Vaccines are not linked to multiple sclerosis

The hypothesis

Concern about the hepatitis B vaccination spread throughout France in the mid-1990s when, following the introduction of mass vaccination, there were reports of cases of multiple sclerosis (MS) occurring a few weeks after vaccination. On October 1, 1998, the French government temporarily suspended hepatitis B vaccination for adolescents in schools to assess whether there was a possible link between hepatitis B and demyelinating diseases. The French decision was misunderstood and misinterpreted, leading to a generalised fear that spread to other countries.

Scientific elements that contradict the hypothesis

Since 1982, more than 500 million people worldwide have been vaccinated against hepatitis B. The hepatitis B vaccine is the first and only vaccine that prevents hepatocellular carcinoma by preventing infection of the B virus.

After the French situation, many studies were carried out to assess the validity of the aforementioned hypothesis, but they have consistently demonstrated the absence of a link between the hepatitis B vaccine and MS1-21.

Of these:

  • A US analysis found no link between requests for hepatitis B vaccination and requests for treatment of demyelinating diseases4
  • A study in Canada examined 578,308 adolescents with MS before and after the introduction of hepatitis B vaccination. The study showed no evidence of a link between hepatitis B and multiple sclerosis or demyelinating diseases 9
  • A 2001 study compared 192 women with MS and 645 control patients. The study showed no increased risk of MS for patients who had received hepatitis B vaccine11
  • Another 2001 study analysed vaccines against hepatitis B, tetanus and influenza in MS patients. The study showed the absence of a link between the hepatitis B vaccine and MS relapses12
  • A US study with more than 1,300 participants showed no link between hepatitis B and MS vaccination or other demyelinating diseases 13
  • A study published in the Archives of Neurology has shown that vaccination against hepatitis B, influenza, tetanus, measles or rubella does not increase the risk of developing MS or optic neuritis (often the first symptom of multiple sclerosis) 17
  • A study carried out in France from 1994 to 2003 found no link between the hepatitis B vaccine and the development of MS in childhood.

The 143 cases included children whose MS appeared before the age of 16 and 1,122 control subjects selected from the general French population 19

Although many studies over the last decade have found no link between hepatitis B vaccine and multiple sclerosis, two recent studies suggest otherwise:

  • 2004 study by Hernan and colleagues 22
  • 2008 study by Mikaeloff and colleagues 23

In both cases the World Health Organization has expressed itself through the committee on vaccine safety (Global Advisory Committee on Vaccine Safety).

Study by Hernan et al. (2004).
Response from the World Health Organization

This study retrospectively analyses the medical records of British adult patients vaccinated against hepatitis B by their General Practitioners (GPs). The authors base their findings on a small number of MS patients (11) who had previously been vaccinated against hepatitis B, and suggest that there may be an increased risk of developing MS in the second or third year after receiving the vaccine .

However, there are many aspects to consider in order to put the study into the right context:

  1. The conclusions reached by the authors were based on data from 11 patients, a sample too small to allow a definitive conclusion, in one way or another.
  2. The study was based on the accurate recording of all data regarding vaccination status and the symptoms of illness by GPs. However, given the few patients involved, even a minimal error in the classification of the vaccination status could alter the results and invalidate the conclusions.
  3. In Britain, at the time of the study, the hepatitis B vaccine was aimed at adult patients who were at high risk of contracting the infection (health workers, travellers to endemic areas, dialysis patients, prostitutes, drug-addicts). Therefore the patients in the study cannot be considered a representative sample of the general population and this may have altered the results of the study. Furthermore, the vaccination of health workers in Great Britain takes place outside of GP's clinics, meaning the information in the medical records used in the study was incomplete.
  4. Although there were 713 cases of MS in the database, 163 patients were selected and, in the end, only 11 were used for the final survey; this may have led to an inaccuracy (selection bias) in the results. This selection process, however careful, is fraught with methodological problems and runs the risk of involuntary distortion.
  5. Information on the number of vaccine doses given and the time they were administered is missing and this means that interpretations regarding the effect of time and vaccine doses cannot be accurately made.
  6. Any association with the hepatitis B vaccine administered more than a year before the onset of MS seems unlikely, given that viruses that could induce the onset of MS are thought to have an effect over weeks.

