Seasonal influenza vaccine strain selection by quantifying viral fitness

The long-standing challenge of seasonal influenza vaccines providing poor protection is attributed to the rapid and continuous evolution of the virus. In theory, the recommendation of vaccine strain is to predict the dominant strain with best fitness in the upcoming season. Here, we develop FutureFlu, a biologically-grounded framework that quantifies the fitness score of influenza variants in upcoming seasons, by integrating metrics on three levels: molecular genetic divergence, individual immune escape, and population-scale transmission dynamics. The fitness scores of influenza variants present strong positive correlation with their actual observed frequencies in the next seasons. Validation across 24 seasons of three influenza subtypes shows FutureFlu recommends antigenically matched vaccine strains more frequently than annual recommendations, particularly for challenging subtypes: 83.3% versus 45.8% seasons for A/H3N2, and 75.0% versus 33.3% seasons for B/Victoria. Furthermore, FutureFlu significantly outperforms the currently used methods in vaccine strain selection whether or not there is available antigenic data from hemagglutination inhibition (HI) assay, which provides a valuable supplement for WHO vaccine recommendation. To support global public health implementation, an open online platform (futureflu.com.cn) has been established to offer real-time viral fitness predictions and vaccine recommendations.