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For instance, influenza A virus subtypes oscillate and peak during winter seasons of the world\u2019s temperate climate zones. Alternation of dominant strains in successive influenza seasons makes epidemic forecasting a major challenge. From the start of the 2009 influenza pandemic we enrolled influenza A virus infected patients (<jats:italic>n<\/jats:italic>\u2009=\u20092980) in a global prospective clinical study. Complete hemagglutinin sequences were obtained from 1078 A\/H1N1 and 1033 A\/H3N2 viruses. We used phylodynamics to construct high resolution spatio-temporal phylogenetic hemagglutinin trees and estimated global influenza A effective reproductive numbers (<jats:italic>R<\/jats:italic>) over time (2009\u20132013). We demonstrate that <jats:italic>R<\/jats:italic> oscillates around <jats:italic>R<\/jats:italic>\u2009=\u20091 with a clear opposed alternation pattern between phases of the A\/H1N1 and A\/H3N2 subtypes. Moreover, we find a similar alternation pattern for the number of global viral spread between the sampled geographical locations. Both observations suggest a between-strain competition for susceptible hosts on a global level. Extrinsic factors that affect person-to-person transmission are a major driver of influenza seasonality. The data presented here indicate that cross-reactive host immunity is also a key intrinsic driver of influenza seasonality, which determines the influenza A virus strain at the onset of each epidemic season.<\/jats:p>","DOI":"10.1038\/s41598-022-08233-w","type":"journal-article","created":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T16:03:33Z","timestamp":1653494613000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Cross-reactive immunity potentially drives global oscillation and opposed alternation patterns of seasonal influenza A viruses"],"prefix":"10.1038","volume":"12","author":[{"given":"Lorenzo","family":"Gatti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mischa H.","family":"Koenen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jitao David","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Anisimova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilly M.","family":"Verhagen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Schutten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ab","family":"Osterhaus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erhard","family":"van der Vries","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,5,25]]},"reference":[{"key":"8233_CR1","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1073\/pnas.96.2.790","volume":"96","author":"N Ferguson","year":"1999","unstructured":"Ferguson, N., Anderson, R. & Gupta, S. 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