Characterising humoral and airway immunity following Respiratory Syncytial Virus infection challenge in older adults

Introduction/Rationale: Respiratory syncytial virus (RSV) is a major cause of respiratory viral illness in older adults, yet the effect of ageing on systemic and mucosal immunity against RSV infection remain unclear. Using a RSV controlled human infection model (CHIM) in young and older adults, we examined early humoral and mucosal immunity, identified age-related immune differences, and explored immune correlates of protection at both systemic and airway sites.

Methods: Twenty-eight older (60–75 years) and 8 young (18–55 years) adults were inoculated intranasally with RSV A Memphis-37. Viral loads were measured by qPCR. Symptoms and paired serum, nasal, and bronchoalveolar lavages (BAL) were collected longitudinally. Neutralising antibodies and F and G protein–specific responses were quantified. Samples from a previous young adult CHIM using the same virus were also included.

Results: Older adults showed higher infection rates (68% vs 31%) and greater viral shedding. Pre-existing serum neutralising titres correlated with protection in older, but not young adults. Serum IgG responses were comparable across age groups and targeted pre-F epitopes. Nasal IgA responses while intact overall, showed limited boosting of pre-F-specific antibodies, that have the most potent neutralising activity. Multiplex analysis confirmed these patterns and demonstrated increased G-specific nasal IgA in older infected adults, which was correlated with protection. A similar pattern was also seen in BAL samples, but these did not correlate with protection from infection.

Conclusion: RSV CHIM in older adults is safe and reveals preserved systemic neutralising and IgG responses. Healthy older adults, however, were more susceptible to infection and exhibited distinct mucosal antibody profiles, with G-specific nasal IgA emerging as a potentially strong correlate of protection. These findings have implications for vaccine design in older adults, particularly as current approved vaccines only target RSV pre-F protein.