Cross-reactive immunity potentially drives global oscillation and opposed alternation patterns of seasonal influenza A viruses

Several human pathogens exhibit distinct patterns of seasonality and circulate as pairs. For instance, influenza A virus subtypes oscillate and peak during winter seasons of the world's 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 (n = 2980) 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 (R) over time (2009-2013). We demonstrate that R oscillates around R = 1 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.