Hepatitis B vaccination and multiple sclerosis (MS)
Extract from report of GACVS of 20-21 June 2002, published in the WHO Weekly Epidemiological Record on 22 November 2002
Hepatitis B vaccine has been used extensively in France in recent years, with more than 20 million persons being vaccinated. Several case reports have raised concerns that hepatitis B immunization may be linked to new cases or relapses of multiple sclerosis (MS). In response to public and professional concern, the French Ministry of Health on 1 October 1998 temporarily suspended the school-based adolescent hepatitis B vaccine programme. France maintained the recommendations for universal infant immunization and administration of the vaccine to adults at special risk, and reiterated their support for adolescent vaccination. This decision was misunderstood and interpreted as a ban on hepatitis B immunization, generating widespread concern in other countries.
Three possible theories explain the link between MS and hepatitis B vaccine: 1) coincidence, due to the large number of hepatitis B vaccine doses administered, many to individuals in the age groups in which MS first occurs; 2) “triggering”, an increased risk of demyelination following hepatitis B vaccine that would act as a “trigger” in individuals predisposed to develop MS or other central nervous system demyelinating disease; and 3) a true causal association between hepatitis B vaccination and MS or other demyelinating disease.
By 2001, more than 700 cases of central demyelinating diseases with a close match to the natural epidemiological distribution of MS had been reported to the French authorities, the majority in adult females. The time delay between the last dose of vaccine and the onset of neurological symptoms was from 1 day to 5 years (median: 60 days). No cases were reported among children < 25 months, despite vaccination of 1.8 million babies. Overall, 9 epidemiological studies have been carried out to estimate the risk (if any) of an association between vaccination with hepatitis b vaccine and a first attack or relapse of ms. None of the initial studies, despite a slightly elevated odds ratio, showed a statistically significantly increase in risk; the most recent studies do not indicate any excess risk. Analysis of data from spontaneous reports and epidemiological studies does not support a causal relationship between ms and hepatitis b vaccine. The most likely explanation is a coincidental association.
The conclusions of a recent report of the United States Institute of Medicine on an association between hepatitis B vaccine and demyelinating neurological disorders also did not support a causal relationship between hepatitis B vaccine administered to adults and MS or relapse of MS. GACVS has concluded that there is no reason to suggest a change in the recommendations for universal infant and adolescent immunization coverage with hepatitis B vaccine.
Full report of GACVS of 20-21 June 2002, published in the WHO Weekly Epidemiological Record on 22 November 2002
Related links
World Health Organization Global Advisory Committee on Vaccine Safety: Response to the paper by MA Hernán and others in Neurology 14th September 2004 issue entitled “Recombinant Hepatitis B Vaccine and the Risk of Multiple Sclerosis”
September 2004
1. The Global Advisory Committee on Vaccine Safety (GACVS) of the World Health Organization has given careful consideration to the article published by MA Hernán and others in the 14th September 2004 issue of Neurology (63(5):838-842) on the risk of multiple sclerosis associated with recombinant hepatitis B vaccine. The findings are based on a case control study conducted within the General Practice Research Database (GPRD) in the United Kingdom. Dr Hernán has previously presented his results and interpretation of them to the GACVS at the December 2003 meeting of the committee. On the basis of the data and argument given by Hernán et al. in their article, the GACVS does not believe that the findings provide convincing support for the hypothesis that immunization with recombinant hepatitis B vaccine is associated with an increased risk of multiple sclerosis.
2. The main misgivings of the committee with the Hernán paper are as follows:
- The authors’ conclusions depend on the results of altogether 11 cases of MS adult patients vaccinated against hepatitis B. Such a sample size is too small for a definite interpretation to be made, one way or the other. On the basis of these 11 cases, Hernán and his colleagues calculate an odds ratio of 3.1 (95% CI 1.5, 6.3 – a wide confidence interval) of MS in patients vaccinated with hepatitis B within 3 years before the index date, compared with an odds ratio of 1 and 0.6, respectively, for influenza and tetanus vaccines. The committee noted that there is inherent risk, however small, of misclassification of vaccination status and that minimal differences in the recorded data would render the results and conclusions insignificant.
