Preclinical Development of GV-MVA-VLP Vaccines Against COVID-19

针对 COVID-19 的 GV-MVA-VLP 疫苗的临床前开发

• 批准号: 10154667
• 负责人: Mark Newman
• 金额: $ 29.99万
• 依托单位: GEOVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-05 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10154667
• 关键词: 2019-nCoV; ACE2; Address; Animal Model; Animals; Antibodies; Antibody-Dependent Enhancement; Antigens; Binding; Biological Assay; Blood group antigen S; COVID-19; COVID-19 monitoring; COVID-19 pandemic; COVID-19 prevention; COVID-19 vaccine; Cells; Country; Dangerousness; Data; Development; Disease; Disease Outbreaks; Economics; Elements; Engineering; Enzyme-Linked Immunosorbent Assay; Future; Genetic; Goals; Histopathology; Human; Immune response; Immunity; Immunize; In Vitro; Infection; Medical; Mus; Paralysed; Pathology; Phase; Production; Readiness; Recurrence; Risk; SARS-CoV-2 immunity; Safety; Sampling; Serum; Severe Acute Respiratory Syndrome; Ships; Speed; T cell response; Technology; Testing; Texas; Tissue Sample; Transgenic Mice; Universities; Vaccine Design; Vaccines; Viral Load result; Work; antibody-dependent cell cytotoxicity; base; clinical candidate; clinical development; cytokine; design; efficacy evaluation; efficacy study; emerging pathogen; human coronavirus; immunogenic; immunogenicity; immunopathology; manufacturability; mouse model; neutralizing antibody; nonhuman primate; novel; pandemic disease; preclinical development; prevent; protective efficacy; response; screening; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation

PROJECT SUMMARY With unprecedented speed and scale, SARS-CoV-2 has caused a deadly global pandemic. A safe and effective vaccine to control this new pathogen is desperately needed. To address this need, GeoVax is leveraging its unique GV-MVA-VLPTM platform and advanced antigen design to develop multiple vaccine candidates against COVID-19. Unique among COVID-19 vaccines, the GeoVax candidates are specifically designed to provide highly protective immunity against SARS-CoV-2 while avoiding antibody-dependent enhancement (ADE) and immunopathology that have the potential to render vaccines not only ineffective but actually dangerous. In addition to the identification of the final vaccine candidate, the work proposed here will generate scientific data that are extremely valuable to the overall field of COVID-19 vaccine development, in that testing of our unique vaccines will determine whether application of our approach is able to overcome the ADE and immunopathology risks that plagued SARS vaccines. Under Specific Aim 1, we will complete the construction of GEO-CM02 through GEO-CM04 vaccine candidates. We will then test these candidates to demonstrate antigen expression, manufacturability, formation of VLPs, and genetic stability under conditions designed to simulate those in manufacturing, which will demonstrate the suitability of each vaccine construct as a candidate for full-scale production. Finally, we will produce adequate amount of each vaccine to enable the animal studies planned in Specific Aim 2 and ship the vaccines to our collaborators at the University of Texas Medical Branch. Under Specific Aim 2, we will then perform an immunogenicity and efficacy study in mice transgenic for human angiotensin converting enzyme 2 (hACE2). The hACE2 transgenic mouse model is a rigorous animal model developed for SARS that is well suited for testing of human coronaviruses. We will immunize animals, sample the animals for analysis of immune responses, challenge the animals with SARS-CoV-2, and monitor the animals post-challenge for development of clinical signs of disease. Under Specific Aim 3, we will analyze samples from the hACE2 mouse study to assess the immunogenicity, efficacy and safety (ADE and immunopathology) of our vaccine candidates. Immunogenicity analyses will include binding antibody (BAb) by ELISA, neutralizing antibody (NAb) by serum neutralization assay, antibody-dependent cellular cytotoxicity (ADCC) by cell-based assay, and T cell responses by intracellular cytokine screening (ICS). Efficacy analyses will include viral load and histopathology relative to unvaccinated controls. We will also analyze serum and tissue samples for evidence of ADE and immunopathology to test the hypothesis that our vaccines will avoid these risks associated with SARS vaccines. All these parameters will help to down select the most immunogenic (inducing broad Ab and T cell responses) and safe (lack of ADE and immunopathology upon challenge) vaccine candidate for further testing in non-human primates and Phase 1 human trials.

项目摘要 SARS-COV-2凭借前所未有的速度和规模，导致致命的全球大流行。安全有效的 迫切需要控制这种新病原体的疫苗。为了满足这一需求，Geovax正在利用 独特的GV-MVA-VLPTM平台和高级抗原设计，以开发多种候选疫苗 新冠肺炎。在COVID-19疫苗中独有的，Geovax候选者是专门设计的 对SARS-COV-2的高度保护性免疫，同时避免抗体依赖性增强（ADE）和 免疫病理学有可能使疫苗不仅无效，而且实际上是危险的。在 除了确定最终疫苗候选者的识别，此处提出的工作将生成科学数据 这对于Covid-19-19疫苗开发的整体领域非常有价值，在测试我们的独特 疫苗将确定我们的方法的应用是否能够克服ADE和免疫病理学 困扰SARS疫苗的风险。在特定目标1下，我们将完成GEO-CM02的构建 通过GEO-CM04候选疫苗。然后，我们将测试这些候选者以证明抗原表达， 在旨在模拟这些条件下的条件下的可制造性，VLP的形成和遗传稳定性 制造业，这将证明每种疫苗构造作为全尺度的候选者的适用性 生产。最后，我们将生产大量的每种疫苗，以实现计划的动物研究 具体目标2并将疫苗运送到我们在德克萨斯大学医学分公司的合作者。在下面 特定目标2，然后我们将在人类的小鼠转基因中进行免疫原性和疗效研究 血管紧张素转化酶2（HACE2）。 HACE2转基因小鼠模型是严格的动物模型 为SARS开发，非常适合测试人类冠状病毒。我们将免疫动物，样品 用于分析免疫反应的动物，用SARS-COV-2挑战动物，并监测动物 促进后发展疾病临床体征。在特定目标3下，我们将分析来自 HACE2小鼠的研究，以评估我们的免疫原性，功效和安全性（ADE和免疫病理学） 候选疫苗。免疫原性分析将包括ELISA结合抗体（BAB），中和 通过血清中和测定，抗体依赖性细胞毒性（ADCC）的抗体（NAB）通过基于细胞的细胞毒性（ADCC） 测定和T细胞细胞因子筛选（ICS）的T细胞反应。功效分析将包括病毒载荷 和组织病理学相对于未接种疫苗的控制。我们还将分析血清和组织样品的 ADE和免疫病理学的证据测试了我们的疫苗将避免这些风险的假设 与SARS疫苗。所有这些参数将有助于选择最免疫原性（诱导宽阔的AB 和T细胞反应）和安全（挑战时缺乏ADE和免疫病理学）候选疫苗 在非人类灵长类动物和1期人类试验中进行测试。