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Integrating genotypes and phenotypes improves long-term forecasts of seasonal influenza A/H3N2 evolution

By John Huddleston, John R. Barnes, Thomas Rowe, Xiyan Xu, Rebecca Kondor, David E Wentworth, Lynne Whittaker, Burcu Ermetal, Rodney S Daniels, John W McCauley, Seiichiro Fujisaki, Kazuya Nakamura, Noriko Kishida, Shinji Watanabe, Hideki Hasegawa, Ian Barr, Kanta Subbarao, Richard A Neher, Trevor Bedford

Posted 13 Jun 2020
bioRxiv DOI: 10.1101/2020.06.12.145151

Seasonal influenza virus A/H3N2 is a major cause of death globally. Vaccination remains the most effective preventative. Rapid mutation of hemagglutinin allows viruses to escape adaptive immunity. This antigenic drift necessitates regular vaccine updates. Effective vaccine strains need to represent H3N2 populations circulating one year after strain selection. Experts select strains based on experimental measurements of antigenic drift and predictions made by models from hemagglutinin sequences. We developed a novel influenza forecasting framework that integrates phenotypic measures of antigenic drift and functional constraint with previously published sequence-only fitness estimates. Forecasts informed by phenotypic measures of antigenic drift consistently outperformed previous sequence- only estimates, while sequence-only estimates of functional constraint surpassed more comprehensive experimentally-informed estimates. Importantly, the best models integrated estimates of both functional constraint and either antigenic drift phenotypes or recent population growth. ### Competing Interest Statement The authors have declared no competing interest.

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