Abstract
H3N2 influenza viruses have now circulated in the human population for 43 years since the pandemic of 1968, accumulating sequence changes in the hemagglutinin (HA) and neuraminidase (NA) that are believed to be predominantly due to selection for escape from antibodies. Examination of mutations that persist and accumulate led to identification of antigenically significant mutations that are contained in five antigenic sites (A–E) mapped on to the H3 HA. In early H3N2 isolates, antigenic site A appeared to be dominant while in the 1990s site B seemed more important. To obtain experimental evidence for dominance of antigenic sites on modern H3 HAs, we have measured antibodies in plasma of human subjects who received the 2006–07 trivalent subunit influenza vaccine (H3 component A/Wisconsin/67/05) or the 2008–09 formulation (H3 component A/Uruguay/716/07). Plasmas were tested against expressed HA of Wisconsin-like influenza A/Oklahoma/309/06 and site-directed mutants in antigenic site A (NNES121-124ITEG, N126T, N133D, TSSS135-138GSNA, K140I, RSNNS142-146PGSG), and antigenic site B (HL156-157KS, KFK158-160GST, NDQI189-192QEQT, A196V). “Native ELISA” analysis and escape mutant selection with two human monoclonal antibodies demonstrated that antibody E05 binds to antigenic site A and 1_C02 binds to site B. We find that most individuals, after vaccination in seasons 2006–07 and/or 2008–09, showed dominance of antigenic site B recognition over antigenic site A. A minority showed dominance of site A in 2006 but these were reduced in 2008 when the vaccine virus had a site A mutation. A better understanding of immunodominance may allow prediction of future antigenic drift and assist in vaccine strain selection.
Highlights
Influenza viruses are major pathogens that cause seasonal epidemics and global pandemics
The phylogenetic analyses [14,39] and serum studies [15,37] suggest that sites A and B are the most important in directing antigenic drift of H3N2 human viruses, and so we have investigated the immunogenicity of antigenic sites A and B of recent H3 HAs
To test if mutations accumulated since 1968 have changed the map of antigenic sites on HA and, second, to map epitopes of monoclonal antibodies made against a recent virus, we mutated the sequence of HA1 of a local Wisconsin-like virus, A/ Oklahoma/309/2006 (H3N2), to those amino acids in HA1 of the earliest human H3N2 virus A/Aichi/2/1968
Summary
Influenza viruses are major pathogens that cause seasonal epidemics and global pandemics. Due to rapid accumulation of mutations to escape host defense mechanisms, the vaccine components must be frequently updated to protect the human population against influenza. There are three types of influenza viruses, A, B and C. Type A viruses are divided into subtypes according to cross-reactivity of sera with viral surface glycoprotein antigens; to date these are subtypes H1 to H16 of the hemagglutinin (HA) and N1 to N9 of neuraminidase (NA) an H17 has been recently proposed [2]. H1N1 and H3N2 along with type B viruses are currently circulating in the human population and these are the antigens in the trivalent vaccines. Neutralizing antibodies directed against the hemagglutinin are considered the most protective against influenza virus infection and vaccine responses are most commonly tested by hemagglutination-inhibition assays
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