Global Vaccine Safety

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.