- The practice of vaccination against hepatitis B in the United Kingdom at the time of the study was targeted towards high-risk individuals. They included health care and laboratory workers, travellers to endemic regions, those with liver damage, dialysis patients, prostitutes and drug addicts. This cannot be regarded as a representative sample of the general population, and the skewed selection might have biased the results of the study. For example, health care workers might bring neurological symptoms to the attention of their physicians earlier than others, or the recall of symptoms might be different. Other potential sources of bias with such a select group cannot be excluded. (This argument has been made in the accompanying editorial in Neurology that covers the Hernán article; refer RT Naismith and AH Cross. Neurology, 2004(63): 772-773.) In general, since vaccination of health care workers in the UK usually takes place in occupational health departments, there is likely to be incomplete information on the vaccination status in this group in the GPRD.
- Of the original 713 cases of MS 163 were selected, and eventually only 11 vaccinated patients were used for deriving actual hazard data. This selection process, however careful it might have been, is fraught with methodological problems and with the risk of inadvertent bias. An inadequate account is given in the article of the cases that were excluded from analysis. Moreover, no population attributable risk is provided.
- Since no association of the onset of MS was found with other vaccinations (influenza and tetanus) in the study, the authors’ suggestion that the association of MS with HBV might be explained by the aluminium or thiomersal content of the latter must be considered unsupported by other studies and even by their own evidence. (It should be pointed out that the authors’ conclusions regarding the other vaccines suffer from the same criticism of small study sample that applies to the HBV analysis.)
- The date of first symptoms was related in the study to the last dose given. There is no information provided of the total number of doses and the time that previous doses were administered, precluding any judgment of a dose-response effect. The biological plausibility of the findings might be questioned by the observation that the risk only appeared greater more than one year after the last immunisation. This delay does not support the hypothesis of a triggering by HBV and is not in accordance with the French pharmacovigilance data which prompted this study.
The GACVS has noted that the findings and conclusions of the Hernán paper are at variance with those of a number of others; namely Ascherio (2001)1, De Stefano (2003)2, Touze (2002)3, Sturkenboom (1999)4, Confraveux (2001)5, Zipp (1999)6, Sadovnick (2000)7. Whereas each of these papers has its own methodological problems, it is notable that the overall conclusion of each is consistently different to those of Hernán. Data accumulated globally during the last 20 years has also provided evidence supporting the safety of hepatitis B immunization in infants and adolescents. Nevertheless, it is important that the questions raised by Hernán and colleagues are put to the test and the GACVS will be keeping a watching brief on the issues. For the time being, the GACVS has advised the WHO that 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.
Hepatitis B vaccination and multiple sclerosis: update
January 2004
At its meeting of 3-4 December 2003, the committee considered an unpublished abstract and oral presentation of a study that drew on data from the United Kingdom General Practice Research Database (GPRD) in proposing a possible association between hepatitis B vaccination and the onset of multiple sclerosis (MS). The authors reported an apparent increase in risk of onset of MS within 3 years of vaccination, using a case-control method. The committee concluded that the details provided of the methods used and the patient data submitted were insufficient to address concerns regarding the likelihood of selection bias that might have distorted the conclusions. The latter were based on small numbers so that the element of a chance finding could not be discounted. The committee concluded, on the basis of the information and argument put before it, that the findings do not provide a basis for changing policy with respect to hepatitis B immunization.
The Global Advisory Committee on Vaccine Safety rejects association between Hepatitis B vaccination and multiple sclerosis (MS)
November 2002
The Global Advisory Committee on Vaccine Safety (GACVS) has concluded that there is no association between administration of the hepatitis B vaccine and multiple sclerosis (MS). Since 1982, hepatitis B vaccine has been given to over 500 million people around the world. The hepatitis B vaccine is the first and only vaccine that prevents liver cancer by preventing hepatitis B infection.
There has been extensive use of hepatitis B vaccine in France in recent years, with more than 25 million people being vaccinated. Several case reports have raised concerns that hepatitis B immunization may be linked to new cases or relapse of multiple sclerosis (MS). As a result of public and professional concern, on 1 October 1998 the French Ministry of Health temporarily suspended the school-based adolescent hepatitis B vaccine programme. It nevertheless maintained the recommendations for universal infant immunization and administration of the vaccine to adults at special risk, and reiterated its support for adolescent vaccination. The French decision was misunderstood and interpreted as a ban on hepatitis B immunization, generating widespread concern in other countries.
There are three possible explanations of the observation linking MS with hepatitis B vaccination: 1) coincidence, due to the large number of hepatitis B vaccine doses administered, many of them in age groups in which MS first occurs; 2) "triggering", i.e. an increased risk of demyelination following hepatitis B vaccine which would act as a "trigger" in individuals predisposed to develop MS or other central nervous system demyelinating disease; and 3) a true causal association between hepatitis B vaccination and MS or other demyelinating disease.
