Quantifying the effects of single mutations on viral escape from broad and narrow antibodies to an H1 influenza hemagglutinin

ABSTRACT Influenza virus can completely escape most antibodies with single mutations. However, rare antibodies broadly neutralize many viral strains. It is unclear how easily influenza virus might escape such antibodies if it was under strong pressure to do so. Here we map all single amino-acid mutations that increase resistance to broad antibodies targeting an H1 hemagglutinin. Crucially, our approach not only identifies antigenic mutations but also quantifies their effect sizes. All antibodies select mutations, but the effect sizes vary widely. The virus can escape a broad antibody that targets residues in hemagglutinin’s receptor-binding site the same way it escapes narrow strain-specific antibodies: via single mutations with huge effects. In contrast, broad antibodies targeting hemagglutinin’s stalk only select mutations with small effects. Therefore, among the antibodies we have examined, breadth is an imperfect indicator of the potential for viral escape via single mutations. Broadly neutralizing antibodies targeting the H1 hemagglutinin stalk are quantifiably harder to escape than the other antibodies tested here.