Hemagglutinin Receptor Binding Avidity Drives Influenza A Virus Antigenic Drift

Flu's Tricky Tricks After vaccination against influenza A virus, single-point mutations are selected in hemagglutinin (the virus molecule that binds to sialic acid molecules on the surface of host cells) that escape neutralization by polyclonal antibody responses. Hensley et al. (p. 734) have discovered that in mice these mutations increased the virus's avidity for sialic acid. Amino acid substitutions that occur during reiterations of immune escape and avidity modulation can thus drive antigenic variation. This constant evolution of influenza viruses requires us to change vaccine components annually, and, for equine influenza, Park et al. (p. 726) show that as the match between virus and vaccine strains drifts apart with time, the probability of becoming infected and the length of the infectious period increase to the point where outbreaks occur. Nevertheless, even imperfect vaccines may be of benefit to a population because increasing the proportion of vaccinated individuals can supply enough herd immunity to offset a poor antigenic match, especially if used in conjunction with antiviral drugs. For humans, Yang et al. (p. 729, published online 10 September) estimate that the rate of transmission within U.S. households puts influenza A 2009 H1N1 (the current pandemic “swine flu”) in the higher range of transmissibility, compared to past seasonal and pandemic strains. Thus, to achieve mitigation this fall, children should be the first recipients of vaccine, followed by adults—aiming overall for 70% coverage of the population. Viruses escape antibody responses by changing surface protein structures to increase the strength of binding to host cells. Rapid antigenic evolution in the influenza A virus hemagglutinin precludes effective vaccination with existing vaccines. To understand this phenomenon, we passaged virus in mice immunized with influenza vaccine. Neutralizing antibodies selected mutants with single–amino acid hemagglutinin substitutions that increased virus binding to cell surface glycan receptors. Passaging these high-avidity binding mutants in naïve mice, but not immune mice, selected for additional hemagglutinin substitutions that decreased cellular receptor binding avidity. Analyzing a panel of monoclonal antibody hemagglutinin escape mutants revealed a positive correlation between receptor binding avidity and escape from polyclonal antibodies. We propose that in response to variation in neutralizing antibody pressure between individuals, influenza A virus evolves by adjusting receptor binding avidity via amino acid substitutions throughout the hemagglutinin globular domain, many of which simultaneously alter antigenicity.