1. Divergent age-related humoral correlates of protection against RSV infection: a controlled human infection challenge model in older and young adults
- Author
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Ascough, S, Dayananda, P, Kalyan, M, Ung, SK, Gardener, Z, Bergstrom, E, Paterson, S, Kar, S, Avadha, V, Thwaites, R, Sanchez Sevilla Uruchurtu, A, Ruckwardt, T, Chen, M, Nair, D, Derrien-Colemyn, A, Graham, B, Begg, M, Hessel, E, Openshaw, P, Chiu, C, and Medical Research Council (MRC)
- Abstract
Background: Respiratory viral infections are typically more severe in older adults. Although age-related changes in immune responses have been described, the causes of this enhanced respiratory disease in older adults remain poorly understood. We therefore performed volunteer challenge with respiratory syncytial virus (RSV) in groups of younger and older adult volunteers. The aim of this study was to establish the safety and tolerability of this model and define age-related clinical, virological and immunological outcomes. Methods: Twelve healthy volunteers aged 60-75 and twenty-one aged 18-55 were inoculated intranasally with RSV Memphis-37. Symptoms were documented by self-completed diaries and viral load determined by qPCR of nasal lavage. Peripheral blood B cell frequencies were measured by enzyme-linked immunospot and antibodies against pre-and post-fusion F, NP, and G proteins in the blood and upper respiratory tract were measured. Findings: Nine of the 12 older volunteers became infected, developing mild-to-moderate upper respiratory tract symptoms that resolved without Serious Adverse Events or sequelae. Viral load peaked on Day 6 post-inoculation and symptoms between Days 6-8. Increases in circulating IgG+ and IgA+ antigen-specific plasmablasts, serum neutralising antibodies and pre-F specific IgG that were similar younger and older adults. However, in contrast to young participants, sIgA titres in older volunteers failed to increase during infection and, unlike serum IgG, did not correlate with protection. Interpretation: Our study shows the feasibility of volunteer challenge in older adult volunteers, revealing age-related differences in outcomes and in immune responses. We identify correlates of protection in older adults, revealing previously unrecognised factors that may partially explain ageing-related susceptibility to viral infections. Funding: Medical Research Council and GlaxoSmithKline EMINENT Consortium.
- Published
- 2022