Most efforts to understand the evolution of seasonal influenza A/H3N2’s surface protein, hemagglutinin (HA), focus on mutations that increase viral fitness by enabling escape from the immune system. We investigated the functional effects of all possible single amino-acid mutations to the HA of a single, recent H3N2 strain in laboratory conditions. We found that mutations with neutral or beneficial effects in the lab were often successful in nature, while mutations with deleterious effects were not.

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