Markers of autoimmunity after hepatitis B vaccination

According to Bogdanos et al (1), “the question of a connection between vaccination [against hepatitis B] and autoimmune disorders is surrounded by controversy”. In 25 years of professional life devoted to the study of drug hazards, I have rarely seen an issue clearer than that related to the potential of hepatitis B vaccine to induce auto-immune diseases.

In a job where no assessment can be more than statistical, the experts’ concern is not to quibble about whether causality is, or is not, “demonstrated-with-certainty”: it is simply to appreciate if the level of evidence for such or such toxicity is the same, less or higher than the level of evidence normally considered by professionals as “sufficient” to take medical or regulatory measures (2). And there can be no doubt that, in the case of hepatitis B vaccine which generated hundreds of published case reports and thousands of spontaneous reports (for not to speak about a number epidemiological inquiries), this level of evidence is far higher than that normally required to take severe measures of restriction or even withdrawal of a pharmaceutical product. Illusions that the contrary is true are fuelled by the stubborn refusal of regulatory authorities to publish alarming studies (3), and to give free access to their database even to authoritative researchers (4). They are fostered also by “Reviews” which challenge the most elementary principles of evidence-based medicine as exemplified by a recent paper supposed to discriminate between “consequence or coincidence” regarding “the significance of autoimmune manifestations after viral vaccines” (5): accepted in Feb 2005, this paper completely ignores the results of Hernan et al which, for the main, were available as early as one and half year before (6), but it persists in quoting those of Zipp et al (7) in spite of their gross inconsistencies (see their Table 2, where an unfortunate misprint – uncorrected to my knowledge – allows the authors to halve the clear increase of multiple scleroses in teenagers and young vaccinated adults) which led the French Agency (still one of the fiercest promoter of the vaccination) to assess that they should be “discarded” (Communiqué of Feb, 2000). Likewise, Schattner’s paper goes on using the assessments of the WHO or like organisations at the same level of evidence as independent investigations, without any consideration for the obvious fact that those experts, some of them more or less sponsored by manufacturers and who have passionately promoted hepatitis B vaccination in spite of long-standing safety concern (8) are of problematic reliability as soon as the issue is now to assess with minimum neutrality the health catastrophes induced by this irresponsible promotion: to be sure, this “controversy” may be long-lasting when based on such evidence…

Having been commissioned as a medical expert witness by French Courts or lawyers in dozens of litigations related to hepatitis B vaccine, I have spent thousands of hours on this subject, and had access to a heap of confidential documents which confirmed to me – amongst others (9;10) – the idea that hepatitis B vaccination is characterized by the number, the variety and the severity of its hazards (3). Although most of my conclusions are still confidential or even secret by Court Order, the beautiful investigations by Martinuc Porobic et al (11) and by Bogdanos et al (1) reveal convincing insights into the molecular mechanisms of autoimmune reactions induced by hepatitis B vaccine. They add to an impressive spectrum of convergent data including long-standing warnings about the auto-immune potential of a vaccine targeted against the hepatitis B virus (8;12) (e.g. crosschecking showing significant similarities between viral genome and myelin basic protein), while making the quite credible hypothesis that the manufacturing process could leave minute amounts of HBV polymerase protein as a biologically active contaminant (13;14) which would explain the interaction between the hepatitis B components and the auto-antibodies produced in patients developing immune diseases just after vaccination (15;16). Of course, this massive body of evidence towards biological plausibility strongly reinforces the reach and significance of an unusual body of case reports (see (3) for a more complete bibliography) as well as of epidemiological data (9;10;17-22). It is also in line with anecdotal evidence taken from an association of victims suggesting that amongst people developing multiple sclerosis after hepatitis B vaccination, HLA distribution is strikingly atypical (Le Houezec, personal communication) with a high frequency of DR15 or DQ6 subtypes.

Martinuc Porobic et al’s results (11) are also crucial to understand how the evidence of auto-immune toxicity due to hepatitis B vaccine may be reversed to deny this toxicity and to protect this “controversy” beyond any rational assessment. The preliminary experiment by Poirriez (16) was related to a 11-year old girl who developed symptoms of a severe (and, unfortunately, irreversible) transverse myelitis 2 months after a hepatitis B booster injection: high titres of antinuclear antibodies were found, which proved to be absorbed by various concentrations of the vaccine, strongly suggesting antigenic interactions between vaccine components and auto-antibodies produced by the patient, in spite of the limitations of this experiment performed in only one subject and under unusual circumstances. Yet, this case was previously subjected to another publication (23) in which the development of other stigma of autoimmunity after vaccination – such as anti-phospholipid antibodies (11) – was interpreted as a clue of an underlying auto-immune disease called “neurolupus” – a very rare, if existing, entity – in order to minimize and even deny the causal role of the vaccine. Having been recently in charge of a new report on this case, I was able to check that this young girl did not have any symptoms of “lupus” except anti-nuclear and anti-phospholipid antibodies: yet, Poirriez (16) demonstrated the striking interaction between these anti-nuclear antibodies and the vaccine’s antigens, whereas it is now clear from Martinuc Porobic et al (11) that hepatitis B vaccine also has a strong potential to induce the development of anti-phospholipid antibodies.

