Cross-reactive CD4+ T cells enhance SARS-CoV-2 immune responses upon infection and vaccination

While evidence for pre-existing SARS-CoV-2-cross-reactive CD4+ T cells in unexposed individuals is increasing, their functional significance remains unclear. Here, we comprehensively determined SARS-CoV-2-cross-reactivity and human coronavirus-reactivity in unexposed individuals. SARS-CoV-2-cross-reactive CD4+ T cells were ubiquitous, but their presence decreased with age. Within the spike glycoprotein fusion domain, we identified a universal immunodominant coronavirus-specific peptide epitope ( iCope ). Pre-existing spike- and iCope -reactive memory T cells were efficiently recruited into mild SARS-CoV-2 infections and their abundance correlated with higher IgG titers. Importantly, the cells were also reactivated after primary BNT162b2 COVID-19 mRNA vaccination in which their kinetics resembled that of secondary immune responses. Our results highlight the functional importance of pre-existing spike-cross-reactive T cells in SARS-CoV-2 infection and vaccination. Abundant spike-specific cross-immunity may be responsible for the unexpectedly high efficacy of current vaccines even with single doses and the high rate of asymptomatic/mild infection courses. ### Competing Interest Statement The authors KS, ME, UR and FKe are employees, HW is chief executive officer of JPT. SM is chief executive officer of Miltenyi Biotec. MAMu and VMC are named together with Euroimmun GmbH on a patent application filed recently regarding the diagnostic of SARS-CoV-2 by antibody testings. All other authors declare that they have no competing interests. ### Funding Statement This work was funded by the Federal Ministery of Health through a resolution of the German Bundestag (Charite Corona Cross (CCC) and Charite Corona Cross 2.0 (CCC 2.0)). Parts of the work was funded by the German Research Foundation through KFO339 to J.B. and SFB-TR84 projects A4, B6, C8, C10 to LES., AH, SH and B8 to MAMa; by the European Union's Horizon 2020 research and innovation program through project RECOVER (GA101003589) to C.D.; the German Ministry of Research through the projects RAPID (01KI1723A) to CD, AH, SH, DZIF (301-4-7-01.703) to CD, VARIPath (01KI2021) to VMC, RECAST to BS, MAMa, JRoe, VMC, LES and NaFoUniMedCovid19 - COVIM, FKZ: 01KX2021 to LES, CD, and VMC. ### 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: This study was approved by the Institutional Review board of the Charite; (EA/152/20) and written informed consent was obtained from all participants included. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. 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 raw data is shown in the supplementary figures or will be provided upon request.