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.
Creators: name: Neale, Isabel
name: Ali, Mohammad
name: Kronsteiner, Barbara
name: Longet, Stephanie
name: Abraham, Priyanka
name: Deeks, Alexandra S
name: Brown, Anthony
name: Moore, Shona C
name: Stafford, Lizzie
name: Dobson, Susan L
name: Plowright, Megan
name: Newman, Thomas AH
name: Wu, Mary Y
name: Pipeline, Crick COVID Immunity
name: Carr, Edward J
name: Beale, Rupert
name: Otter, Ashley D
name: Hopkins, Susan
name: Hall, Victoria
name: Tomic, Adriana
name: Payne, Rebecca P
name: Barnes, Eleanor
name: Richter, Alex
name: Duncan, Christopher JA
name: Turtle, Lance
name: de Silva, Thushan I
name: Carroll, Miles
name: Lambe, Teresa
name: Klenerman, Paul
name: Dunachie, Susanna
name: Consortium, PITCH
Publisher: name: The Francis Crick Institute
Year: 2023
Subjects: classificationCode: Infectious Disease
subject: Infectious Disease
classificationCode: Immunology
subject: Immunology
subject: FOS: Clinical medicine
classificationCode: Cell Biology
subject: Cell Biology

description: 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.