This paradoxical assessment of causality – excluding the role of hepatitis B vaccine on the basis of auto-immune markers after vaccination – is not at all exceptional in my experience as an expert medical witness. The latest piece of a very consistent body of data, Martinuc Porobic et al’s results (11), gives convincing evidence of biological plausibility and strongly supports the view that, far from excluding a causal role of the vaccine, biological markers of auto-immunity in a subject complaining of post-vaccine adverse reactions may represent an important clue to keeping the antigens in this vaccine as the trigger for the subject’s auto-immune disorders.

Declaration of interest: Marc Girard works as an independent consultant for pharmaceutical industry, including vaccine manufacturers and a number of their competitors. There was no grant support for this paper.

Acknowledgments: Many thanks to Paul G. King for his precious help in improving the English manuscript.

References

1. Bogdanos DP, Smith H, Ma Y, Baum H, Mieli-Vergani G, Vergani D. A study of molecular mimicry and immunological cross-reactivity between hepatitis B surface antigen and myelin mimics. Clin Dev Immunol 2005 Sep;12(3):217-24.

2. Girard M. Vaccination and auto-immunity: reassessing evidence. Medical Veritas 2005;2:549-54.

3. Girard M. Autoimmune hazards of hepatitis B vaccine. Autoimmun Rev 2005 Feb;4(2):96-100.

4. Arranga E, Geier M, Geier D, et al. Interview with Dr Mark Geier and David Geir concerning Thimerosal, testosterone, and autism treatment hypothesis. Medical Veritas 2005;2:465-71.

5. Schattner A. Consequence or coincidence? The occurrence, pathogenesis and significance of autoimmune manifestations after viral vaccines. Vaccine 2005 Jun 10;23(30):3876-86.

6. Hernan M, Jick S, Olek M, Ascherio A, Jick H. Recombinant hepatitis B vaccine and the risk of multiple sclerosis. Pharmacoepidemiology and Drug Safety 2003;12:S59-S60.

7. Zipp F, Weil JG, Einhaupl KM. No increase in demyelinating diseases after hepatitis B vaccination [letter]. Nat Med 1999 Sep;5(9):964-5.

8. Zuckerman A. Hepatitis vaccine: a note of caution. Nature 1975;255:104-5.

9. Geier MR, Geier DA. A case-series of adverse events, positive re-challenge of symptoms, and events in identical twins following hepatitis B vaccination: analysis of the Vaccine Adverse Event Reporting System (VAERS) database and literature review. Clin Exp Rheumatol 2004 Nov-2004 Dec 31;22(6):749-55.

10. Geier D, Geier M. A case-control study of serious autoimmune adverse events following hepatitis B immunization. Autoimmunity 2005;38:295-301.

11. Martinuc Porobic J, Avcin T, Bozic B, Kuhar M, Cucnik S, Zupancic M, Prosenc K, Kveder T, Rozman B. Anti-phospholipid antibodies following vaccination with recombinant hepatitis B vaccine. Clin Exp Immunol 2005 Nov;142(2):377-80.

12. Hilleman, MR. Human retroviruses, cancer and AIDS: approaches to prevention and therapy. In: Bolognesi, D. Perspectives in the quest for a vaccine against AIDS. New York: Liss AR Inc; 1988. pp. 291-311.

13. Faure E. Multiple sclerosis and hepatitis B vaccination: Could minute contamination of the vaccine by partial Hepatitis B virus polymerase play a role through molecular mimicry? Med Hypotheses 2005 May 19;65:509-20.

14. Comenge Y, Girard M. Multiple sclerosis and hepatitis B vaccination: Adding the credibility of molecular biology to an unusual level of clinical and epidemiological evidence. Med Hypotheses 2006;66(1):84-6.

15. Pennesi M, Torre G, Del Santo M, Sonzogni A. Glomerulonephritis after recombinant hepatitis B vaccine. Pediatr Infect Dis J 2002 Feb;21(2):172-3.

16. Poirriez J. A preliminary experiment of absorption of antinuclear antibodies by the hepatitis B vaccine components, in a case of neurolupus. Vaccine 2004 Aug 13;22(23-24):3166-8.

17. Fisher MA, Eklund SA. Hepatitis B vaccine and liver problems in U.S. children less than 6 years old, 1993 and 1994. Epidemiology 1999 May;10(3):337-9.

18. Fisher MA, Eklund SA, James SA, Lin XH. Adverse events associated with hepatitis B vaccine in US children less than six years of age, 1993 and 1994. Ann Epidemiol 2001 Jan;11(1):13-21.

19. Begaud B, Alperovitch A. Vaccinations and multiple sclerosis. N Engl J Med 2001 Jun 7;344(23):1793.

20. Hernan M, Jick S, Olek M, Jick H. Recombinant hepatitis B vaccine and the risk of multiple sclerosis. A prospective study. Neurology 2004;63:838-42.

21. Geier DA, Geier MR. A one year followup of chronic arthritis following rubella and hepatitis B vaccination based upon analysis of the Vaccine Adverse Events Reporting System (VAERS) database. Clin Exp Rheumatol 2002;20(6):767-71.

22. Geier DA, Geier MR. Hepatitis B vaccination and arthritic adverse reactions: a followup analysis of the Vaccine Adverse Events Reporting System (VAERS) database. Clin Exp Rheumatol 2002;20(1):119.

23. Legout L, Hachulla E, Chérin P, et al. Maladies auto-immunes et vaccination contre l’hépatite B: faut-il vacciner nos patients? Rev Méd Int 2001;22:402-5.