The evolution of influenza viruses is fundamentally shaped by within-host processes. However, the within-host evolutionary dynamics of influenza viruses remain incompletely understood, in part because most studies have focused on within-host virus diversity of infections in otherwise healthy adults based on single time point data. Here, we analysed the within-host evolution of 82 longitudinally-sampled individuals, mostly young children, infected with A/H3N2 or A/H1N1pdm09 viruses between 2007 and 2009. For A/H1N1pdm09 infections during the 2009 pandemic, nonsynonymous changes were common early in infection but decreased or remained constant throughout infection. For A/H3N2 viruses, early infection was dominated by purifying selection. However, as infections progressed, nonsynonymous variants increased in frequencies even though within-host virus titres decreased, leading to the maintenance of virus diversity via mutation-selection balance. Our findings suggest that this maintenance of genetic diversity in these children combined with their longer duration of infection may provide important opportunities for within-host virus evolution.

Separate from seasonal IAVs, zoonotic IAVs constantly pose new pandemic threats. Prior to 74 becoming human-adapted seasonal strains, IAVs are introduced into the human population 75 from an animal reservoir through the acquisition of host adaptive mutations, sometimes via reassortment, resulting in global pandemics such as the 2009 swine influenza pandemic13 76 . In 77 the 2009 pandemic, global virus genetic diversity increased rapidly during the early phases of 78 the pandemic as a result of rapid transmissions in the predominantly naïve human population14 79 . Over subsequent waves of the pandemic, host adapting mutations that 80 incrementally improved viral fitness and transmissibility in humans of A/H1N1pdm09 viruses emerged15, eventually reaching fixation in the global virus population.

Here, we deep sequenced 275 longitudinal clinical specimens sampled from 82 individuals 96 residing in Southeast Asia between 2007 and 2009 that were either infected with seasonal 97 A/H3N2 or pandemic A/H1N1pdm09 viruses. By analysing minority variants found across 98 the whole IAV genome, we characterised the evolutionary dynamics of within-host virus 99 populations in these samples collected up to two weeks post-symptom onset.

Journal of Women’s Health and Reproductive Medicine is an interdisciplinary journal that explores clinical, medical, social and economic aspects of female reproductive health and medication worldwide.

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