Third exposure to COVID-19 infection or vaccination differentially impacts T cell responses More about Open Access at the Crick

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Gift Ahimbisibwe David Greenwood Katalin Wilkinson Joshua Gahir Hermaleigh Townsley Murad Miah Philip Bawumia Charlotte Chaloner Dina Levi Philip Hobson Andy Riddell Agnieszka Hobbs Giulia Dowgier Becky Penn Theodore Sanderson Phoebe Stevenson-Leggett Odiesia Daley James Bazire Ruth Harvey Ashley Fowler Callie Smith Mauro Miranda Nicola O'Reilly Scott Warchal Karen Ambrose

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Abstract

BACKGROUND: In 2021, rapid rollout of two doses of SARS-CoV-2 vaccines reduced COVID-19 severity and mortality. However, further vaccine doses as a prime-boost schedule were limited, and lifting of public health restrictions by late 2021 frequently led to infection, rather than vaccine, as a third exposure. OBJECTIVE: To compare how third exposure through mRNA booster or SARS-CoV-2 infection shapes humoral and cellular immunity following two vaccine doses. METHODS: We compared immune responses after third exposure in healthy adults enrolled in the UCLH-Crick Legacy cohort study (NCT04750356) between those receiving ancestral spike-encoded mRNA booster (vaccine immunity, n = 38) or COVID-19 infection (hybrid immunity, n = 13) following two vaccine doses. Immune profiles were evaluated using live virus neutralization assays, IFN-γ ELISpot, Luminex assay, flow cytometry and mass cytometry. RESULTS: Both total anti-Spike IgG and variant-specific neutralising antibodies were comparable following infection or vaccine as a third exposure. Overall, T cell populations were similar, but functionally different. CD8⁺ Effector Memory (TEM) cells in the vaccine group showed higher expression of CD69 and Granzyme B following stimulation with SARS-CoV-2 Spike peptides. In contrast, the hybrid group produced higher levels of innate immune associated cytokines IL-10 and IL-34, as well as the T cell homing chemokine CCL25, after stimulation. CONCLUSIONS: While both exposures generated comparable breadth of protection against SARS-CoV-2 variants, our findings suggest that the route of third exposure influences different aspects of the immune response, warranting further investigation into long-term immunity at both systemic and mucosal sites.