Research ArticleInfluenza

A multimechanistic antibody targeting the receptor binding site potently cross-protects against influenza B viruses

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Science Translational Medicine  18 Oct 2017:
Vol. 9, Issue 412, eaam5752
DOI: 10.1126/scitranslmed.aam5752

An antibody to battle flu B

Although it circulates globally and is prevalent enough to warrant inclusion in the seasonal influenza vaccine, influenza B is far less well studied than its cousin, influenza A, and therapeutics are lacking. Shen et al. have now generated a potent antibody that inhibits diverse strains of influenza B virus. The antibody recognizes the receptor binding site in hemagglutinin, a region critical to viral entry, and was shown to be therapeutically effective in mice and ferrets. This antibody could be widely deployed to treat or prevent influenza B infection around the world.

Abstract

Influenza B virus causes considerable disease burden worldwide annually, highlighting the limitations of current influenza vaccines and antiviral drugs. In recent years, broadly neutralizing antibodies (bnAbs) against hemagglutinin (HA) have emerged as a new approach for combating influenza. We describe the generation and characterization of a chimeric monoclonal antibody, C12G6, that cross-neutralizes representative viruses spanning the 76 years of influenza B antigenic evolution since 1940, including viruses belonging to the Yamagata, Victoria, and earlier lineages. Notably, C12G6 exhibits broad cross-lineage hemagglutination inhibition activity against influenza B viruses and has higher potency and breadth of neutralization when compared to four previously reported influenza B bnAbs. In vivo, C12G6 confers stronger cross-protection against Yamagata and Victoria lineages of influenza B viruses in mice and ferrets than other bnAbs or the anti-influenza drug oseltamivir and has an additive antiviral effect when administered in combination with oseltamivir. Epitope mapping indicated that C12G6 targets a conserved epitope that overlaps with the receptor binding site in the HA region of influenza B virus, indicating why it neutralizes virus so potently. Mechanistic analyses revealed that C12G6 inhibits influenza B viruses via multiple mechanisms, including preventing viral entry, egress, and HA-mediated membrane fusion and triggering antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity responses. C12G6 is therefore a promising candidate for the development of prophylactics or therapeutics against influenza B infection and may inform the design of a truly universal influenza vaccine.

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