A pan-variant mRNA-LNP T cell vaccine protects HLA transgenic mice from mortality after infection with SARS-CoV-2 Beta.
A pan-variant mRNA-LNP T cell vaccine protects HLA transgenic mice from mortality after infection with SARS-CoV-2 Beta.
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DOI：
10.3389/fimmu.2023.1135815
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发表时间：
2023
影响因子：
7.3
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中科院分区：
文献类型：
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获得许可的COVID-19疫苗通过诱导产生中和抗体来改善病毒感染，这些抗体结合SARS-CoV-2刺突蛋白并抑制病毒进入细胞。然而，这些疫苗的临床有效性是暂时的，因为病毒变体逃避抗体中和。仅依赖于T细胞应答来对抗SARS-CoV-2感染的有效疫苗可能是转化性的，因为它们可以利用高度保守的短泛变体肽表位，但mRNA-LNP T细胞疫苗尚未显示出提供有效的抗SARS-CoV-2预防。在这里，我们展示了一种基于高度保守的短肽表位的mRNA-LNP疫苗（MIT-T-COVID）激活了CD 8+和CD 4 + T细胞应答，从而减轻了SARS-CoV-2 Beta（B.1.351）感染的HLA-A*02：01转基因小鼠的发病率并预防死亡。我们发现用MIT-T-COVID疫苗免疫的小鼠中的CD 8 + T细胞在感染前和感染后7天（dpi）分别从总肺有核细胞的1.1%显著增加到24.0%，表明循环特异性T细胞动态募集到感染的肺中。用MIT-T-COVID免疫的小鼠的肺浸润性CD 8 + T细胞比未免疫的小鼠多2.8倍（2 dpi）和3.3倍（7 dpi）。用MIT-T-COVID免疫的小鼠的肺浸润性CD 4 + T细胞比未免疫的小鼠多17.4倍（7 dpi）。在MIT-T-COVID免疫的小鼠中检测不到特异性抗体应答，表明特异性T细胞应答单独可以有效减弱SARS-CoV-2感染的发病机制。我们的研究结果表明，对于泛变体T细胞疫苗，包括不能产生中和抗体或帮助缓解长期COVID的个体，值得进一步研究。
Licensed COVID-19 vaccines ameliorate viral infection by inducing production of neutralizing antibodies that bind the SARS-CoV-2 Spike protein and inhibit viral cellular entry. However, the clinical effectiveness of these vaccines is transitory as viral variants escape antibody neutralization. Effective vaccines that solely rely upon a T cell response to combat SARS-CoV-2 infection could be transformational because they can utilize highly conserved short pan-variant peptide epitopes, but a mRNA-LNP T cell vaccine has not been shown to provide effective anti-SARS-CoV-2 prophylaxis. Here we show a mRNA-LNP vaccine (MIT-T-COVID) based on highly conserved short peptide epitopes activates CD8+ and CD4+ T cell responses that attenuate morbidity and prevent mortality in HLA-A*02:01 transgenic mice infected with SARS-CoV-2 Beta (B.1.351). We found CD8+ T cells in mice immunized with MIT-T-COVID vaccine significantly increased from 1.1% to 24.0% of total pulmonary nucleated cells prior to and at 7 days post infection (dpi), respectively, indicating dynamic recruitment of circulating specific T cells into the infected lungs. Mice immunized with MIT-T-COVID had 2.8 (2 dpi) and 3.3 (7 dpi) times more lung infiltrating CD8+ T cells than unimmunized mice. Mice immunized with MIT-T-COVID had 17.4 times more lung infiltrating CD4+ T cells than unimmunized mice (7 dpi). The undetectable specific antibody response in MIT-T-COVID-immunized mice demonstrates specific T cell responses alone can effectively attenuate the pathogenesis of SARS-CoV-2 infection. Our results suggest further study is merited for pan-variant T cell vaccines, including for individuals that cannot produce neutralizing antibodies or to help mitigate Long COVID.