Distinct patterns of within-host virus populations between two subgroups of human respiratory syncytial virus

Lin, Gu-Lung; Drysdale, Simon B.; Snape, Matthew D.; O’Connor, Daniel; Brown, Anthony; MacIntyre-Cockett, George; Mellado-Gomez, Esther; de Cesare, Mariateresa; Bonsall, David; Ansari, M. Azim; Öner, Deniz; Aerssens, Jeroen; Butler, Christopher; Bont, Louis; Openshaw, Peter; Martinón-Torres, Federico; Nair, Harish; Bowden, Rory; Golubchik, Tanya; Pollard, Andrew J.

Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in young children globally, but little is known about within-host RSV diversity. Here, we characterised within-host RSV populations using deep-sequencing data from 319 nasopharyngeal swabs collected during 2017–2020. RSV-B had lower consensus diversity than RSV-A at the population level, while exhibiting greater within-host diversity. Two RSV-B consensus sequences had an amino acid alteration (K68N) in the fusion (F) protein, which has been associated with reduced susceptibility to nirsevimab (MEDI8897), a novel RSV monoclonal antibody under development. In addition, several minor variants were identified in the antigenic sites of the F protein, one of which may confer resistance to palivizumab, the only licensed RSV monoclonal antibody. The differences in within-host virus populations emphasise the importance of monitoring for vaccine efficacy and may help to explain the different prevalences of monoclonal antibody-escape mutants between the two subgroups.