Sustained T Cell Immunity, Protection and Boosting Using Extended Dosing Intervals of BNT162b2 mRNA Vaccine

Abstract

Extension of the interval between vaccine doses for the BNT162b2 mRNA vaccine was introduced in the UK to accelerate population coverage with a single dose. In a study of 503 healthcare workers, we show that after priming following the first vaccine there is a marked decline in SARS-CoV-2 neutralizing antibody (NAb) levels, but, in contrast, a sustained T cell response to spike protein. This divergent immune profile was accompanied by robust protection from infection over this period from the circulating alpha (B.1.1.7) variant. Importantly, following the second vaccine dose, NAb levels were higher after the extended dosing interval (6-14 weeks) compared to the conventional 3-4 week regimen, accompanied by a clear enrichment of CD4+ T cells expressing IL2. These data on dynamic cellular and humoral responses indicate that extension of the dosing interval is an effective, immunogenic protocol and that antiviral T cell responses are a potential mechanism of protection.

Trial Registration Details: PITCH is a sub-study of the SIREN study which is registered with ISRCTN, number ISRCTN11041050,

Funding Information: This work was funded by the UK Department of Health and Social Care as part of the PITCH (Protective Immunity from T cells to Covid-19 in Health workers) Consortium, 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).EB and PK are NIHR Senior Investigators and PK is funded by WT109965MA. SJD is funded by an NIHR Global Research Professorship (NIHR300791). TdS is funded by a Wellcome Trust Intermediate Clinical Fellowship (110058/Z/15/Z). RPP is funded by a Career Re-entry Fellowship (204721/Z/16/Z). CJAD is funded by a Wellcome Clinical Research Career Development Fellowship (211153/Z/18/Z). DS is supported by the NIHR Academic Clinical Lecturer programme in Oxford. LT is supported by the Wellcome Trust (grant number 205228/Z/16/Z) and the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emerging and Zoonotic Infections (NIHR200907) at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford. DGW is supported by an NIHR Advanced Fellowship in Liverpool. LT and MC are supported by U.S. Food and Drug Administration Medical Countermeasures Initiative contract 75F40120C00085.

Declaration of Interests: AJP is Chair of UK Dept. Health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI), but does not participate in policy decisions on COVID-19 vaccines. He is a member of the WHO’s SAGE. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, or WHO. AJP is chief investigator on clinical trials of Oxford University’s COVID-19 vaccine funded by NIHR. Oxford University has entered a joint COVID-19 vaccine development partnership with AstraZeneca.

Ethics Approval Statement: 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). 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 patients enrolled in the study.