Abstract

Introduction

The first doubts regarding vaccines as a possible cause or exacerbation of multiple sclerosis (MS) were formulated by Miller more than half century ago [1]. Hepatitis B (HB) vaccine has been the subject of greatest concern, especially in France where mass HB vaccine administration was performed in a short time. In 1992, the World Health Organization (WHO) recommended undertaking a universal HB vaccination of all young infants in order to eradicate the HB virus. WHO explained that the teenagers’ vaccination could also be used in addition to or instead of the vaccination of young children in low-endemic countries. In 1994, the French health authorities launched a national vaccination campaign of all pupils in the first year of secondary school. The following year, HB vaccine was added to the national immunization program for all young babies and preteenagers. This intensive campaign had quickly exceeded its expected targets by also encouraging the adult population to be mass-vaccinated, whereas the vaccination of the infants remained less significant. This resulted in an unprecedented “wave” of immunization in adults, with 20 million French individuals vaccinated against HB, concentrated in 4 years, from 1994 to 1997.

MS cases in some vaccinated adults were rapidly notified to the French national pharmacovigilance system (ANSM), triggering investigation by this agency. This inquiry, started in 1994, was therefore already underway when French media revealed possible occurrence of post-immunization MS in 1998. This year, French health authorities abruptly terminated routine school-based vaccination of preteens, and adult HB vaccination began to be less widespread.

Several epidemiological studies have been evaluating the correlation between HB vaccination and MS in adults for a decade. Most of these publications found the absence of a link [2–6] or a slightly increased risk, but not sufficiently significant on the statistical level [7–9]. However, different opinions have also been formulated. A study aiming at quantifying underreporting in Fourrier’s article [8] was conducted by D. Costagliola on request of the French pharmacovigilance. This unpublished study showed by the “capture–recapture” method that the real number of MS cases linked to HB vaccine was 2–2.5 higher than the officially registered number [10]. This additional calculation makes Fourrier’s publication [8] clearly significant. Another case–control epidemiological study was conducted to evaluate serious post-vaccination adverse events registered in the United States through a spontaneous reporting system in the VAERS database. Adults receiving HB immunization had significantly increased odds ratios (OR) for MS (OR 5.2; CI 1.9–20) in comparison with an age-, sex-, and vaccine year-matched unexposed tetanus-containing vaccine group [11]. A Hernan’s paper, based on a case–control study in the United Kingdom within the General Practice Research Database (GPRD), found an increased risk (OR 3.1; CI 1.5–6.3) of MS within the 3 years following HB immunization [12]. In the same way, a French study on demyelination in childhood [13] showed that Engérix B^® vaccine administration was associated with an increased trend of confirmed MS after 3 years (OR 2.77; CI 1.23–6.24).

On these grounds, we compared temporal HB vaccine dose distribution and MS occurrence in the French population, using the official data collected by the French pharmacovigilance system (ANSM) and the national health insurance (CNAM). The results confirmed, at the global population level, a significant correlation between the number of immunizations and both the number of MS cases declared to the pharmacovigilance system 1–2 years later and an overall increase in identified MS cases in the country.