CD4+ and CD8+ T cell and antibody correlates of protection against Delta vaccine breakthrough infection: A nested case-control study within the PITCH study

T cell correlates of protection against SARS-CoV-2 infection after vaccination (‘vaccine breakthrough’) are incompletely defined, especially the specific contributions of CD4+ and CD8+ T cells. We studied 279 volunteers in the Protective Immunity from T Cells in Healthcare Workers (PITCH) UK study, including 32 cases (with SARS-CoV-2 positive testing after two vaccine doses during the Delta-dominant era) and 247 controls (no positive test nor anti-nucleocapsid seroconversion during this period). 28 days after second vaccination, before all breakthroughs occurred, cases had lower ancestral S- and RBD-specific immunoglobulin G titres and S1- and S2-specific T cell interferon gamma (IFNγ) responses compared with controls. In a subset of matched cases and controls, cases had lower CD4+ and CD8+ IFNγ and tumour necrosis factor responses to Delta S peptides with reduced CD8+ responses to Delta versus ancestral peptides compared with controls. Our findings support a protective role for T cells against Delta breakthrough infection. ### Competing Interest Statement S.D. is a Scientific Advisor to the Scottish Parliament on COVID-19 for which she receives a fee. Oxford University has entered a joint COVID-19 vaccine development partnership with AstraZeneca. All other authors have declared no competing interests. ### Clinical Protocols ### Funding Statement This research was funded in part by the Wellcome Trust (WT109965MA, 110058/Z/15/Z, 204721/Z/16/Z, 211153/Z/18/Z, 205228/Z/16/Z, 090532/Z/09/Z, CC2230, CC2087). This work was funded by the United Kingdom Department of Health and Social Care as part of the PITCH (Protective Immunity from T cells to COVID-19 in Healthcare Workers) Consortium, UKRI as part of "Investigation of proven vaccine breakthrough by SARS-CoV-2 variants in established UK healthcare worker cohorts: SIREN consortium & PITCH Plus Pathway" (MR/W02067X/1), with contributions from UKRI/NIHR through the UK Coronavirus Immunology Consortium (UK-CIC), the Huo Family Foundation and The National Institute for Health Research (UKRIDHSC COVID-19 Rapid Response Rolling Call, Grant Reference Number COV19-RECPLAS). This work was supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (CC2230, CC2087), the UK Medical Research Council (CC2230, CC2087), and the Wellcome Trust (CC2230, CC2087). S.D. is funded by an NIHR Global Research Professorship (NIHR300791). E.B. and P.K. are NIHR Senior Investigators and P.K. is funded by WT109965MA. T.I.d.S is funded by a Wellcome Trust Intermediate Clinical Fellowship (110058/Z/15/Z). R.P.P. is funded by a Career Re-entry Fellowship (204721/Z/16/Z). C.J.A.D. is funded by a Wellcome Clinical Research Career Development Fellowship (211153/Z/18/Z). L.T. is supported by the Wellcome Trust (205228/Z/16/Z), the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emerging and Zoonotic Infections (EZI) (NIHR200907) and the Centre of Excellence in Infectious Diseases Research (CEIDR) and the Alder Hey Charity. The HPRU-EZI at University of Liverpool is in partnership with UK Health Security Agency, in collaboration with Liverpool School of Tropical Medicine and the University of Oxford. M.C., S.L., and L.T. are supported by US Food and Drug Administration Medical Countermeasures Initiative contract 75F40120C00085. The Wellcome Centre for Human Genetics is supported by the Wellcome Trust (090532/Z/09/Z). The Sheffield Teaching Hospitals Observational Study of Patients with Pulmonary Hypertension, Cardiovascular and other Respiratory Diseases (STH-ObS) was supported by the British Heart Foundation (PG/11/116/29288). The STH-ObS Chief Investigator Allan Lawrie is supported by a British Heart Foundation Senior Basic Science Research Fellowship (FS/18/52/33808). We gratefully acknowledge financial support from the UK Department of Health via the Sheffield NIHR Clinical Research Facility award to the Sheffield Teaching Hospitals Foundation NHS Trust. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health and Social Care or UK Health Security Agency, or the US Food and Drug Administration. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: PITCH is a sub-study of the SIREN study, which was approved by the Berkshire Research Ethics Committee, Health Research 250 Authority (IRAS ID 284460, REC reference 20/SC/0230), with PITCH recognised as a sub-study on 2 December 2020. SIREN is registered with ISRCTN (Trial ID: 252 [ISRCTN11041050][1]). Some participants were recruited under aligned study protocols. In Birmingham participants were recruited under the "Determining the immune response to SARS-CoV-2 infection in convalescent health care workers" (COCO) study (IRAS ID: 282525). In Liverpool some participants were recruited under the "Human immune responses to acute virus infections" Study (16/NW/0170), approved by North West - Liverpool Central Research Ethics Committee on 8 March 2016, and amended on 14th September 2020 and 4th May 2021. In Oxford, participants were recruited under the GI Biobank Study 16/YH/0247, approved by the research ethics committee (REC) at Yorkshire & The Humber - Sheffield Research Ethics Committee on 29 July 2016, which has been amended for this purpose on 8 June 2020. In Sheffield, participants were recruited under the Observational Biobanking study STHObs (18/YH/0441), which was amended for this study on 10 September 2020. The study was conducted in compliance with all relevant ethical regulations for work with human participants, and according to the principles of the Declaration of Helsinki (2008) and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. Written informed consent was obtained for all participants enrolled in the study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN11041050