DNA Nanoparticle Vaccine for COVID-19

项目摘要/摘要 新冠肺炎在几个月内从SARS-CoV-2病毒中脱颖而出，以致命的 这是一场大流行，全球死亡人数接近50万人。而一百多种疫苗 目前正在开发中，有几个已经在人体临床试验中，这些早期候选药物中的大多数都包括 用于瞬时表达SARS-CoV-2亚单位蛋白的信使RNA或DNA制剂，其可能 不能引起足够的中和、长期的抗体反应。增强抗原性、抗体的策略 亲和力成熟和对亚单位疫苗的记忆诱导与设计具有广泛的相关性 针对新冠肺炎等传染病的有效疫苗，可能对 中和SARS-CoV-2病原体。提高亚单位疫苗效力的一种方法是制定 多价、纳米颗粒形式的抗原，它促进体液免疫的几个方面，大多数 尤其是B细胞受体(BCR)的交联性。这种方法已经在授权的疫苗中得到了应用 (例如，人乳头瘤病毒和乙肝疫苗)，以及临床前和临床开发中的各种疫苗。在……里面 在这个项目中，我们利用独特的支架DNA折纸技术在 10-100纳米级，能够结合SARS-CoV-2抗原的受控拷贝数 受控的抗原间间隔。我们测试拷贝数量、间距和类似病毒的相对重要性 纳米粒子大小对B细胞体外活化的影响。用体外B细胞活化试验确定最佳构建体 随后将用于通过小鼠模型表征体内T细胞和B细胞的反应。成功 从体内研究中确定的疫苗构造将与商业合作伙伴共享，以促进后续研究 包括非人灵长类在内的高等动物模型的毒性、安全性和有效性研究。我们的结果将提供 一种新的亚单位疫苗配方，可推广到包括SARS-CoV在内的其他SARS-CoV变种- 1通过异价蛋白抗原呈递，作为通用疫苗平台，避免未来 冠状病毒引起的大流行。

PROJECT SUMMARY/ABSTRACT COVID-19 has emerged from SARS-CoV-2 within the course of several months to spread worldwide as a deadly pandemic, with the number of deaths approaching one-half million worldwide. While over one hundred vaccines are currently in development, and several already in human clinical trials, most of these early candidates consist of messenger RNA or DNA formulations used to transiently express SARS-CoV-2 subunit proteins, which may not elicit sufficiently neutralizing, long-term antibody response. Strategies to enhance antigenicity, antibody affinity maturation, and memory induction in response to subunit vaccines are of broad relevance for the design of effective vaccines against infectious diseases such as COVID-19, and may be particularly important to neutralize the SARS-CoV-2 pathogen. One approach to enhance the efficacy of subunit vaccines is to formulate antigens in a multivalent, nanoparticulate form, which promotes several aspects of humoral immunity, most notably crosslinking of B cell receptors (BCRs). This approach has been exploited both in licensed vaccines (e.g., the HPV and HBV vaccines), and in a great variety of vaccines in preclinical and clinical development. In this project, we use the unique technology of scaffolded DNA origami to engineer virus-like nanoparticles on the 10–100 nanometer scale that offer the ability to conjugate controlled copy numbers of SARS-CoV-2 antigens at controlled inter-antigen spacings. We test the relative importance of copy number, spacing, and virus-like nanoparticle size on B cell activation in vitro. Optimal constructs identified using B cell activation assays in vitro will subsequently be used to characterize T-cell and B-cell response in vivo using mouse models. Successful vaccine constructs identified from in vivo studies will be shared with commercial partners to facilitate follow-on toxicity, safety, and efficacy studies in higher animal models including non-human primates. Our results will offer a novel subunit vaccine formulation that may be generalized to other SARS-CoV variants including SARS-CoV- 1 through heterovalent protein antigen presentation, as a generalized vaccine platform to avoid future coronavirus-induced pandemics.