Pandemic H1N1 Influenza Infection and Vaccination in Humans Induces Cross-Protective Antibodies that Target the Hemagglutinin Stem

Abstract

Most monoclonal antibodies (mAbs) generated from humans infected or vaccinated with the 2009 pandemic H1N1 (pdmH1N1) influenza virus targeted the hemagglutinin (HA) stem. These anti-HA stem mAbs mostly used IGHV1-69 and bound readily to epitopes on the conventional seasonal influenza and pdmH1N1 vaccines. The anti-HA stem mAbs neutralized pdmH1N1, seasonal influenza H1N1 and avian H5N1 influenza viruses by inhibiting HA-mediated fusion of membranes and protected against and treated heterologous lethal infections in mice with H5N1 influenza virus. This demonstrated that therapeutic mAbs could be generated a few months after the new virus emerged. Human immunization with the pdmH1N1 vaccine induced circulating antibodies that when passively transferred, protected mice from lethal, heterologous H5N1 influenza infections. We observed that the dominant heterosubtypic antibody response against the HA stem correlated with the relative absence of memory B cells against the HA head of pdmH1N1, thus enabling the rare heterosubtypic memory B cells induced by seasonal influenza and specific for conserved sites on the HA stem to compete for T-cell help. These results support the notion that broadly protective antibodies against influenza would be induced by successive vaccination with conventional influenza vaccines based on subtypes of HA in viruses not circulating in humans.

Focused antibody response to influenza linked to antigenic drift

“…Our study has confirmed that staining and sorting peripheral B cells with soluble HA can greatly enrich for virus HA-specific clones (19,23). This enabled us to analyze a large sample of monoclonal antibodies from a single individual, for which heavy and light chains and function could be assigned.…”

Preexisting human antibodies neutralize recently emerged H7N9 influenza strains

“…First, we demonstrate that H7 cross-reactive antibodies induced by vaccination with H1N1 or H3N2 influenza A strains are not uncommon. Previous studies have shown that broadly reactive antibodies binding to the HA stalk region are relatively rare (25), but they were preferentially induced by exposure to the highly unique 2009 pandemic H1N1 strain (16,26,27). It was hypothesized that exposure to this pandemic strain, which has a globular head domain that is highly divergent from prepandemic seasonal H1N1 strains, was activating cross-reactive memory B cells reactive with conserved epitopes (e.g., in the stalk region) that the virus shared with previous seasonal strains (2, 28).…”

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

“…Blood samples were collected from individuals treated for IPAP. Individual memory B cells binding to GM-CSF were sorted into individual wells (55) (Fig. S6).…”