Post-pandemic memory T-cell response to SARS-CoV-2 is durable, broadly targeted and cross-reactive to hypermutated BA.2.86

The COVID-19 post-pandemic period is characterised by infection waves of uncertain size (due to low rates of SARS-CoV-2 testing and notification), as well as limited uptake or global access to updated variant vaccines. Ongoing SARS-CoV-2 evolution has given rise to recombinant Omicron lineages that dominate globally (XBB.1), as well as the emergence of hypermutated variants (BA.2.86). In this context, durable and cross-reactive T-cell immune memory is critical for continued protection against severe COVID-19. We examined T-cell responses to SARS-CoV-2 approximately 1.5 years since Omicron first emerged. We describe sustained CD4+ and CD8+ spike-specific T-cell memory responses in healthcare workers in South Africa (n=39), most of whom had received 2 doses of Ad26.CoV2.S (Johnson & Johnson/Janssen) vaccine and experienced at least one SARS-CoV-2 infection. Spike-specific T cells were highly cross-reactive with all Omicron variants tested, including BA.2.86. Abundant non-spike (nucleocapsid and membrane)-specific T cells were detectable in most participants, augmenting the total T-cell resources available for protection. The bulk of SARS-CoV-2-specific T-cell responses had an early-differentiated phenotype, explaining their persistent nature. Thus, hybrid immunity leads to the accumulation of spike and non-spike T cells evident 3.5 years after the start of the pandemic, with preserved recognition of highly mutated SARS-CoV-2 variants. Long-term T-cell immune memory is likely to provide continued protection against severe outcomes of COVID-19. In Brief Nesamari et al. investigate T-cell responses in the context of hybrid immunity 3.5 years after the start of the COVID-19 pandemic. They show that T-cell memory is highly durable and cross-reactive with recombinant variants XBB.1 and hypermutated BA.2.86. Abundant non-spike responses augment the overall T-cell response. ### Competing Interest Statement Alex Sette is a consultant for AstraZeneca Pharmaceuticals, Calyptus Pharmaceuticals, Inc, Darwin Health, EmerVax, EUROIMMUN, F. Hoffman-La Roche Ltd, Fortress Biotech, Gilead Sciences, Granite bio., Gritstone Oncology, Guggenheim Securities, Moderna, Pfizer, RiverVest Venture Partners, and Turnstone Biologics. Alba Grifoni is a consultant for Pfizer. LJI has filed for patent protection for various aspects of T cell epitope and vaccine design work. All other authors declare no competing interests. ### Funding Statement Wellcome Trust (226137/Z/22/Z) South African Medical Research Council (SA-MRC) with funds received from the South African Department of Science and Innovation (DSI) Bill and Melinda Gates Foundation (INV-046743) Poliomyelitis Research Foundation (21/65) Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) which is supported by core funding from the Wellcome Trust (203135/Z/16/Z and 222754) W.A.B. and C.R. are supported by the EDCTP2 program of the European Unions Horizon 2020 program (TMA2016SF-1535-CaTCH-22 to W.A.B and TMA2017SF-1951-TB-SPEC to C.R.) R.N. is supported by the Harry Crossley Foundation N.A.B.N. acknowledges funding from the SA-MRC, MRC UK, NRF, and the Lily and Ernst Hausmann Trust This project has been funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. 75N93021C00016 to A.G. and Contract No. 75N93019C00065 to A.S. ### 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: The study was approved by the University of Cape Town Human Research Ethics Committee (HREC 190/2020 and 291/2020), and written informed consent was obtained from all participants. 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data reported in this paper will be shared by the lead contacts upon request. This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contacts upon request.