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Screening of HLA-A restricted T cell epitopes of SARS-CoV-2 and induction of CD8+ T cell responses in HLA-A transgenic mice

By Xiaoxiao Jin, Yan Ding, Shihui Sun, Xinyi Wang, Zining Zhou, Xiaotao Liu, Miaomiao Li, Xian Chen, Anran Shen, Yandan Wu, Bicheng Liu, Jianqiong Zhang, Jian Li, Yi Yang, Haibo Qiu, Chuanlai Shen, Yuxian He, Guangyu Zhao

Posted 01 Apr 2021
bioRxiv DOI: 10.1101/2021.04.01.438020

While SARS-CoV-2-specific T cells have been characterized to play essential roles in host immune protection in COVID-19 patients, few researches focus on the functional validation of T cell epitopes and development of vaccines inducing specific T cell responses. In this study, 120 CD8 T cell epitopes from E, M, N, S and RdRp proteins were validated. Among them, 110 epitopes have not been reported previously; 110, 15, 6, 14 and 12 epitopes were highly homologous with SARS-CoV, OC43, NL63, HKU1, and 229E, respectively; 4 epitopes from S protein displayed one amino acid distinct from the current variants of SARS-CoV-2. Thirty-one epitopes restricted by HLA-A2 molecule were used to generate peptide cocktail vaccines in combination with Poly I:C, R848 or polylactic-co-glycolic acid nanoparticles, which elicited robust specific CD8 T cell responses in wild-type and HLA-A2DR1 transgenic mice. Seven of the 31 epitopes were found to be cross-presented by HLA-A2 and H-2KDb molecules. Unlike previous researches, this study established a modified cell co-culture system of DC-peptide-PBL using healthy donors PBMCs to validate the CD8 T cell epitope on-silicon predicted; provided a library of CD8 T cell epitopes restricted by a series of high-frequency HLA-A allotypes which covering broad Asian populations; identified the HLA-A cross-restrictions of these CD8 T cell epitopes using competitive binding experiments with HMy2.CIR cell lines expressing indicated HLA-A molecules; and initially confirmed the in vivo feasibility of 9 or 10-mer peptide cocktail vaccines of SARS-CoV-2. These data will facilitate the development of vaccines inducing antiviral CD8 T cell responses.

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