Measuring convergent evolution in global H3N2 influenza phylogenies through log convergence ratios prospectively identifies amino acid substitutions that cause major antigenic changes, with cluster transition substitutions nearly always ranking among the top few positively selected substitutions at key antigenic positions more than one year before the new antigenic cluster becomes established, enabling earlier vaccine strain selection.

The antigenic evolution of human seasonal influenza viruses is primarily driven by single amino acid substitutions immediately adjacent to the receptor binding site in the hemagglutinin (HA) protein. The ability to predict these substitutions would allow vaccine strains to be selected with an understanding of likely future antigenic variation. Here, we estimate the effect of HA substitutions on viral fitness using measurements of convergent evolution in a large phylogeny. We show that the substitutions which have historically caused major antigenic changes in H3N2 influenza viruses were nearly always one of few substitutions near the HA receptor binding site estimated to be under positive selection in sequences collected before the antigenic transition, based on convergent acquisition of the substitution in multiple independent lineages. Furthermore, this signal predates the establishment of the major clade containing the antigenic substitution by more than one year, so is highly informative for prospective prediction.