HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Correspondence to:

ARTICLES: Yann Mikaeloff, Guillaume Caridade, Samy Suissa, and Marc Tardieu Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood Neurology 2008; 0: 01.wnl.0000335762.42177.07v1 [Abstract]

Correspondence: Submit a response to this article

Correspondence published:

Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood

Michel Lievre, Members of the Epidemiology working group of the French pharmacovigilance commission: Dominique Costagliola, Stephen Evans, Annie Fourrier, Jean-Louis Imbs, Daniel Levy-Bruhl, Louis Merle, Joelle Micallef, Emmanuel Oger   (10 March 2009)

Editor's Note

Richard J. Kryscio, PhD   (10 March 2009)

Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood

Alain Braillon, Gérard Dubois   (5 December 2008)

Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood 10 March 2009
Michel Lievre, Lyon 1 University Service de Pharmacologie Clinique, Faculté de Médecine, rue Guillaume Paradin, 69008 Lyon, France, Members of the Epidemiology working group of the French pharmacovigilance commission: Dominique Costagliola, Stephen Evans, Annie Fourrier, Jean-Louis Imbs, Daniel Levy-Bruhl, Louis Merle, Joelle Micallef, Emmanuel Oger Send Correspondence to journal: Re: Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood ml{at}upcl.univ-lyon1.fr Michel Lievre, et al.	In a new analysis of a case-control study based on the French KIDSEP cohort, Mikaeloff et al. conclude that there is no overall association of hepatitis B vaccine (HB) with acute onset demyelinating disease but that there is a long-term increase in the risk of multiple sclerosis (MS) in children compliant with national vaccination schedules and immunized against HB with the Engerix B® vaccine. [1] Unfortunately, these results were leaked to the lay press before their publication in Neurology®, fueling new rumors about the risk of HB vaccination. We would like to stress major interpretational issues that preclude any reliable conclusion from being drawn about a possible link in this study, between the Engerix R® vaccine, and the risk of MS in children. A very large number of analyses were undertaken. A total of 50 results appear in the article, and the list of “sensitivity” analyses suggests that many more were done. The probability of detecting several significant associations through pure chance was therefore very high. Concluding that there is a difference between Engerix B® and other vaccines because the odds ratio for MS is significant for Engerix B® and non-significant for the other vaccines results from an error in interpretation. The confidence intervals of the odds ratios for the various vaccines largely overlap, and a significant interaction between the risk of MS and vaccine brand cannot therefore be demonstrated. Restricting the investigation to children compliant with the French vaccine recommendations was based on the assumption of a possible bias in the responses of the controls in favor of the best vaccinated children. However, the very existence of such a bias should have been questioned by the investigators when confronted with similar levels of compliance in cases and controls. The sub-group analysis results in a considerable reduction in sample size, with a loss of more than 50% of cases. The role played by the delay between vaccination and MS is not clear. In the sub-analysis of “compliant” children, the odds ratio is 0.45 (IC 95% = [0.12 – 1.71]) for a 1-2 year delay, and moves to 2.12 (IC 95% = [1.00 – 4.48]) for a >3 year delay. In conclusion, the benefit/risk balance of vaccination with any vaccine against HB in children should not be called into question on the basis of sub-group results in this study. Reference 1. Mikaeloff Y, MD, Caridade G, Suissa S, Tardieu M. Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood. Neurology 2009;72:873-880. Disclosure: The authors report no disclosures. The authors and the editorialists were offered the opportunity to respond but declined.
Editor's Note 10 March 2009
