Production of antibodies to the group antigenic determinant a mediates crossprotection against all subtypes, as has been demonstrated by challenge with a second subtype of the virus following recovery from an initial experimental infection. The epitope a is located in the region of amino acids 124-148 of the major surface protein, and appears to have a double-loop conformation. A monoclonal antibody which recognises a region within this a epitope is capable of neutralising the infectivity of HBV for chimpanzees, and competitive inhibition assays using the same monoclonal antibody demonstrate that equivalent antibodies are present in the sera of subjects immunised with either plasma-derived or recombinant hepatitis B vaccine.
During a study of the immunogenicity and efficacy of hepatitis B vaccines in Italy, a number of individuals who had apparently mounted a successful immune response and became anti-surface antibody (anti-HBs)-positive, later became infected with HBV. These cases were characterised by the coexistence of noncomplexed anti-HBs and HBsAg, and there were other markers of hepatitis B infection. Further examination of the antigen using monoclonal antibodies suggested that the a epi-tope was either absent or masked by antibody. Subsequent sequence analysis of the virus from one of these cases revealed a mutation in the nucleotide sequence encoding the a epitope, the consequence of which was a substitution of arginine for glycine at amino acid position 145. There is now considerable evidence for a wide geographical distribution of the point mutation in the genome of HBV from guanosine to adenosine at position 587, resulting in an amino acid substitution at position 145 from glycine to arginine in the highly antigenic group determinant a of the surface antigen. This is a stable mutation which has been found in viral isolates from children and adults and it has been described in Italy, Singapore, Japan, Brunei, Taiwan, India, USA and elsewhere, and from liver transplant recipients with hepatitis B in the USA, Germany and the UK who had been treated with specific hepatitis B immunoglobulin or humanised hepatitis B monoclonal antibody, and in patients with chronic hepatitis in Japan and elsewhere.
Other point mutations and substitutions have also been described. The 145 mutation appears to be the most common and to be stable. The region in which this mutation occurs is an important virus epitope to which vaccine-induced neutralising antibody binds, as discussed above, and the mutant virus is not neutralised by antibody to this specificity. The 145 variant virus can replicate as a competent virus, implying that the amino acid substitution does not alter the attachment of the virus to the liver cell. Variants of HBV with altered anti-genicity of the envelope protein show that HBV is not as antigenically singular as believed previously and that humoral escape mutation can occur in vivo. This finding gives rise to two causes for concern: failure to detect HBsAg may lead to transmission through donated blood or organs, and HBV may infect individuals who are anti-HBs positive after immunisation.
Mathematical modelling suggests that HBV variants may become dominant over the current wild-type virus in 50-100 years.
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