An editorial accompanying Hernan's study stated that the "the evidence and argument submitted by Hernán et al are insufficient to support the hypothesis of a link between hepatitis B vaccination and MS, and do not justify discontinuation or modification of immunisation programmes with HBV. The latter have had a demonstrated profound beneficial public health benefit worldwide". The WHO states that "does not believe that the findings provide convincing support for the hypothesis that immunisation with recombinant hepatitis B vaccine is associated with an increased risk of multiple sclerosis". Because of the methodological problems of the Hernan study and the fact that it is at variance with many other studies, experts believe that the results of the study do not provide sufficient proof of a link between the vaccine and MS.

Study by Mikaeloff et al. (2008).
Response from the World Health Organization

This is a case-control study conducted in France on children under the age of 16. This study follows that by KIDSEP which involved children who had a first episode of demyelination in the central nervous system between 1994 and 2003. The KIDSEP study had evaluated the exposure to hepatitis B vaccination in children with MS and in the control group and had concluded that no link was found between the vaccine and MS.

The new study expanded the group to include children who had a first episode of acute inflammatory demyelination in the CNS but who had not developed MS. The authors found that a history of hepatitis B vaccination was less common among children with MS at all examined time intervals before the onset of the disease and regardless of the brand of HB vaccine. The authors then carried out a large series of subgroup analyses. From epidemiological studies, it is known that when subgroup analysis is performed spurious associations can be found, unless an adjustment is made for the different statistical tests – such an adjustment was not made in this study. Subgroup analysis found a higher frequency of MS onset for one brand of HB vaccine given more than three years before the onset of symptoms. In the discussion of their article the authors recognise that these results "were obtained by subgroup analyses and are therefore subject to possible false results". The World Health Organization considers that the results of this study do not provide convincing evidence that the vaccine for hepatitis B is associated with an increased risk of MS or an acute episode of demyelination in the CNS.

Can the hepatitis B vaccine make MS symptoms worse?

Worsening of MS can occur after viral infections due to an activation of the immune system caused by the infection itself. Although isolated cases of MS patients have been reported to have worsened symptoms after vaccination, various studies on different types of vaccines have refuted this hypothesis. Furthermore, a study carried out in Europe involving 643 individuals with MS showed no evidence of a link between recent vaccination against hepatitis B, tetanus or influenza and relapse of MS12.

The National Multiple Sclerosis Society highlights the importance for people with MS to receive all appropriate vaccines, including that against hepatitis B.

A recent Argentine study of 7 patients with relapsing-remitting MS who had received yellow fever vaccination prior to a trip found an increased risk of MS relapse within 6 weeks after vaccination 24. In this regard, the National Multiple Sclerosis Society states "for people with MS who have to travel to areas where yellow fever is endemic, the increased risk of relapse must be weighed against the likelihood of exposure to yellow fever, a potentially fatal disease".

Conclusions of the literature review by the experts

Hepatitis B and MS vaccine studies have been reviewed and analysed by WHO through the Global Advisory Committee on Vaccine Safety. The committee affirms that "many studies and literature reviews state that there is no link between MS and hepatitis B vaccine". A review by the Institute of Medicine (Immunization Safety Review Committee) states that epidemiological evidence does not support a causal relationship between the hepatitis B vaccine and multiple sclerosis25. A systematic review of the evidence by the Cochrane Vaccine Field in 2003 found no association between the hepatitis B vaccine and MS.

Conclusions

The results from studies that have investigated a possible link between the hepatitis B vaccine and the development of multiple sclerosis are not only reassuring, but further support the recommendations to vaccinate against this virus.

