Global Molecular Epidemiology of Respiratory Syncytial Virus from the 2017−2018 INFORM-RSV Study

Abstract

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection among infants and young children, resulting in annual epidemics worldwide. INFORM-RSV is a multi-year clinical study designed to describe the global molecular epidemiology of RSV in children under five years of age by monitoring temporal and geographical evolution of current circulating RSV strains, F protein antigenic sites, and their relationships with clinical features of RSV disease. During the pilot season (2017–2018), 410 RSV G-F gene sequences were obtained from 476 RSV-positive nasal samples collected from 8 countries (United Kingdom, Spain, the Netherlands, Finland, Japan, Brazil, South Africa, and Australia). RSV B (all BA9 genotype) predominated over RSV A (all ON1 genotype) globally (69.0% vs. 31.0%) and in all countries except South Africa. Geographic clustering patterns highlighted wide transmission and continued evolution with viral spread. Most RSV were from infants <1 year of age (81.2%), males (56.3%), and patients hospitalized >24 hours (70.5%) with no differences in subtype distribution. Compared to 2013 reference sequences, variations at F protein antigenic sites were observed for both RSV A and B strains with high frequency polymorphisms at antigenic site Ø (I206M/Q209R) and site V (L172Q/S173L/K191R) in RSV B strains. The INFORM-RSV 2017–2018 pilot season establishes an important molecular baseline of RSV strain distribution and sequence variability with which to track the emergence of new strains and provide an early warning system of neutralization escape variants that may impact transmission or the effectiveness of vaccines and mAbs under development.

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

“…Several other minor variants were also identified in the antigenic sites of the F protein. None of these variants have been reported before except for S255N 25 , whose susceptibility to monoclonal antibodies has not been examined. Stochastic (random) patterns were found in the temporal changes of within-host virus diversity and minor variants.…”

Functional Features of the Respiratory Syncytial Virus G Protein

“…Sequence studies replaced mAb reactivity to identify strain differences and found both in subsequent studies of RSV transmission in healthcare settings [ 52 , 53 ]. G gene sequence studies have also helped understand community RSV outbreaks and shown the co-circulation of multiple genotypes in one season in a community, different patterns of genotypes in nearby communities during the same season, and clarified household transmission [ 17 , 18 , 54 , 55 , 56 ]. One conclusion from these studies is that yearly community RSV outbreak strains are not dominated by regional or national strains.…”

“…In this strain, aa 261–283 are duplicated and inserted between aa 284 and 285, which results in a 23 aa longer G protein. Viruses with the G duplication, both Subgroup A and B, have spread globally, and variants of the original viruses have become the dominant currently circulating strains [ 55 , 66 , 67 ]. In vitro studies on reverse genetics-derived Subgroup B viruses with and without the G duplication showed that, the duplication likely improved virus attachment in binding to heparin sulfate proteoglycans on the cell surface and conferred a competitive replication advantage [ 68 ].…”

Bringing Preventive RSV Monoclonal Antibodies to Infants in Low- and Middle-Income Countries: Challenges and Opportunities

“…Molecular surveillance of the 2017–2018 F sequences from eight countries showed high-frequency polymorphisms at antigenic sites Ø and V of RSV B that included 100% detection of the nonconservative polymorphisms in suptavumab target site V (L172Q/S173L). Conservative polymorphisms in nirsevimab target site Ø (I206M/Q209R) [ 54 ] were detected in 77% of RSV B strains, but they retained susceptibility to neutralization by nirsevimab [ 55 ].…”