High Conservation of the Human Metapneumovirus Fusion Protein in Contemporary Global Sequences Supports Its Continued Relevance for Therapeutic and Prophylactic Consideration

Human metapneumovirus (hMPV) is associated with severe disease in young children, older adults, and medically high-risk individuals. The hMPV F protein is highly immunogenic and a well-established target of neutralizing antibodies. In-depth hMPV surveillance data remain limited and may provide valuable insight into therapeutic development. Here we assembled a contemporary dataset of F gene sequences acquired from hMPV-positive nasal swab specimens collected between 2022 and 2023, together with contemporary F gene sequences from public surveillance databases, collected between 2017 and 2025. All sequences were subtyped and evaluated for residue-level similarity to reference alleles. Of 724 sequences in the combined contemporary dataset, A2 was the most predominant subtype accounting for nearly half of all sequences (50.83%). The mean F gene sequence similarity to reference alleles was 99.90%, 99.95%, and 99.84% for A2, B1, and B2, respectively; the least conserved residues were the stalk residue 518 for A2 (88.52% similarity to reference allele); BinD residue 450 for B1 (96.60% similarity); and site III residue 36 for B2 (77.88% similarity). Structural analysis showed that observed mutations were predominantly surface-exposed, with no evidence of novel N-linked glycosylation sequons, and were not predicted to significantly alter F protein structure. Overall, these findings indicate that the F protein is highly conserved across subtypes, with sequence variation unlikely to result in meaningful structural differences, thereby supporting development of F-targeted therapeutics against hMPV infection.