Sources / Bibliography
  1. Quast U, Herder C, Zwisler O. Vaccination of patients with encephalomyelitis disseminata. Vaccine 1991;9(4):228–230
  2. Herrolen L, DeKeyser J, Ebinger G. Central nervous system demyelination after immunisation with recombinant hepatitis B vaccine. Lancet 1991;338(8776):1174–1175
  3. Niu MT, Rhodes P, Salive M, Davis DM, Black S, Shinefield H, Chen RT, Ellenberg SS. Comparative safety of two recombinant hepatitis B vaccines in children: data from the Vaccine Adverse Event Reporting System (VAERS) and Vaccine Safety Datalink (VSD). Journal of Clinical Epidemiology 1998; 51(6):503-510
  4. Zipp F, Weil JG, Einhaupl KM. No increase in demyelinating diseases after hepatitis B vaccination. Nature Medicine 1999;5(9):964–965
  5. Hall A, Kane M, Roure C, Meheus A. Multiple sclerosis and hepatitis B vaccine? Vaccine 1999;17:2473-2475
  6. Halsey NA, Duclos P, Van Damme P, Margolis H. Hepatitis B vaccine and central nervous system demyelinating diseases. Pediatric Infectious Disease Journal 1999;18:23-24
  7. Fourrier A, Touze E, Alperovitch A, Begaud B. Association between hepatitis B vaccine and multiple sclerosis: a case-control study. Pharmacoepidemiology & Drug Safety 1999;8:S140–141
  8. Sturkenboom MCJM, Abenhaim L, Wolfson C, Roulet E, Heinzelf O, Gout O. Vaccinations, demyelination, and multiple sclerosis study (VDAMS). Pharmacoepidemiology & Drug Safety 1999;8:S170–171
  9. Sadovnik AD, Scheifele DW. School-based hepatitis B vaccination programme and adolescent multiple sclerosis. Lancet 2000;355(9203):549–550
  10. Touzé E, Gout O, Verdier-Taillefer MH, Lyon-Caen O, Alpérovitch A. The first episode of central nervous system demyelinization and hepatitis B vaccination. Revue Neurologique 2000;156(3):242–246.
  11. Ascherio A, Zhang SM, Hernan MA, et al. Hepatitis B vaccination and the risk of multiple sclerosis. New England Journal of Medicine 2001;344(5):327–332
  12. Confavreux C, Suissa S, Saddier P et al. Vaccinations and the risk of relapse in multiple sclerosis. New England Journal of Medicine 2001;344(5):319–326
  13. Verstraeten T, DeStefano F, Jackson L, Benson P, Okoro C, Black S, Shinefield H., Mullooly J, Chen R.; VSD Team. Risk of demyelinating disease after hepatitis B vaccination—West Coast, United States, 1995–1999. Paper presented at the 50th Annual Epidemic Intelligence Service Conference, 2001, Atlanta GA
  14. MacIntyre CR. Hepatitis B vaccine: risks and benefits of universal neonatal vaccination. Journal of Paediatrics & Child Health 2001;37:215-217
  15. Lewis E, Shinefield HR, Woodruff BA, Black SB, DeStefano F, Chen RT, Ensor R. Safety of neonatal hepatitis B vaccine administration. Pediatric Infectious Disease Journal 2001;20: 10489-1054
  16. Rutschmann OT, McCrory DC, Matchar DB, Immunization Panel of the Multiple Sclerosis Council for Clinical Practice Guidelines. Immunization and MS: a summary of published evidence and recommendations. Neurology 2002;59:1837-1843
  17. DeStefano F, Verstraeten T, Jackson LA. Vaccinations and risk of central nervous system demyelinating diseases in adults. Archives of Neurology 2003;60:504-509
  18. Demicheli V, Rivetti A, Di Pietrantonj C, Clements CJ, Jefferson T. Hepatitis B vaccination and multiple sclerosis: evidence from a systematic review. Journal of Viral Hepatitis 2003;10:343-344
  19. Mikaeloff Y, Caridade G, Rossier M, Suissa S, Tardieu M. Hepatitis B vaccination and the risk of childhood-onset multiple sclerosis. Archives of Pediatrics and Adolescent Medicine 2007: 161(12): 1214-15
  20. DeStefano F, Weintraub ES, Chen RT. Hepatitis B vaccine and risk of multiple sclerosis [letter] Pharmacoepidemiology and Drug Safety 2007;16(6):705–707
  21. Farez MF, Correale J. Immunizations and risk of multiple sclerosis: systematic review and meta-analysis. Journal of Neurology 2011;258(7):1197-1206
  22. Hernán M, Jick SS, Olek MJ, Jick H. Recombinant hepatitis B vaccine and the risk of multiple sclerosis: a prospective study. Neurology 2004;63:838-842
  23. Mikaeloff Y, Caridade G, Suissa S, Tardieu M. Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood. Neurology 2008
  24. Farez MF, Correale J. Yellow fever vaccination and increased relapse rate in travelers with multiple sclerosis. Archives of Neurology 2011;68(10):1267-1271
  25. Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders. The National Academies Press. 2002