T Cell Responses Induced by SARS-CoV-2 mRNA Vaccination Are Associated With Clonal Replacement

mRNA vaccines against the Spike glycoprotein of severe acute respiratory syndrome type 2 coronavirus (SARS-CoV-2) elicit strong T-cell responses. However, it is unknown whether T cell clones induced by the first vaccination or newly generated T cell clones dominate responses to the secondary vaccination. Here, we analyzed the kinetic profile of Spike-reactive T-cell clones before the first dose, one week after the first and second dose, and four weeks after the second dose of the BNT162b mRNA vaccine. Interestingly, a new set of Spike-reactive CD8 + T cell clones exhibited the greatest expansion following secondary vaccination and replaced the clones that had responded to the primary vaccination. Single-cell mRNA/protein/TCR analysis revealed that the first-responder clones exhibited a terminally differentiated phenotype, whereas second-responder clones exhibited an actively proliferating phenotype. These results show that Spike-reactive T cell responses induced by repetitive mRNA vaccination are augmented and maintained by replacement with newly-generated clones with proliferative potential.Funding Information: This work was supported by Japan Society for the Promotion of Science (JSPS) under Grant Number 17929397 and 20281832, and Japan Agency for Medical Research and Development (AMED) under Grant Number JP22fk0310509, JP22ama221306, and P21gm6210025.Declaration of Interests: H.A. reports stock for ImmunoGeneTeqs, Inc. S.S. reports advisory role for ImmunoGeneTeqs, Inc; stock for ImmunoGeneTeqs, Inc, T.I. reports research funding from Rohto Pharmaceutical Co., Ltd. and Biometrics Sympathies Inc. K.M. reports consulting or advisory role for Kyowa-Hakko Kirin, ImmunoGeneTeqs, Inc; research funding from Kyowa-Hakko Kirin, and Ono; stock for ImmunoGeneTeqs, Inc, IDAC Theranostics, Inc. S.U. reports advisory role for ImmunoGeneTeqs, Inc; stock for ImmunoGeneTeqs, Inc, IDAC Theranostics, Inc. M.K., H.A., A.H., and N.O.S. report no conflict of interest to disclose.Ethics Approval Statement: The Nara Medical University Ethics Committee approved the study (No. 3168). The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines, following approval by the ethics board in each institution. All study participants provided written informed consent.