DNA Nanoparticle Vaccine for COVID-19

COVID-19 DNA 纳米颗粒疫苗

• 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
• 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

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.

项目总结/摘要 COVID-19在几个月内从SARS-CoV-2中脱颖而出，作为一种致命的疾病在全球范围内传播。 大流行，全世界死亡人数接近50万。超过一百种疫苗 目前正在开发中，其中几个已经在人体临床试验中，这些早期候选人中的大多数包括 用于瞬时表达SARS-CoV-2亚单位蛋白的信使RNA或DNA制剂， 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 亲和力成熟和记忆诱导对亚单位疫苗的反应是设计的广泛相关性 有效的疫苗对抗传染病，如COVID-19，并可能特别重要， 中和SARS-CoV-2病原体增强亚单位疫苗功效的一种方法是配制 多价、纳米颗粒形式的抗原，其促进体液免疫的几个方面， 尤其是B细胞受体（BCR）的交联。这种方法已经在许可的疫苗中得到利用， (e.g., HPV和HBV疫苗），以及临床前和临床开发中的多种疫苗。在 在这个项目中，我们使用独特的支架DNA折纸技术，在细胞表面设计病毒样纳米颗粒。 10-100纳米尺度，提供了在200 - 300纳米范围内结合控制拷贝数的SARS-CoV-2抗原的能力。 受控的抗原间间距。我们测试了拷贝数、间隔和病毒样的相对重要性， 纳米颗粒大小对体外B细胞活化的影响。使用体外B细胞活化测定鉴定最佳构建体 随后将用于使用小鼠模型表征体内T细胞和B细胞应答。成功 从体内研究中确定的疫苗结构将与商业合作伙伴共享，以促进后续工作 包括非人灵长类动物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制剂，可以推广到其他SARS-CoV变体，包括SARS-CoV- 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。