A newly emergent N1 neuraminidase associated with clade 2.3.4.4b highly pathogenic avian influenza A(H5) viruses in North America

We investigated the evolutionary history of the newly emergent neuraminidase (am4N1) associated with the D1.1 and D1.2 genotypes of highly pathogenic avian influenza A(H5N1) viruses in North America. Phylogenetic inference places am4N1 in a sister clade to Eurasian avian, swine, and human A(H1N1)pdm09 viruses and distinct from 1918, pre-2009 human seasonal, and classical swine A(H1N1) lineages. Am4N1 descends from diverse avian N1 genes endemic to the Americas. Phylodynamic analysis indicates a monophyletic am4N1 lineage with numerous introductions of viruses carrying the am4N1 gene likely originating from western Canada into the United States during emergence of the D1.1 and D1.2 genotypes. The lineage has diversified and accumulated deletions in the stalk domain. Despite amino acid divergence, structural modeling shows conserved neuraminidase architecture in the globular head. Given its distinct ancestry and amino acid sequence, further studies are needed to assess cross-reactivity of antibodies from prior human A(H1N1)pdm09 infections.