Major change in swine influenza virus diversity in France owing to emergence and widespread dissemination of a newly introduced H1N2 1C genotype in 2020.

Swine influenza A viruses (swIAVs) are a major cause of respiratory disease in pigs worldwide, presenting significant economic and health risks. These viruses can reassort, creating new strains with varying pathogenicity and cross-species transmissibility. This study aimed to monitor the genetic and antigenic evolution of swIAV in France from 2019 to 2022. Molecular subtyping revealed a marked increase in H1N2 cases from 2020 onwards, altering the previously stable subtypes' distribution. Whole-genome sequencing and phylogenetic analyses of H1 (1C) strains identified 10 circulating genotypes, including 5 new genotypes. The most predominant genotype from 2020 onwards, denominated H1N2#E, was characterized by an HA-1C.2.4, an N2-Gent/84, and internal protein-encoding genes belonging to a newly defined subclade within the Eurasian avian-like (EA) lineage termed EA-DK. H1N2#E emerged in Brittany, the country's most pig-dense region, and rapidly became the most frequently detected swIAV genotype across France. This drastic change in the swIAV lineage proportions at a national scale was unprecedented, making H1N2#E a unique case for understanding swIAV evolution and spreading patterns. Phylogenetic analyses suggested an introduction of the H1N2#E genotype from a restricted source, likely originating from Denmark. It spread rapidly with low genetic diversity at the start of the epizootic in 2020, showing increasing diversification in 2021 and 2022 as the inferred population size grew and stabilized, and exhibited reassortments with other enzootic genotypes. Amino acid sequence alignments of H1N2#E antigenic sites revealed major mutations and deletions compared to commercial vaccine 1C strain (HA-1C.2.2) and previously predominant H1N1 strains (HA-1C.2.1). Antigenic cartography confirmed significant antigenic distances between H1N2#E and other 1C strains, suggesting that the new genotype has escaped the pre-existing immunity of the swine population. Epidemiologically, the H1N2#E virus exhibited epizootic hallmarks with more severe clinical outcomes compared to H1N1 viruses. These factors likely contributed to the spread of H1N2#E within the pig population. The rapid rise of H1N2#E highlighted the dynamic nature of swIAV genetic and antigenic diversity, underscoring the importance of tailored surveillance programs to support risk assessment during potential new outbreaks. It also demonstrates the need to strengthen biosecurity measures when introducing pigs into a herd, including swIAV positivity assessment followed by quarantine, and restrict the trade of swIAV-excreting live swine between European countries.