Abstract
A longstanding question is how influenza virus evolves to escape human immunity, which is polyclonal and can target many distinct epitopes. Here, we map how all amino-acid mutations to influenza's major surface protein affect viral neutralization by polyclonal human sera. The serum of some individuals is so focused that it selects single mutations that reduce viral neutralization by over an order of magnitude. However, different viral mutations escape the sera of different individuals. This individual-to-individual variation in viral escape mutations is not present among ferrets that have been infected just once with a defined viral strain. Our results show how different single mutations help influenza virus escape the immunity of different members of the human population, a phenomenon that could shape viral evolution and disease susceptibility.
Highlights
Infection of humans with influenza virus elicits potent neutralizing antibodies targeting the viral hemagglutinin (HA) protein
We show that human serum can select single mutations that reduce viral neutralization by over an order of magnitude
We have mapped the selection that polyclonal human sera exert on all amino-acid mutations to a H3N2 influenza virus HA
Summary
Infection of humans with influenza virus elicits potent neutralizing antibodies targeting the viral hemagglutinin (HA) protein. The effectiveness of this immunity against future strains is rapidly degraded by viral antigenic evolution (Bedford et al, 2014; Smith et al, 2004), such that the typical human is infected by influenza virus roughly every 5 years (Couch and Kasel, 1983; Kucharski et al, 2015; Ranjeva et al, 2019) Classic studies of this evolutionary process demonstrated that it is easy to experimentally select mutant viruses that escape neutralization by individual monoclonal antibodies (Yewdell et al, 1979; Laver et al, 1979; Webster and Laver, 1980; Gerhard et al, 1981).
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