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.
Highlights
Each year seasonal influenza causes serious illnesses in 3–5 million humans and 200,000–500,000 deaths (Chen and Subbarao, 2009)
Would circulating levels of heterosubtypic antibodies reach protective levels? Would the pandemic H1N1 (pdmH1N1) vaccine induce a protective heterosubtypic antibody response? What was different about infection with pdmH1N1 and why were there not a high frequency of anti-HA stem monoclonal antibodies (mAbs) induced by infection with seasonal influenza? Here we provide answers to these questions
Our data show that vaccination with the pdmH1N1 vaccine or infection with the virus, induced in many humans a dominant cross-protective, heterosubtypic antibody response against a conserved site on the HA stem
Summary
Each year seasonal influenza causes serious illnesses in 3–5 million humans and 200,000–500,000 deaths (Chen and Subbarao, 2009). If antibodies against the head of the hemagglutinin are of sufficient affinity/avidity and sterically inhibit the receptor-binding site, they block attachment of the virus to the host cell (Knossow et al, 2002). These protective antibodies are very specific for a given isolate/subtype of influenza virus because the replication of the influenza virus genome is error-prone. Influenza viruses are rapidly selected with mutants of the HA that decrease the affinity of the protective antibodies so that they no longer block attachment of the mutant virus. This variation in the influenza virus is called “antigenic drift” and three dominant drifted influenza viruses are incorporated into updated seasonal influenza vaccines to induce protective antibodies to these variants
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