DNA Nanoparticle Vaccine for COVID-19

COVID-19 DNA 纳米颗粒疫苗

基本信息

批准号：
10181143
负责人：
Mark Bathe
金额：
$ 37.01万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-21 至 2022-12-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10181143
关键词：
2019-nCoV Adjuvant Animal Model Antibody Affinity Antibody Formation Antibody Response Antigen Presentation Antigens B-Cell Activation B-Cell Antigen Receptor B-Lymphocytes Binding COVID-19 COVID-19 outbreak COVID-19 patient COVID-19 vaccine Cell Line Cells Cellular Immunity Cessation of life Clinical Trials Collaborations Communicable Diseases Coronavirus DNA Development Dimensions Disease Disease Outbreaks Engineering Epitopes Formulation Future Generations Glycoproteins HIV Hepatitis B Vaccines Human Human Papilloma Virus Vaccine Humoral Immunities Immune Immune signaling Immunization Immunology In Vitro Inbred BALB C Mice Influenza Injections Investigation Laboratories Libraries Life Macaca Malaria Memory Messenger RNA Modification Nanotechnology Nucleotides Pathway interactions Protein Binding Domain Protein Fragment Protein Subunits Proteins Publishing Receptor Signaling Reporter SARS coronavirus SARS-CoV-2 antibody SARS-CoV-2 antigen Signal Pathway Stimulator of Interferon Genes Structure Subunit Vaccines T-Lymphocyte Technology Testing Toxic effect Translating Untranslated RNA Vaccine Production Vaccines Variant Viral Proteins Virus Virus-like particle chemokine clinical development crosslink cytokine design efficacy study efficacy testing human monoclonal antibodies immunogenicity in vitro Assay in vivo long term memory monomer mouse model nanoparticle nanoparticulate nanoscale neutralizing antibody nonhuman primate novel pandemic disease pathogen preclinical development receptor binding response safety study safety testing scaffold screening vaccine candidate vaccine development vaccine efficacy vaccine evaluation

项目摘要

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.

项目摘要/摘要 Covid-19在几个月内从SARS-COV-2出来，作为致命的全球传播大流行，全世界的死亡人数接近一半。而超过一百个阴道目前正在开发中，并且已经进行了一些人类临床试验，这些早期候选人中的大多数用于瞬时表达SARS-COV-2亚基蛋白的Messenger RNA或DNA公式的没有引起足够中和的长期抗体反应。增强抗原性，抗体的策略亲和力成熟和对亚基疫苗的记忆诱导与设计具有广泛的相关性针对Covid-19等传染病的有效疫苗，并且可能对中和SARS-COV-2病原体。提高亚基疫苗效率的一种方法是制定抗原以多价，纳米描述的形式促进了体液免疫学的几个方面，大多数 B细胞受体（BCR）的交联值得注意。在许可疫苗中探索了这种方法（例如，HPV和HBV疫苗），以及临床前和临床发育中各种各样的疫苗。在这个项目，我们使用脚手架DNA折纸的独特技术来设计类似病毒的纳米颗粒 10–100纳米量表，可提供连接的SARS-COV-2抗原的受控拷贝数的能力受控的抗原间距。我们测试拷贝数，间距和类似病毒的相对重要性纳米颗粒在体外B细胞激活上的大小。在体外使用B细胞激活测定鉴定的最佳构建体随后，将使用鼠标模型在体内表征T细胞和B细胞响应。成功的从体内研究确定的疫苗构建体将与商业伙伴共享，以促进后续在包括非人类隐私在内的高级动物模型中的毒性，安全性和效率研究。我们的结果将提供一种新型的亚基疫苗配方，可以推广到其他SARS-COV变体，包括SARS-COV- 1通过杂异的蛋白抗原表现，作为避免未来的广义疫苗平台冠状病毒引起的大流行病。