How single mutations affect viral escape from broad and narrow antibodies to H1 influenza hemagglutinin

Influenza virus can 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 there was strong pressure to do so. Here, we map all single amino-acid mutations that increase resistance to broad antibodies to H1 hemagglutinin. 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 to hemagglutinin’s receptor-binding site the same way it escapes narrow strain-specific antibodies: via single mutations with huge effects. In contrast, broad antibodies to hemagglutinin’s stalk only select mutations with small effects. Therefore, among the antibodies we examine, breadth is an imperfect indicator of the potential for viral escape via single mutations. Antibodies targeting the H1 hemagglutinin stalk are quantifiably harder to escape than the other antibodies tested here. Influenza A virus can escape antibodies, but it is unclear how the ease of escape depends on the epitope targeted by an antibody. Here, the authors show that neutralization breadth is an imperfect indicator of the ease of viral escape by single mutations, and that antibodies targeting the stalk of hemagglutinin are harder to escape.