Background:
As a dominant seasonal influenza virus, H3N2 virus rapidly evolves in human and is a constant threat to public health. Despite sustained research efforts, the efficacy of H3N2 vaccine has decreased rapidly. Even though antigenic drift and passage adaptation (substitutions accumulated during vaccine production in embryonated eggs) have been implicated in reduced vaccine efficacy, their respective contributions to the phenomenon remain controversial.
Methods:
We utilized mutational mapping, a powerful probabilistic method of studying sequence evolution, to analyze patterns of substitutions in different passage conditions for an unprecedented amount of H3N2 hemagglutinin sequences (n=32278).
Results:
We found that passage adaptation in embryonated eggs is driven by repeated convergent evolution over 12 codons. Based on substitution patterns at these sites, we developed a metric, Adaptive Distance (AD), to quantify the strength of passage adaptation and subsequently identified a strong negative correlation between AD and vaccine efficacy.
Conclusions:
The high correlation between AD and vaccine efficacy implies that passage adaptation in embryonated eggs may be a strong contributor to the recent reduction in H3N2 vaccine efficacy. We developed a computational package called MADE to measure the strength of passage adaptation and predict the efficacy of a candidate vaccine strain. Our findings hence shed light on strategies that reducing Darwinian evolution within the passaging medium can potentially restore an effective vaccine program in the coming future.