Richard J. Kryscio, PhD, Associate Editor, Biostatistics Neurology Send Correspondence to journal: Re: Editor's Note kpieper{at}neurology.org Richard J. Kryscio, PhD	Editor’s Note – Richard J. Kryscio, PhD, Associate Editor, Biostatistics The case control study reported by Mikaeloff et al. is negative since its primary analysis failed to demonstrate a relationship between use of HB vaccine and the risk of CNS inflammatory demyelination. The authors carefully examined several factors that could influence the risk including the time interval between the last delivery of the vaccine and the index case report, the most recently used brand of the vaccine, and the interaction between the time interval and the last brand. None of these and other factors produced a positive result. Then an unspecified number of subgroups were examined. The subgroup analysis reported in Table 3 relied on one of several possible definitions of a vaccine schedule compliant with the guidelines for optimal immunization. For that subgroup, an interaction was found. The most widely used vaccine, Energix, delivered at least 3 years prior to the index case was associated with a significant elevated risk for the demyelination (1.74; 95% C.I.: 1.03-2.95). Unfortunately, the press took advantage of this report and presented it as a definitive finding prompting a Correspondence challenging this finding from Michel Lievre and several of his colleagues in the Epidemiology Working Group of the French pharmacovigilance commission. Lievre et al. argue that this subgroup analysis could simply be an artifact produced from multiple comparisons and it could be biased since it based on vaccine compliers. These are legitimate concerns but Lievre et al. fail to acknowledge that Mikaeloff et al.--in the Discussion section--admit that the P value associated with this result could be affected by multiple looks at the data. While an analysis based on a specific definition of a completer could be biased, this interaction remains significant under various definitions of a compliant subject. The Working Group argues that the database is not large enough to rule out a difference among the vaccine brands. The authors likely contributed to this reaction since they state that differential HB antigen targets and varying production processes could explain why one vaccine is involved in a significant interaction while the other is not. Both parties appear to be ignoring the fact that the second vaccine examined (GenHevac B) is associated with an non-significant but elevated risk for the interaction with the three year window (risk 1.5; 95% C.I. 0.71-3.17). The latter could be attributed to a lack of power since the second vaccine is not nearly as popular as the first. Finally, Lievre et al argue that the choice of a three-year window is not justified and that the interaction between specific vaccines and shorter windows are associated with relative risks less than one. However, these risks do increase as the length of the window increases. In conclusion, I believe the authors generated a hypothesis worthy of investigation in future studies. However, this is just a hypothesis, a yellow light at best but not a a definitive finding. Disclosure: The author reports no disclosures.
Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood 5 December 2008
Alain Braillon, Department of Public Health Hôpital Nord, 80054 Amiens CEDEX 1, France, Gérard Dubois Send Correspondence to journal: Re: Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood braillon.alain{at}chu-amiens.fr Alain Braillon, et al.	Mikaeloff et al. assert that Engerix B® vaccine appears to increase the risk of CNS inflammatory demyelination in childhood. [1] This type of subgroup analysis and conclusion should be based on known mechanisms or made in response to previous findings. A subgroup analysis should also include the declaration of the number of analyses performed and adjustments should be made for multiple testing with tests for heterogeneity. Media coverage following the release of this article stated that "the children with MS were 1.74 times more likely to have received a certain type of hepatitis B vaccine called Engerix B®." [2] The repercussions from this type of claim may inhibit physicians from administering the vaccine. France has the lowest rate for immunization against the Hepatitis B virus (HBV) among developed countries. In 2006, the percentage of one-year-old children immunized with three doses of Hepatitis B in France was 29%. When compared to countries such as Germany (86%), France's immunization record may worsen to the level of Dominica (7%)-one of the poorest countries in the world. [3] When applied carefully and self critically, epidemiological methods offer a way to improve a population's health. References 1. 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. 2. Majority Of Children Vaccinated Against Hepatitis B Not At Increased Risk Of Multiple Sclerosis, Study Shows. Science Daily News, September 28, 2008. http://www.sciencedaily.com/releases/2008/09/080925144808.htm (accessed October 31 2008). 3. Data available at http://www.who.int/whosis/data (accessed November 14, 2008). Disclosure: The authors report no disclosures. Editor’s Note: The authors of the article were offered the opportunity to respond but declined.