Genomic and Immunological Characterisation Shows Increased Respiratory Syncytial Virus Cases Not Due to Waning Antibody Mediated Immunity

Background: Seasonal epidemics of respiratory syncytial virus (RSV) in the Southern Hemisphere typically occur in late autumn and winter. However, implementation of public health measures for the Coronavirus Disease (COVID-19) pandemic resulted in an almost complete absence of RSV detections during the 2020 season. This was followed by unusual summer outbreaks worldwide throughout 2021, and in 2022 the seasonal RSV epidemic in Sydney (Australia) saw an unprecedented number of RSV detections.Methods: Whole genome sequences of RSV were generated from 264 RSV-infected infants and linked to case-matched clinical data from the 2022 Southern Hemisphere RSV season. We then performed immunological analysis of baseline RSV-specific humoral immunity in women of childbearing age before and throughout the COVID-19 pandemic.Findings: Clinical analysis found a high burden of disease across patients of all health backgrounds. Over half of RSV-related healthcare visits by infants resulted in hospitalization, and one quarter required high-flow respiratory support or a higher level of care. Viral phylogenetic analyses found that 2022 Sydney RSV sequences were closely related to viruses that were circulating globally since 2017, including those detected in recent USA outbreaks. Non-synonymous mutations within the palivizumab and nirsevimab binding sites were detected at low frequencies. There was no difference in baseline RSV-neutralizing antibody titres between 2020 and 2022.Interpretation: Collectively, these findings suggest an interplay of factors unrelated to changes in local host immunity to RSV contributed to the surge of RSV cases and hospitalisations in 2022. That is, we did not demonstrate the emergence of a novel RSV genotype or hypothesized immune debt associated with the increase in cases. Continued genomic and immunological surveillance is required to further understand factors driving outbreaks of RSV globally, and to inform guidelines for the rollout and ongoing use of recently developed immunotherapeutics and vaccines.Funding: Laboratory consumable costs were supported by the Thrasher Research Fund (Early Career Award, GW). This study was partly supported by MRFF (#2023323, PW, AB) and NHMRC (#2006755, AK, WR) grants.Declaration of Interest: The authors have no conflicts of interest to declare.Ethical Approval: This study was approved by the Sydney Children’s Hospitals Network Human Research Ethics Committee (2020/ETH00718).