Heterosubtypic antibodies to influenza A virus have limited activity against cell-bound virus but are not impaired by strain-specific serum antibodies

Wyrzucki A, Bianchi M, Kohler I, Steck M, et al.. Heterosubtypic antibodies to influenza A virus have limited activity against cell-bound virus but are not impaired by strain-specific serum antibodies. J Virol. 2014 Dec 31. pii: JVI.03069-14
submited by kickingbird at Jan, 4, 2015 15:41 PM from J Virol. 2014 Dec 31. pii: JVI.03069-14

The majority of influenza virus-specific antibodies elicited by vaccination or natural infection is only effective against the eliciting 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 with the endosomal membrane. The epitopes recognized by these hmAbs are therefore considered promising targets for the development of pan-influenza vaccines. Here we report the isolation of a novel human HA-stem-reactive monoclonal antibody, mAb 1.12, with exceptionally broad neutralizing activity encompassing viruses from 15 distinct HA subtypes. Using mAb 1.12 and two other monoclonal antibodies, we could 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 serum antibodies was found, indicating that apically binding antibodies do not impair access to the membrane-proximal heterosubtypic epitopes. Our findings therefore encourage 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.