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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            <jats:italic>n<\/jats:italic>\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            <jats:italic>n<\/jats:italic>\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 (IFN\u03b3) 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-na\u00efve cases and controls, vaccine breakthrough cases had lower CD4+ and CD8+ IFN\u03b3 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.\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/mbio.01212-23","type":"journal-article","created":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T13:02:04Z","timestamp":1693573324000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":10,"title":["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"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7026-7390","authenticated-orcid":false,"given":"Isabel","family":"Neale","sequence":"first","affiliation":[{"name":"Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford , Oxford, United Kingdom"},{"name":"NDM Centre For Global Health Research, Nuffield Department of 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United Kingdom"},{"name":"NDM Centre For Global Health Research, Nuffield Department of Clinical Medicine, University of Oxford , Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8895-317X","authenticated-orcid":false,"given":"Alexandra S.","family":"Deeks","sequence":"additional","affiliation":[{"name":"Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford , Oxford, United Kingdom"},{"name":"Oxford University Hospitals NHS Foundation Trust , Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6751-3300","authenticated-orcid":false,"given":"Anthony","family":"Brown","sequence":"additional","affiliation":[{"name":"Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford , Oxford, United 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A.","family":"Duncan","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute Immunity and Inflammation Theme, Newcastle University , Newcastle, United Kingdom"},{"name":"Department of Infection and Tropical Medicine, Newcastle upon Tyne Hospitals NHS Foundation Trust , Newcastle, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0778-1693","authenticated-orcid":false,"given":"Lance","family":"Turtle","sequence":"additional","affiliation":[{"name":"NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool , Liverpool, United Kingdom"},{"name":"Liverpool University Hospitals NHS Foundation Trust , Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6498-9212","authenticated-orcid":false,"given":"Thushan I.","family":"de Silva","sequence":"additional","affiliation":[{"name":"Sheffield Teaching Hospitals NHS Foundation Trust , Sheffield, United Kingdom"},{"name":"Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield , Sheffield, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7026-7187","authenticated-orcid":false,"given":"Miles","family":"Carroll","sequence":"additional","affiliation":[{"name":"Nuffield Department of Medicine, Pandemic Sciences Institute, University of Oxford , Oxford, United Kingdom"},{"name":"Nuffield Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford , Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7711-897X","authenticated-orcid":false,"given":"Teresa","family":"Lambe","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Oxford Vaccine Group, University of Oxford , Oxford, United Kingdom"},{"name":"Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford , Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4307-9161","authenticated-orcid":false,"given":"Paul","family":"Klenerman","sequence":"additional","affiliation":[{"name":"Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford , Oxford, United Kingdom"},{"name":"Oxford University Hospitals NHS Foundation Trust , Oxford, United Kingdom"},{"name":"Translational Gastroenterology Unit, University of Oxford , Oxford, United Kingdom"},{"name":"NIHR Oxford Biomedical Research Centre, University of Oxford , Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5665-6293","authenticated-orcid":false,"given":"Susanna","family":"Dunachie","sequence":"additional","affiliation":[{"name":"Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford , Oxford, United Kingdom"},{"name":"NDM Centre For Global Health Research, Nuffield Department of Clinical Medicine, University of Oxford , Oxford, United Kingdom"},{"name":"Mahidol-Oxford Tropical Medicine Research Unit , Bangkok, Thailand"},{"name":"Oxford University Hospitals NHS Foundation Trust , Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"On behalf of the PITCH Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc2119270"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)02183-8"},{"key":"e_1_3_3_4_2","unstructured":"UK Health Security Agency . 2022. 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