Longitudinal humoral analysis in RSV-infected infants identifies pre-existing RSV strain-specific G and evolving cross-reactive F antibodies

Respiratory syncytial virus (RSV) is among the most common causes of lower respiratory tract infection (LRTI) and hospitalization in infants. However, the mechanisms of immune control in infants remain incompletely understood. Antibody profiling against attachment (G) and fusion (F) proteins in children less than 2 years of age, with mild (outpatients) or severe (inpatients) RSV disease, indicated substantial age-dependent differences in RSV-specific immunity. Maternal antibodies were detectable for the first 3 months of life, followed by a long window of immune vulnerability between 3 and 6 months and a rapid evolution of FcγR-recruiting immunity after 6 months of age. Acutely ill hospitalized children exhibited lower G-specific antibodies compared with healthy controls. With disease resolution, RSV-infected infants generated broad functional RSV strain-specific G-responses and evolved cross-reactive F-responses, with minimal maternal imprinting. These data suggest an age-independent RSV G-specific functional humoral correlate of protection, and the evolution of RSV F-specific functional immunity with disease resolution. [Display omitted] •Observed age-dependent differences in RSV antibodies in the first 2 years of life•G-responses were decreased in severe RSV disease but enriched in mild RSV infection•Strain-specific G-specific immunity, but cross-reactive F-specific immunity, evolves over time•No evidence of maternal imprinting was observed on newly evolving RSV humoral immunity Infants are highly vulnerable to RSV infection. However, the contribution of the evolving RSV-specific humoral immune response to RSV immunity remains incompletely understood. Nziza et al. profiled pediatric humoral immunity to RSV fusion and attachment antigens. The study identifies age-dependent RSV-specific humoral profiles, demonstrating a profound window of immune vulnerability in infants, and functional immune correlates of protection against RSV disease.