Project Details
Early Career
Status: Funded - Closed
Viral genetic determinants of respiratory syncytial virus (RSV) underlying clinical disease severity in pediatric infection
Summary
BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and pneumonia in young children. An interplay of viral, host, and environmental factors direct RSV epidemiology and clinical outcomes of infection. The seasonality and magnitude of RSV outbreaks have been unpredictable since the onset of the COVID-19 pandemic. GAP: Clinical, genomic, and immunological analysis is needed to characterize factors associated with recent RSV outbreaks. HYPOTHESIS: We hypothesized that the surge of RSV cases in 2022 was caused by either a) the emergence of a new RSV genotype/variant, or b) a lack of RSV-specific immunity at the population level, stemming from reduced exposure associated with pandemic-mitigation strategies. 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 an immunologic analysis of baseline RSV-specific humoral immunity in women of childbearing age before and throughout the coronavirus disease 2019 pandemic. RESULTS: Clinical analysis revealed a high burden of disease across patients of all health backgrounds. More than one-half of RSV-related health care visits by infants resulted in hospitalization, and one-quarter required high-flow respiratory support or a higher level of care. Viral phylogenetic analyses revealed that 2022 Sydney RSV sequences were closely related to viruses that had been circulating globally since 2017, including those detected in recent US outbreaks. Nonsynonymous mutations within the palivizumab and nirsevimab binding sites were detected at low frequencies. There was no difference in baseline RSV-neutralizing antibody titers between 2020 and 2022. IMPACT: Collectively, these findings suggest that neither the emergence of a novel RSV genotype nor hypothesized immune debt was associated with the surge of RSV cases and hospitalizations in 2022. Continued genomic and immunologic surveillance is required to further understand the factors driving outbreaks of RSV globally, particularly in the context of recent regulatory approvals of RSV-specific monoclonal antibodies and vaccines.
Publications:
Walker GJ, Foster CSP, Sevendal A, Domazetovska A, Kamalakkannan A, Williams PCM, Kim KW, Condylios A, Stelzer-Braid S, Bartlett AW, Rawlinson W. Clinical, Genomic, and Immunological Characterization of RSV Surge in Sydney, Australia, 2022. Pediatrics. 2024 Jan 16:e2023063667. doi: 10.1542/peds.2023-063667. Epub ahead of print. PMID: 38225912.