SARS-CoV-2 infection in vaccinated individuals induces virus-specific nasal resident CD8 and CD4 T cells of broad specificity

Rapid recognition of SARS-CoV-2-infected cells by T cells resident in the upper airway might provide an important layer of protection against COVID-19. Whether parenchymal SARS-CoV-2 vaccination or infection induce nasal resident T cells specific for distinct SARS-CoV-2 proteins is unknown. We collected T cells from the nasal secretion of COVID-19 vaccinees, who either experienced SARS-CoV-2 infection after vaccination (n=20) or not (n=15) and analyzed their phenotype, SARS-CoV-2 specificity and function. Nasal-resident IFN-γ producing SARS-CoV-2-specific CD8 and CD4 T cells were detected exclusively in vaccinees who experienced SARS-CoV-2 breakthrough infection. Importantly, the vaccine priming of Spike-specific T cells does not suppress the induction of CD8 and CD4 T cells specific for different SARS-CoV-2 proteins (i.e. NP and NSP-12) that persisted in the nasal cavity up to 3 months after infection. These data highlight the importance of viral nasal challenge in the formation of SARS-CoV-2 specific antiviral immunity at the site of primary infection and further define the immunological features of SARS-CoV-2 hybrid immunity. ### Competing Interest Statement N. Le Bert and A. Bertoletti reported a patent for a method to monitor SARS-CoV-2-specific T cells in biological samples pending. ### Funding Statement This study was funded by the Singapore Ministry of Health National Medical Research Council under its COVID-19 Research Fund COVID19RF3-0060, COVID19RF-001 and COVID19RF-008. ### 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 protocol was reviewed and approved by SingHealth Centralized Institutional Review Board (CIRB/F 2021/2014). All donors provided written consent for enrolment I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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 work are contained in the manuscript