By 2001, more than 700 cases of central demyelinating diseases with a close match to the natural epidemiologic distribution of MS had been reported to the French authorities, the majority in adult females. No cases were reported among children less than 25 months despite vaccination of 1.8 million babies. Overall, 9 epidemiological studies have been carried out to estimate the risk (if any) of an association between vaccination with hepatitis B and a first attack or relapse of multiple sclerosis. Despite a slightly elevated odds ratio observed in the initial studies, none showed a statistically significantly elevated risk, and the most recent studies do not indicate any excess risk. The analysis of data from spontaneous reports and results of epidemiological studies do not support a causal relationship between MS and hepatitis B vaccination. The most likely explanation is a coincidental association.
The conclusions of a recent report of the United States Institute of Medicine on an association between hepatitis B and demyelinating neurological disorders also did not support a causal relationship between hepatitis B vaccine administered to adults and multiple sclerosis or a relapse of multiple sclerosis. The GACVS has concluded that there is no reason to suggest that the recommendations for universal infant and adolescent immunization coverage with hepatitis B vaccine should change.
Global Advisory Committee on Vaccine Safety: response to the paper (in press) by Y. Mikaeloff and colleagues in Neurology entitled "Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood", October 2008
8 October 2008
The Global Advisory Committee on Vaccine Safety (GACVS) of the World Health Organization has given preliminary consideration to this article. The findings are based on a case-control study conducted in France. Children aged less than 16 years with a first episode of acute central nervous system (CNS) inflammatory demyelination occurring between 1994 and 2003 were identified from a national neuropaediatric study “KIDSEP”. Their histories of exposure to hepatitis B (HB) vaccination (ascertained for most children through inspection of vaccination certificates) were compared with those of a control group of children. Controls were individually matched to the cases for age, sex and area of residence and selected from the general population by random telephone dialling. A previous analysis from KIDSEP of children with multiple sclerosis (MS) had found no association with HB vaccine. The new study expanded the case group to include children who had a first episode of acute CNS inflammatory demyelination but who did not go on to develop MS.
The authors found that a history of hepatitis B vaccination was less common among cases than among controls at all time intervals examined before onset of disease in the cases and regardless of the brand of HB vaccine that had last been used. This suggests that there is no increased risk of disease associated with HB vaccination. The differences in vaccination status between cases and controls were not statistically significant for any time intervals between vaccination and onset of disease.
The authors then conducted a large series of subgroup analyses. It is well known in epidemiological studies that if multiple subgroup analyses are conducted then spurious “significant” results are likely to be found, unless adjustment is made for the number of different statistical tests performed, which was not done in this paper. In this part of the study, the authors first restricted analyses to cases and controls who were “compliant with vaccination” (thus excluding half of the cases) and then restricted analyses to patients with MS only (reducing the original case group from 349 down to 72). In this latter set of analyses they found a “significantly” higher frequency of the last administration of one brand of HB vaccine more than three years before onset among cases than among controls. On the basis of the subgroup analysis, the authors concluded that this one brand of vaccine appeared to increase the risk of CNS inflammatory demyelination, particularly for MS. Of note, there was not a higher frequency of administration of this HB vaccine among the cases for the period less than three years before onset. In the discussion of their paper the authors acknowledge that the results concerning the one brand of vaccine “were obtained from subgroup analyses, and were thus subject to false significance from multiple comparisons”. We strongly agree with that statement and also note that the uncertainty in the estimates for each brand on its own was so large that there was no convincing evidence that the brands actually differed. Furthermore, the authors appeared to have no prior hypothesis to suspect differences in risk according to vaccine brand or that risk would be apparent only three or more years after vaccination.
GACVS considers that the findings from this study do not provide convincing evidence that HB vaccination, or use of any brand of HB vaccine, is associated with an increased risk of MS or of an episode of acute CNS inflammatory demyelination.
- Mikaeloff Y, Caridade G, Suissa S, Tardieu M. Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood. Neurology 2008, doi:10.1212/01.wnl.0000335762.42177.07, published online before print October 8, 2008.
- Mikaeloff Y, Caridade G, Rossier M, Suissa S, Tardieu M. Hepatitis B vaccination and the risk of childhood onset multiple sclerosis. Arch Pediatr Adolesc Med 2007;161:1176-1182.