Neale, Isabel; Ali, Mohammad; Kronsteiner, Barbara; Longet, Stephanie; Abraham, Priyanka; Deeks, Alexandra S; Brown, Anthony; ... PITCH Consortium; + view all Neale, Isabel; Ali, Mohammad; Kronsteiner, Barbara; Longet, Stephanie; Abraham, Priyanka; Deeks, Alexandra S; Brown, Anthony; Moore, Shona C; Stafford, Lizzie; Dobson, Susan L; Plowright, Megan; Newman, Thomas AH; Wu, Mary Y; Crick COVID Immunity Pipeline; Carr, Edward J; Beale, Rupert; Otter, Ashley D; Hopkins, Susan; Hall, Victoria; Tomic, Adriana; Payne, Rebecca P; Barnes, Eleanor; Richter, Alex; Duncan, Christopher JA; Turtle, Lance; de Silva, Thushan I; Carroll, Miles; Lambe, Teresa; Klenerman, Paul; Dunachie, Susanna; PITCH Consortium; - view fewer (2023) CD4+ and CD8+ T cells and antibodies are associated with protection against Delta vaccine breakthrough infection: a nested case-control study within the PITCH study. mBio , Article e0121223. 10.1128/mbio.01212-23.

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Abstract

Serological correlates of protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection after vaccination ("vaccine breakthrough") have been described. However, T cell correlates of protection against breakthrough are incompletely defined, especially the specific contributions of CD4+ and CD8+ T cells. Here, 279 volunteers in the Protective Immunity from T Cells in Healthcare Workers (PITCH) UK cohort study were enrolled in a nested case-control study. Cases were those who tested SARS-CoV-2 PCR or lateral flow device (LFD) positive after two vaccine doses during the Delta-predominant era (n = 32), while controls were those who did not report a positive test or undergo anti-nucleocapsid immunoglobulin G (IgG) seroconversion during this period (n = 247). Previous SARS-CoV-2 infection prior to vaccination was associated with reduced odds of vaccine breakthrough. Using samples from 28 d after the second vaccine dose, before all breakthroughs occurred, we observed future cases had lower ancestral spike (S)- and receptor binding domain-specific IgG titers and S1- and S2-specific T cell interferon gamma (IFNγ) responses compared with controls, although these differences did not persist when individuals were stratified according to previous infection status before vaccination. In a subset of matched infection-naïve cases and controls, vaccine breakthrough cases had lower CD4+ and CD8+ IFNγ and tumor necrosis factor (TNF) responses to Delta S peptides compared with controls. For CD8+ responses, this difference appeared to be driven by reduced responses to Delta compared with ancestral peptides among cases; this reduced response to Delta peptides was not observed in controls. Our findings support a protective role for T cells against Delta breakthrough infection. IMPORTANCE Defining correlates of protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine breakthrough infection informs vaccine policy for booster doses and future vaccine designs. Existing studies demonstrate humoral correlates of protection, but the role of T cells in protection is still unclear. In this study, we explore antibody and T cell immune responses associated with protection against Delta variant vaccine breakthrough infection in a well-characterized cohort of UK Healthcare Workers (HCWs). We demonstrate evidence to support a role for CD4+ and CD8+ T cells as well as antibodies against Delta vaccine breakthrough infection. In addition, our results suggest a potential role for cross-reactive T cells in vaccine breakthrough.

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