Do Vaccines Cause Acute Disseminated Encephalomyelitis (ADEM)?

Conclusion | Epidemiological Evidence | Proposed Biological Mechanism | Archives | References


Conclusion

Older formulations of rabies vaccine did cause Acute Disseminated Encephalomyelitis (ADEM), but newer formulations of rabies vaccine have not been shown to cause ADEM, and rabies vaccine is not routinely recommended to the general population in the United States. Other vaccines that are currently routinely recommended to the general population in the U.S.* have not been shown to cause ADEM.

Epidemiological Evidence

The Institute of Medicine (IOM), now called the National Academy of Medicine (NAM), found no relevant studies of quality in the literature assessing an association between vaccination and ADEM, since the only applicable studies available used passive surveillance systems and therefore lacked an unvaccinated comparison group [1]. Studies published since the 2012 IOM report have found no association between ADEM and the pandemic H1N1 influenza vaccine Pandremix [2], quadrivalent HPV vaccine (Gardasil) [3-5] or hepatitis B vaccine [4]. However, one recent Vaccine Safety Datalink study did find a possible association between ADEM and Tdap vaccine estimated at no more than 1.16 excess cases per million vaccines administered [6].

Proposed Biological Mechanism

ADEM has been reported very rarely after natural infections with wild-type measles, mumps, rubella, varicella, influenza, hepatitis A, and other viruses [1]. However, the pathophysiology of ADEM is not fully understood. Also, ADEM has been reported very rarely after immunizations, but in most instances infections with other agents have not been ruled out and there is no available test to determine a causal association with a particular infection or vaccine. Biological mechanisms proposed to explain the immunogenic etiology of ADEM following infection or immunization include direct destruction [7] and molecular mimicry [8, 9], which refers to the possibility that similar epitopes shared between self-peptides and foreign peptides (introduced via infection or immunization) inadvertently cause the activation of autoreactive T or B cells, leading to autoimmunity. In the case of ADEM, this abnormal immune response would be directed against the hostís myelin protein [10]. Although a temporal association with ADEM has been described for vaccines such as Japanese encephalitis, yellow fever, measles, influenza, varicella, and hepatitis [11-13], the only clear pathological association ever demonstrated was with the Semple rabies vaccine [14].

The 2012 IOM report described two cases of ADEM after administration of the Engerix-B hepatitis B vaccine showing a reoccurrence of symptoms after vaccine rechallenge [15, 16]; however, these were insufficient to conclude a causal association [1]. The report also described one case of ADEM after tetanus toxoid vaccination [17]; however, even after considering knowledge about the aforementioned natural infection, the IOM concluded that this mechanistic evidence was weak. The IOM concluded that the only mechanistic evidence for an association between ADEM and MMR, varicella or influenza vaccines was knowledge about the natural infections, and that there was no mechanistic evidence for all other vaccines, as the publications reviewed provided no evidence beyond a temporal association [1].

References

1. Institute of Medicine. In: Stratton K, Ford A, Rusch E, Clayton EW, eds. Adverse Effects of Vaccines: Evidence and Causality. Washington (DC): National Academies Press (US); 2012.
2. Persson I, Granath F, Askling J, Ludvigsson JF, Olsson T, Feltelius N. Risks of neurological and immune-related diseases, including narcolepsy, after vaccination with Pandemrix: a population- and registry-based cohort study with over 2 years of follow-up. J Intern Med 2014;275:172-90.
3. Chao C, Klein NP, Velicer CM, et al. Surveillance of autoimmune conditions following routine use of quadrivalent human papillomavirus vaccine. J Intern Med 2012;271:193-203.
4. Langer-Gould A, Qian L, Tartof SY, et al. Vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases. JAMA neurology 2014;71:1506-13.
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6. Baxter R, Lewis E, Goddard K, et al. Acute Demyelinating Events Following Vaccines: A Case-Centered Analysis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2016.
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8. Miller SD, McRae BL, Vanderlugt CL, et al. Evolution of the T-cell repertoire during the course of experimental immune-mediated demyelinating diseases. Immunological reviews 1995;144:225-44.
9. Evans CF, Horwitz MS, Hobbs MV, Oldstone MB. Viral infection of transgenic mice expressing a viral protein in oligodendrocytes leads to chronic central nervous system autoimmune disease. The Journal of experimental medicine 1996;184:2371-84.
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11. Ohtaki E, Murakami Y, Komori H, Yamashita Y, Matsuishi T. Acute disseminated encephalomyelitis after Japanese B encephalitis vaccination. Pediatr Neurol 1992;8:137-9.
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13. Karussis D, Petrou P. The spectrum of post-vaccination inflammatory CNS demyelinating syndromes. Autoimmun Rev 2014;13:215-24.
14. Hemachudha T, Griffin DE, Giffels JJ, Johnson RT, Moser AB, Phanuphak P. Myelin basic protein as an encephalitogen in encephalomyelitis and polyneuritis following rabies vaccination. The New England journal of medicine 1987;316:369-74.
15. 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. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2001;33:1772-3.
16. Tourbah A, Gout O, Liblau R, et al. Encephalitis after hepatitis B vaccination: recurrent disseminated encephalitis or MS? Neurology 1999;53:396-401.