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

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

doi:10.1038/s41467-021-25265-4

Abstract

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.

Highlights

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
We find that RSV-B exhibits greater within-host diversity than RSV-A, with two RSV-B consensus strains and one RSV-B minor variant likely conferring resistance to nirsevimab or palivizumab
After removing five samples containing both RSV-A and RSV-B, 322 samples were included in the within-host virus diversity analysis

Summary

Introduction

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. The median frequency of minor variants was significantly higher in the G gene than in the F gene, either at potential antigenic sites (median: 9.3% vs 4.6%; Mann–Whitney U-test, P = 0.022) or across the whole coding sequences (median: 8.3% vs 4.4%; Mann–Whitney U-test, P = 0.004), consistent with previous studies identifying the G gene as the most variable gene in the virus genome[14].

Results

Conclusion