40]. Adjuvants are administered simultaneously with vaccines to induce a more vigorous immune response to the vaccinated antigens [90–93]. There is growing appreciation of a direct link between adjuvant administration and “autoimmune”-like clinical syndromes (ASIA syndrome). Adjuvants may mimic specific sets of conserved molecules such as bacterial polysaccharides, endocytosed nucleic acids and unmethylated CpG-DNA that activate the innate immune response [14,90]. Adjuvants may exert immune-enhancing effects by: (a) translocation of antigens to lymph nodes which enhances antigen recognition by, and stimulation of, T cells; (b) antigen protection so that delivery and prolonged exposure to the immune system stimulates B and T cell production; (c) increase of local injection site reaction which enhances release of stimulatory chemokines by T cells and mast cells; (d) promoting release of inflammatory cytokines which recruit B and T cells to infection sites and increase translational events, or (e) interaction with pattern recognition receptors on leukocyte (accessory cell) surfaces [94–97]. The development and incorporation of safe and novel adjuvants into future vaccines should help motivate population compliance with recommended immunization programs worldwide. 7. Conclusion Case histories, retrospective reviews and epidemiological studies report on the occurrence of immune adverse events after HBV vaccination. These study methods lack sensitivity to categorically prove a causal relationship between vaccination and acute myelitis, but leave open to doubt a faint possibility of linkage. The concept of HBV vaccine-associated myelitis is difficult to ignore completely, and rests mainly on the temporal association of events and inference from the biological plausibility of vaccine-triggered autoimmune events. The rarity of acute transverse myelitis hinders study, but reviewed literature suggests that it is not unreasonable to at least consider a link between HBV vaccination and a variety of autoimmune diseases (including acute myelitis) in a close and defined period following immunization in presumed genetically/immunologically susceptible
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adult vaccine recipients. Clinicians are encouraged to approach patient care according to the dictum “absence of proof does not equate proof of absence”. Take-home messages • HBV vaccination of children and at-risk adults reduced rate of new infections. • Recombinant HBV vaccines are effective, safe and well tolerated. • HBV vaccination has been associated with various autoimmune phenomena. • The concept of HBV vaccine-associated myelitis is difficult to ignore completely. • Post-vaccination myelitis is presumably immune-mediated. • Post-vaccination myelitis may benefit from immunomodulatory therapy. References [1] Frohman EM, Wingerchuk DM. Transverse myelitis. N Engl J Med 2010;263: 564–72. [2] De Seze J, Stojkovic T, Breteau G, Lucas C, Michon-Pasturel U, Gauvrit JY, et al. Acute myelopathies: clinical, laboratory and outcome profiles in 79 cases. Brain 2001;124:1509–21. [3] De Seze J, Lanctin C, Lebrun C, Malikova I, Papeix C, Wiertlewski S, et al. Idiopathic acute transverse myelitis: application of recent diagnostic criteria. Neurology 2005;65:1950–3. [4] Berman M, Feldman S, Alter M, Zilber N, Kahana E. Acute transverse myelitis: incidence and etiologic considerations. Neurology 1982;31:966–71. [5] Christensen PB, Wermuth L, Hinge HH, Bomers K. Clinical course and long-term prognosis of acute transverse myelopathy. Acta Neurol Scand 1990;81:431–5. [6] Jeffrey DR, Mandler RN, Davis LE. Transverse myelitis. Retrospective analysis of 33 cases, with differentiation of cases associated with multiple sclerosis and parainfectious events. Arch Neurol 1993;50:532–5. [7] Bhat A, Naguwa S, Cheema G, Gershwin ME. The epidemiology of transverse myelitis. Autoimmun Rev 2010;9:A395–9. [8] Maldonaldo YA. Current controversies in vaccination. Vaccine 2002;288:3155–8. [9] Chen RT, Pless R, DeStefano F. Epidemiology of autoimmune reactions induced by vaccination. J Autoimmun 2001;16:309–18. [10] Schattner A. Consequence or coincidence? The occurrence, pathogenesis and significance of autoimmune manifestations after viral vaccines. Vaccine 2005;23: 3876–86. [11] Stratton KR, Howe CJ, Johnston Jr RB. Adverse events associated with childhood vaccines other than pertussis and rubella. Summary of a report from the Institute of Medicine. JAMA 1994;271:1602–5. [12] Salemi S, D'Amelio R. Could autoimmunity be induced by vaccination? Int Rev Immunol 2010;29:247–9. [13] Shoenfeld Y, Aron-Maor A. Vaccination and autoimmunity — ‘vaccinosis’: a dangerous liaison? J Autoimmun 2000;14:1–10. [14] Agmon-Levin N, Kivity S, Szyper-Kravitz M, Shoenfeld Y. Transverse myelitis and vaccines: a multi-analysis. Lupus 2009;18:1198–204. [15] Centers for Disease Control, Prevention. Protection against viral hepatitis. Recommendations of the immunization practices advisory committee (ACIP). MMWR 1990;39:1–26. [16] Centers for Disease Control and Prevention. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: recommendations of the immunization practices advisory committee (ACIP). MMWR 1991;40:1–19. [17] Wasley A, Grytdal S, Gallagher K. Centers for Disease Control and Prevention (CDC). Surveillance for acute viral hepatitis — United States, 2006. MMWR Surveill Summ 2008;57:1–24. [18] Francis DP, Favero MS, Maynard JE. Transmission of hepatitis B virus. Semin Liver Dis 1981;1:27–32. [19] McMahon BJ, Helminiak C, Wainwright RB, Bulkow L, Trimble BA, Wainwright K. Frequency of adverse reactions to hepatitis B vaccine in 43,618 persons. Am J Med 1992;92:254–6. [20] Liang TJ. Hepatitis B: the virus and disease. Hepatology 2009;49(Suppl.):S13–21. [21] Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337:1733–45. [22] Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2001;34:1225–41. [23] Geier MR, Geier DA, Zahalsky AC. A review of hepatitis B vaccination. Expert Opin Drug Saf 2003;2:113–22. [24] Tron F, Degos F, Bréchot C, Couroucé AM, Goudeau A, Marie FN, et al. Randomized dose range study of a recombinant hepatitis B vaccine produced in mammalian cells and containing the S2 and preS2 sequences. J Infect Dis 1989;160:199–204. [25] Da Villa G, Picciottoc L, Elia S, Peluso F, Montanaro F, Maisto T. Hepatitis B vaccination: universal vaccination in newborn babies and children at 12 years of age versus high risk groups. A comparison in the field. Vaccine 1995;13:1240–2. [26] Shouval D. Hepatitis B vaccines. J Hepatol 2003;39(Suppl. 1):S70–6. [27] Geier DA, Geier MR. A case–control study of serious autoimmune adverse events following hepatitis B immunization. Autoimmunity 2005;38:295–301.
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