ORIGINAL INVESTIGATION Gilbert Greub á FreÂdeÂric Zysset á Blaise Genton FrancËois Spertini á Philippe C. Frei Absence of anti-hepatitis B surface antibody after vaccination does not necessarily mean absence of immune response Received: 16 June 2000 Abstract A small number of subjects vaccinated against hepatitis B do not produce anti-hepatitis B surface HBs) antibody levels detectable by commercial assays. Others lose detectable anti-HBs at some time after vaccination. The absence of clinical hepatitis despite potential expo- sure to hepatitis B virus HBV) in both kinds of subjects suggests that they might be protected by low antibody levels. However, besides anti-HBs, T helper response and memory cells which may be induced by the vaccine are certainly also important for immunity against HBV. In the present study, samples from vaccinated subjects, found to be anti-HBs negative in an initial assay, sub- sequently showed positive results in, respectively, 25%, 36% and 38% of the cases, when a second, third and fourth assay was used. In addition, 360 samples from ``nonresponders'' and from vaccinees who had lost anti- HBs, the reactivity of which was under the enzyme-linked immunoassay-cut-o value were compared to that of nonvaccinated controls. The absorbances were found to be signi®cantly higher in the nonresponders 0.038) and in the vaccinees having lost anti-HBs 0.041), than in the controls 0.025). Such ®ndings contribute to explaining why so-called nonresponders as well as vaccinees who have lost anti-HBs nevertheless appear to be protected. Key words Hepatitis B vaccine á Anti-hepatitis B surface antibody á Hepatitis B infection á Serology Introduction Hepatitis B vaccines were introduced in 1981 as plasma- derived vaccines and, in 1986, as the recombinant vac- cines that are still in use. The quality of the protection conferred by such vaccines can now be estimated on the basis of the 19 years that have elapsed since their initial introduction. The ecacy of the vaccination has been assessed with the help of the anti-hepatitis B surface antibody anti- HBs) levels obtained. Levels reached 1 month after the last injection of the primovaccination schedule have often been considered. Subjects with no anti-HBs at this point, as measured by commercial enzyme-linked immunoassays EIA), are said to be ``nonresponders''. Their proportion of the population depends on various factors, including gender, age, body mass index, smok- ing habits and immunogenetic factors [12, 14]. The risk for such subjects of becoming infected with HBV and/or of developing clinical hepatitis is not well de®ned. Since the earliest studies [6, 16], an anti-HBs titer higher than 10 mUI/ml has been accepted as protective. Despite its arbitrary character, this limit has bene®ted from a consensus that has proven useful for comparing the immunogenicity of various vaccine preparations or of vaccination schedules. The risk of developing hepa- titis for subjects having anti-HBs levels between 0 and 10 mIU/ml is, however, not better known than in subjects having 0 mIU/ml. It seems that there are practically no clinical cases of hepatitis which occur today in subjects who have undergone the entire vac- cination schedule, including the nonresponders and the subjects having anti-HBs between 0 and 10 mIU/ml. Two exceptional cases, one clinical and one with en- zyme elevations only, have been reported [1, 10]. This suggests that protection can be achieved thanks to undetected levels of anti-HBs or to another type of immune response. Such consideration also applies to vaccinees, who have lost a previously demonstrable anti-HBs level. In Med Microbiol Immunol 2001) 189: 165±168 Ó Springer-Verlag 2001 G. Greub &) á F. Spertini á P. C. Frei Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland Tel.: +41-21-3140523; Fax: +41-21-3141008 e-mail: Gilbert.Greub@chuv.hospvd.ch F. Zysset Division of Preventive Hospital Medicine, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland B. Genton Travel Clinic, University Medical Policlinic, 1011 Lausanne, Switzerland