Publication

Journal	Journal of Virology
Volume (Issue)	89(6)
Page(s)	3136 - 3144
Title of proceedings	Journal of Virology
DOI	10.1128/JVI.03069-14

The majority of influenza virus-specific antibodies elicited by vaccination or natural infection are effective only against the elicit- ing or closely related viruses. Rare stem-specific heterosubtypic monoclonal antibodies (hMAbs) can neutralize multiple strains and subtypes by preventing hemagglutinin (HA)-mediated fusion of the viral membrane with the endosomal membrane. The epitopes recognized by these hMAbs are therefore considered promising targets for the development of pan-influenza virus vac- cines. Here, we report the isolation of a novel human HA stem-reactive monoclonal antibody, hMAb 1.12, with exceptionally broad neutralizing activity encompassing viruses from 15 distinct HA subtypes. Using MAb 1.12 and two other monoclonal anti- bodies, we demonstrate that neutralization by hMAbs is virtually irreversible but becomes severely impaired following virus attachment to cells. In contrast, no interference by human anti-influenza virus serum antibodies was found, indicating that api- cally binding antibodies do not impair access to the membrane-proximal heterosubtypic epitopes. Our findings therefore en- courage development of new vaccine concepts aiming at the induction of stem-specific heterosubtypic antibodies, as we provide support for their effectiveness in individuals previously exposed to influenza virus.