Evolution of Long-Term Hybrid Immunity in Healthcare Workers after Different Covid-19 Vaccination Regimens: A Longitudinal Observational Cohort Study

Both infection and vaccination, alone or in combination, generate antibody and T cell responses against SARS-CoV-2. However, the maintenance of such responses – and hence protection from disease – requires careful characterisation. In a large prospective study of UK healthcare workers (Protective immunity from T cells in Healthcare workers (PITCH), within the larger SARS-CoV-2 immunity & reinfection evaluation (SIREN) study) we previously observed that prior infection impacted strongly on subsequent cellular and humoral immunity induced after long and short dosing intervals of BNT162b2 (Pfizer/BioNTech) vaccination. Here, we report longer follow up of 684 HCWs in this cohort over 6-9 months following two doses of BNT162b2 or AZ1222 (Oxford/AstraZeneca) vaccination and up to 6 months following a subsequent mRNA booster vaccination. We make three observations: Firstly, the dynamics of humoral and cellular responses differ; binding and neutralising antibodies declined whereas T and memory B cell responses were maintained after the second vaccine dose. Secondly, vaccine boosting restored IgG levels, broadened neutralising activity against variants of concern including omicron BA.1, BA.2 and BA.5, and further boosted T cell responses. Thirdly, prior infection maintained its impact driving larger as well as broader T cell responses compared with never-infected people – a feature maintained even after the third dose. In conclusion, broadly cross-reactive T cell responses are well maintained over time – especially in those with “hybrid” vaccine and infection-induced immunity – and may contribute to continued protection against severe disease.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, 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).Declaration of Interests: S.J.D. is a Scientific Advisor to the Scottish Parliament on COVID-19 for which she receives a fee. A.J.P. 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 was previously 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. G.S. sits on the GSK Vaccines Scientific Advisory Board and is a founder member of RQ Biotechnology. All other authors have nothing to declare. 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. We also included some participants from Cambridge from a study approved by the National Research Ethics Committee and Health Research Authority (East of England – Cambridge Research Ethics Committee (SCORPIO study, SARS-CoV-2 vaccination response in obesity amendment of ‘‘NIHR BioResource’’ 17/EE/0025).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.