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 multiyear clinical study designed to describe the global molecular epidemiology of RSV in children under 5 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% versus 31.0%) and in all countries except South Africa. Geographic clustering patterns highlighted wide transmission and continued evolution with viral spread. Most RSV strains were from infants of <1 year of age (81.2%), males (56.3%), and patients hospitalized for >24 h (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.

Keywords: evolution; genetic variation; molecular epidemiology; resistance; respiratory syncytial virus; surveillance.

FIG 1

Geographic distribution of RSV A (n = 128) and RSV B (n = 283) subtypes, 2017–2018 (n = 8 countries). Overall size of the pies is proportional to the number of RSV isolates and the segments of the pies are proportional to the frequency of subtype A (red) and subtype B (blue) (Table 1). Northern hemisphere: GBR, United Kingdom (n = 2); ESP, Spain (n = 36); NLD, The Netherlands (n = 43); FIN, Finland (n = 45); JPN, Japan (n = 91). Southern hemisphere: BRA, Brazil (n = 64); ZAF, South Africa (n = 95); AUS, Australia (n = 34). (The figure was created with Microsoft PowerPoint.)

FIG 2

Monthly collection of RSV-positive(+) samples by country and overall number of RSV(+) detected, collected, and isolated/sequenced for RSV G-F gene analysis.

FIG 3

RSV A ON1 (n = 127) and RSV B BA9 (n = 283) G-based clades by country.

FIG 4

Individual frequency and structural location of amino acid polymorphisms in RSV A F (n = 127) and RSV B F (n = 283) protein sequences. (Top) Major structural features of full-length RSV F protein (amino acids [AA] 1–574), including the extracellular region (F₂: AA 24–109 and F₁: 137-524); SP, signal peptide; p27 peptide; FP, fusion peptide; HR, heptad repeats; and TM/CT, transmembrane/carboxy terminus. (Middle) Linear plot of individual amino acid variation frequency in full-length RSV A F (red) and RSV B F (blue) protein sequences compared to year 2013 RSV A/13-005275 and RSV B/13-001273 reference strains, respectively. Amino acid polymorphisms detected at ≥10% frequency (Table 2) are denoted. (Bottom) Proximal locations of amino acid polymorphisms in antigenic sites of mature prefusion and postfusion RSV F protein trimers. Previously defined antigenic sites (Ø and I to V) (13) are delineated in color. Amino acid positions at which polymorphisms were detected at ≥1% frequency (Table 2) are highlighted in black with adjoining arrows. A and B superscripts denote subtype A and B, respectively.