Forecasting influenza A pandemic lineage dominance in the United States using relative reproduction rates

The 2009 H1N1 pandemic (pdm09) lineage is a major component of the H1 influenza A virus (IAV) that causes seasonal outbreaks annually. Since its introduction in the 2009-10 season, this lineage has evolved into distinct, successive clades in humans. Predicting the fitness of influenza clades is essential to forecasting future prevalence, providing a critical opportunity to develop a response to mitigate infection. The relative fitness of pdm09 lineages was retrospectively inferred via relative reproduction rate (RR_e) through RelRe, a programme that implements a renewal equation to estimate the relative difference in reproduction number between cocirculating clades. For this analysis, pdm09 lineage sequences from the USA, collected from 2017 to 2023 in both human and swine hosts, were downloaded from public databases. Clade designations were assigned using Nextclade. Human case count data were divided by each influenza season, and the RR_e was estimated at 3-month intervals. The RR_e was then used to forecast clade frequency 90 days into the future, and the predictions were compared to the historical data. The highest predicted frequency at 90 days corresponded to the most frequently detected lineage in 9 out of 13 predictions (69%). The pdm09 lineage plays an important role at the human-swine influenza interface. Bayesian inference using both human and swine data indicated unequal transmission rates of the pdm09 lineage, with 53-79 noted transmissions from human to swine and 0-2 in reverse using the available genetic data. Metadata analysis revealed that new clades of pdm09 in humans were typically detected in swine as early as ~8-20 months after clade emergence in humans. Understanding RR_e and the fitness of contemporary IAV strains enables the identification of high-risk reverse-zoonotic strains and provides critical time for responding to emergent human clades.