Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, United States.
Unit for Laboratory Animal Medicine, Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, United States.
Front Immunol. 2020 Jul 3;11:1581. doi: 10.3389/fimmu.2020.01581. eCollection 2020.
To ultimately combat the emerging COVID-19 pandemic, it is desired to develop an effective and safe vaccine against this highly contagious disease caused by the SARS-CoV-2 coronavirus. Our literature and clinical trial survey showed that the whole virus, as well as the spike (S) protein, nucleocapsid (N) protein, and membrane (M) protein, have been tested for vaccine development against SARS and MERS. However, these vaccine candidates might lack the induction of complete protection and have safety concerns. We then applied the Vaxign and the newly developed machine learning-based Vaxign-ML reverse vaccinology tools to predict COVID-19 vaccine candidates. Our Vaxign analysis found that the SARS-CoV-2 N protein sequence is conserved with SARS-CoV and MERS-CoV but not from the other four human coronaviruses causing mild symptoms. By investigating the entire proteome of SARS-CoV-2, six proteins, including the S protein and five non-structural proteins (nsp3, 3CL-pro, and nsp8-10), were predicted to be adhesins, which are crucial to the viral adhering and host invasion. The S, nsp3, and nsp8 proteins were also predicted by Vaxign-ML to induce high protective antigenicity. Besides the commonly used S protein, the nsp3 protein has not been tested in any coronavirus vaccine studies and was selected for further investigation. The nsp3 was found to be more conserved among SARS-CoV-2, SARS-CoV, and MERS-CoV than among 15 coronaviruses infecting human and other animals. The protein was also predicted to contain promiscuous MHC-I and MHC-II T-cell epitopes, and the predicted linear B-cell epitopes were found to be localized on the surface of the protein. Our predicted vaccine targets have the potential for effective and safe COVID-19 vaccine development. We also propose that an "Sp/Nsp cocktail vaccine" containing a structural protein(s) (Sp) and a non-structural protein(s) (Nsp) would stimulate effective complementary immune responses.
为了最终应对新兴的 COVID-19 大流行，人们希望开发一种针对由 SARS-CoV-2 冠状病毒引起的这种高度传染性疾病的有效且安全的疫苗。我们的文献和临床试验调查表明，已经针对 SARS 和 MERS 开发了整个病毒、刺突（S）蛋白、核衣壳（N）蛋白和膜（M）蛋白疫苗。然而，这些候选疫苗可能缺乏完全保护的诱导作用，并且存在安全性问题。然后，我们应用了 Vaxign 和新开发的基于机器学习的 Vaxign-ML 反向疫苗学工具来预测 COVID-19 疫苗候选物。我们的 Vaxign 分析发现，SARS-CoV-2 N 蛋白序列与 SARS-CoV 和 MERS-CoV 保守，但与导致轻症的另外四种人类冠状病毒不同。通过研究 SARS-CoV-2 的整个蛋白质组，预测了包括 S 蛋白和 5 种非结构蛋白（nsp3、3CL-pro 和 nsp8-10）在内的 6 种蛋白为黏附素，这些蛋白对于病毒黏附和宿主入侵至关重要。Vaxign-ML 还预测 S、nsp3 和 nsp8 蛋白可诱导高保护性抗原性。除了常用的 S 蛋白外，nsp3 蛋白尚未在任何冠状病毒疫苗研究中进行测试，因此被选为进一步研究。研究发现，nsp3 蛋白在 SARS-CoV-2、SARS-CoV 和 MERS-CoV 之间比在感染人类和其他动物的 15 种冠状病毒之间更为保守。该蛋白还预测含有混杂的 MHC-I 和 MHC-II T 细胞表位，预测的线性 B 细胞表位位于蛋白表面。我们预测的疫苗靶标具有开发有效和安全 COVID-19 疫苗的潜力。我们还提出，包含结构蛋白（Sp）和非结构蛋白（Nsp）的“Sp/Nsp 鸡尾酒疫苗”将刺激有效的互补免疫反应。
