Emergence and Epidemiology of Dominant Variants of Human Metapneumovirus in the United States between 2016 and 2021

Human metapneumovirus (HMPV) causes acute respiratory disease worldwide and is the second leading cause of lower respiratory infection and hospitalization in young children in the US. There is no licensed vaccine or therapeutic. HMPV mutates rapidly; however, the specific genomic features that explain strain dominance remain undefined because there is limited routine genomic surveillance of HMPV. We analyzed prospectively collected nasal specimens and medical data from 8,000 pediatric acute respiratory infection cases and sequenced 219 HMPV whole genomes from Pittsburgh, PA between 2016-2021. Only A2, B1, and B2 subgroups were detected; the dominant subgroup varied between seasons. Variants with an in-frame 111- or 180-nucleotide (nt) insertion that nearly duplicates the preceding flanking region in the 660-nt G gene (encodes the attachment protein) were the predominant A2 viruses detected by 2016-17. Among B2 viruses, variants with smaller in-frame insertions in the same location of the G gene became dominant by 2017-18. Each insertion length formed a distinct phylogenetic clade. The insertions are in the ectodomain and contain positively-charged residues or predicted O-glycosylation sites. Epidemiological analysis revealed that HMPV infection was independently associated with age, insurance type, and comorbidities. Elevated disease severity was independently associated with age and comorbidities, though not with HMPV subgroup. To our knowledge, in the US, this is the earliest detection of the A2 insertion variants and the first report of the B2 insertion variants. It is the largest population-based genomic HMPV study that provides a detailed phylodynamics and epidemiological analysis of prospectively collected clinical specimens.