NEC Laboratories Europe GmbH, Kurfuersten-Anlage 36, 69115, Heidelberg, Germany.
NEC OncoImmunity AS, Ullernchausseen 64/66, 0379, Oslo, Norway.
Sci Rep. 2020 Dec 23;10(1):22375. doi: 10.1038/s41598-020-78758-5.
The global population is at present suffering from a pandemic of Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The goal of this study was to use artificial intelligence (AI) to predict blueprints for designing universal vaccines against SARS-CoV-2, that contain a sufficiently broad repertoire of T-cell epitopes capable of providing coverage and protection across the global population. To help achieve these aims, we profiled the entire SARS-CoV-2 proteome across the most frequent 100 HLA-A, HLA-B and HLA-DR alleles in the human population, using host-infected cell surface antigen presentation and immunogenicity predictors from the NEC Immune Profiler suite of tools, and generated comprehensive epitope maps. We then used these epitope maps as input for a Monte Carlo simulation designed to identify statistically significant "epitope hotspot" regions in the virus that are most likely to be immunogenic across a broad spectrum of HLA types. We then removed epitope hotspots that shared significant homology with proteins in the human proteome to reduce the chance of inducing off-target autoimmune responses. We also analyzed the antigen presentation and immunogenic landscape of all the nonsynonymous mutations across 3,400 different sequences of the virus, to identify a trend whereby SARS-COV-2 mutations are predicted to have reduced potential to be presented by host-infected cells, and consequently detected by the host immune system. A sequence conservation analysis then removed epitope hotspots that occurred in less-conserved regions of the viral proteome. Finally, we used a database of the HLA haplotypes of approximately 22,000 individuals to develop a "digital twin" type simulation to model how effective different combinations of hotspots would work in a diverse human population; the approach identified an optimal constellation of epitope hotspots that could provide maximum coverage in the global population. By combining the antigen presentation to the infected-host cell surface and immunogenicity predictions of the NEC Immune Profiler with a robust Monte Carlo and digital twin simulation, we have profiled the entire SARS-CoV-2 proteome and identified a subset of epitope hotspots that could be harnessed in a vaccine formulation to provide a broad coverage across the global population.
目前,全球正遭受由新型冠状病毒 Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2)引发的 2019 年冠状病毒病(COVID-19)大流行。本研究的目的是利用人工智能(AI)预测针对 SARS-CoV-2 的通用疫苗设计蓝图,这些蓝图包含足够广泛的 T 细胞表位 repertoire,能够为全球人口提供覆盖和保护。为了实现这些目标,我们使用来自 NEC 免疫分析器套件的宿主感染细胞表面抗原呈递和免疫原性预测器,对人群中最常见的 100 个 HLA-A、HLA-B 和 HLA-DR 等位基因进行了 SARS-CoV-2 全蛋白组分析,并生成了全面的表位图谱。然后,我们将这些表位图谱用作输入,用于进行蒙特卡罗模拟,旨在识别病毒中最有可能在广泛的 HLA 类型中具有免疫原性的统计学显著“表位热点”区域。然后,我们去除了与人类蛋白质组中蛋白质具有显著同源性的表位热点,以降低诱导非靶向自身免疫反应的机会。我们还分析了跨越病毒的 3400 个不同序列的所有非同义突变的抗原呈递和免疫景观,以确定一种趋势,即 SARS-COV-2 突变被预测为宿主感染细胞呈递的潜力降低,并且因此被宿主免疫系统检测到。然后,进行序列保守性分析,以去除发生在病毒蛋白质组中较少保守区域的表位热点。最后,我们使用大约 22000 个人的 HLA 单倍型数据库来开发一种“数字孪生”类型模拟,以模拟不同组合的热点在多样化的人类群体中的有效性;该方法确定了一组最佳的表位热点,可以在全球人口中提供最大的覆盖范围。通过将 NEC 免疫分析器的感染宿主细胞表面的抗原呈递和免疫原性预测与稳健的蒙特卡罗和数字孪生模拟相结合,我们对 SARS-CoV-2 的整个蛋白质组进行了分析,并确定了一组表位热点,可以在疫苗配方中加以利用,为全球人口提供广泛的覆盖范围。
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