Development of a rapid response nucleic acid vaccine strategy for coronavirus epidemics

开发针对冠状病毒流行的快速反应核酸疫苗策略

• 批准号: 10265630
• 负责人: Kenneth C Bagley
• 金额: $ 95.54万
• 依托单位: ORLANCE, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-02 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265630
• 关键词: 2019-nCoV; Adjuvant; Antibodies; Antibody Response; Antigens; Attenuated Vaccines; Avidity; Blood Chemical Analysis; CD8-Positive T-Lymphocytes; COVID-19; COVID-19 pandemic; Cells; Clinical Trials; Cold Chains; Complex; Coronavirus; DNA; DNA Vaccines; Development; Dose; Emerging Communicable Diseases; Epidemic; Exhibits; Formulation; Funding; Future; Genetic; Goals; Human; Immune response; Immunity; Immunization; In Situ; Infection; Injections; Lead; Lung; Mediating; Messenger RNA; Methods; Modality; Modeling; Molecular Conformation; Mucous Membrane; Mus; Needles; Nucleic Acid Vaccines; Nucleic Acids; Phase; Plasmids; Population; Production; Protein Subunits; Proteins; RNA vaccine; Recombinant Proteins; Regimen; Replicon; SARS-CoV-2 spike protein; Safety; Savings; Specificity; Standardization; T cell response; Technology; Temperature; Time; Vaccination; Vaccines; Viral; Virus; base; clinical development; cost; cross reactivity; design; experimental study; gene gun; immunogenicity; in vivo; lead candidate; manufacturing process development; neutralizing antibody; nonhuman primate; novel; novel vaccines; pandemic disease; parent grant; pathogen; pre-clinical; primate development; research clinical testing; response; universal influenza vaccine; vaccine candidate; vaccine development; vaccine evaluation; vaccine response; vaccine trial

ABSTRACT In response to the emerging COVID-19 (SARS-CoV-2) pandemic, this supplement proposal to R44 AI138733- 01 will leverage our cutting-edge nucleic acid vaccine strategies, some of which that were developed under this parent grant. Here, we request supplement funding to develop candidate COVID-19 DNA and RNA vaccines expressing optimally designed immunogens for the SARS-CoV-2 spike protein. Nucleic acid (DNA and RNA) vaccines offer significant promise for providing a rapid response solution to emerging infectious diseases because only a partial genetic sequence of the pathogen is needed to generate a new vaccine. Following in vivo delivery, DNA and RNA vaccines lead to in situ production of antigens, negating the need for a complex manufacturing and process development required for purified recombinant protein, inactivated or live attenuated vaccines. Nucleic acids can also be manufactured at low cost and are very stable at room temperature eliminating the need for a cold chain. This provides a significant savings in the time needed to advance a new vaccine from identification of genetic sequence to clinical testing and distribute it to the population. In addition, possibly due to the ability of nucleic acid vaccines to present antigens in their natural conformation in vivo, antibody responses are generally of higher avidity and broader specificity when compared to antibody induced by subunit protein vaccines. Further, the intracellular expression of antigens also induces robust T cell responses including potent CD8+ T cell responses that can more broadly recognize different viral strains and mediate protection via enhanced clearance of the infection. Our approach will compare our optimized DNA and RNA vaccine platform technologies alone and in combinations to identify a lead approach that induces the highest and most rapid development of protective levels of neutralizing antibody after a single administration. In addition, since nucleic acid vaccines tested in our lab have been shown to induce antibody and/or T cell responses that induce cross-protective immunity in our universal influenza vaccine studies under our parent grant, we will determine if the candidate vaccines exhibit cross reactivity against other coronavirus strains for broader protection against future coronavirus strains with epidemic or pandemic potential. Our Aims include: Aim 1- Design and compare immunogenicity of candidate SARS-CoV-2 DNA and RNA vaccines. Aim 2 - Maximize immunogenicity of nucleic acid vaccines and rapid manufacture by combining DNA and replicon mRNA vaccines together or with recombinant protein and optimizing DNA and mRNA formulations. Aim 3 - Safety and immunogenicity of the lead COVID-19 nucleic acid ± protein vaccine in the preclinical nonhuman primate model. If successful, should identify a lead candidate COVID-19 nucleic acid vaccine for phase I human clinical trials.

抽象的 为了响应新兴的COVID-19（SARS-COV-2）大流行，该补充提案对R44 AI138733-- 01将利用我们尖端的核酸疫苗策略，其中一些是在此下开发的 父母赠款。在这里，我们要求补充资金以开发候选covid-19-19 DNA和RNA疫苗 为SARS-COV-2峰值蛋白表达最佳设计的免疫原。核酸（DNA和RNA） 疫苗为新兴传染病提供快速反应解决方案提供了巨大的希望 因为仅需要病原体的部分遗传序列才能产生新的疫苗。跟随体内 递送，DNA和RNA疫苗导致抗原的原位产生，消除了对复合物的需求 纯化的重组蛋白所需的制造和过程开发，灭活或衰减 疫苗。核酸也可以低成本制造，并且在室温下非常稳定 消除了对冷链的需求。这为推进新的时间提供了重大节省 疫苗从鉴定遗传序列到临床测试并将其分配给人群。此外， 可能是由于核酸疫苗在体内自然构象中表现出抗原的能力， 与抗体相比 通过亚基蛋白疫苗。此外，抗原的细胞内表达也诱导了强大的T细胞反应 包括潜在的CD8+ T细胞反应，可以更广泛地识别不同的病毒菌株并进行介导 通过增强感染的清除来保护。我们的方法将比较我们优化的DNA和RNA 疫苗平台技术单独并结合使用，以识别诱导最高的铅方法 以及单个给药后，受保护水平中和抗体水平的最快发展。此外， 由于在我们实验室中测试的核酸疫苗已被证明会诱导抗体和/或T细胞反应 在我们的普遍影响力疫苗研究中诱导交叉保护免疫学，我们将 确定候选疫苗是否针对其他冠状病毒菌株暴露了交叉反应性，以使其更广泛 防止流行或大流行潜力的未来冠状病毒菌株。我们的目标包括：目标1- 设计和比较候选SARS-COV-2 DNA和RNA疫苗的免疫原性。目标2-最大化 核酸疫苗的免疫原性和通过结合DNA和复制mRNA疫苗的快速生产 AIM 3-安全以及重组蛋白以及优化的DNA和mRNA公式。 临床前非人类私有模型中铅共证核酸-19核酸±蛋白疫苗的免疫原性。 如果成功，应确定I期人类临床试验的铅候选核酸-19核酸疫苗。