Age-dependent heterogeneity in the antigenic effects of mutations to influenza hemagglutinin.

Human influenza virus evolves to escape neutralization by polyclonal antibodies. However, we have a limited understanding of how the antigenic effects of viral mutations vary across the human population and how this heterogeneity affects virus evolution. Here, we use deep mutational scanning to map how mutations to the hemagglutinin (HA) proteins of two H3N2 strains, A/Hong Kong/45/2019 and A/Perth/16/2009, affect neutralization by serum from individuals of a variety of ages. The effects of HA mutations on serum neutralization differ across age groups in ways that can be partially rationalized in terms of exposure histories. Mutations that were fixed in influenza variants after 2020 cause greater escape from sera from younger individuals compared with adults. Overall, these results demonstrate that influenza faces distinct antigenic selection regimes from different age groups and suggest approaches to understand how this heterogeneous selection shapes viral evolution.
Competing Interests: Declaration of interests J.D.B. is on the scientific advisory boards of Apriori Bio, Invivyd, Aerium Therapeutics, and the Vaccine Company. J.D.B., A.N.L., and F.C.W. receive royalty payments as inventors on Fred Hutch licensed patents related to viral deep mutational scanning. H.Y.C. reports consulting with Ellume, Pfizer, and the Bill and Melinda Gates Foundation. She has served on advisory boards for Vir, Merck, and Abbvie. She has conducted CME teaching with Medscape, Vindico, and Clinical Care Options. She has received research funding from Gates Ventures and support and reagents from Ellume and Cepheid outside of the submitted work. J.A.E. receives institutional funding from AstraZeneca, Merck, GlaxoSmithKline, and Pfizer. She is a consultant for Abbvie, AstraZeneca, GlaxoSmithKline, Meissa Vaccines, Moderna, Pfizer, and SanofiPasteur. A.L.G. reports contract testing from Abbott, Cepheid, Novavax, Pfizer, Janssen, and Hologic and research support from Gilead outside of the submitted work.
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