dd class="first" id="idm140056325546208">A virus (IAV) hemagglutinin (HA) initiates infection by attaching virus to host cell surface sialic acids and catalysing the fusion of viral and cellular membranes. The neuraminidase (NA) ends the infectious cycle by releasing nascent virions from the infected cell surface. Antibodies (Abs) to HA block viral entry and play a critical role in immunity following infection or vaccination. Due to the rapid appearance of HA-escape mutants in human populations, vaccines must be constantly reformulated. To better understand antigenic drift, we are modelling IAV infections in mice and guinea pigs. Our findings indicate that antigenic drift is likely to be more than direct escape from neutralizing antibodies. Instead, they point to a key role for HA binding avidity for host cell sialic acid receptors, and an oft-neglected feature of antibody mediated neutralization: it represents a ternary competition between receptor and antibody for virus. Facing a partially neutralizing antibody response, virus can escape by increasing receptor avidity. Partial neutralization must be a common occurrence in nature due to variability in human immune responses and infection with drifted variants that demonstrate fractional escape from the Ab response to (un-drifted) parent. Predictably, increased viral receptor avidity incurs fitness costs in vivo. Re-passage of adsorptive mutants in naïve mice selected HA-single substitution mutants with diminished receptor avidity. Despite the lack of Ab pressure, some of the substitutions occurred in antigenic regions. That single substitutions in the HA globular domain simultaneously modulate antigenicity and receptor binding, confounds retrospective analysis of genetic variation in HA. The situation is complicated further by the occurrence of epistatic changes within HA and between HA and NA to maximizeviral fitness following selection. Moreover, substitutions selected to modulate receptor avidity will inevitably modify receptor specificity for various sialic acid terminated-glycans and vice versa. From leaves to forest: even in the simplest species (viruses), evolution is complicated, and oversimplified analysis leads to all sorts of errors, including those with practical ramifications in interpreting sequences for choosing vaccine strains.

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