Final Preclinical Testing and Formulation of a Scalable, Live-attenuated SARS-CoV-2 Vaccine

可扩展的 SARS-CoV-2 减毒活疫苗的最终临床前测试和配制

• 批准号: 10255845
• 负责人: Steffen Mueller
• 金额: $ 99.93万
• 依托单位: CODAGENIX, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-06 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10255845
• 关键词: 2019-nCoV; Abate; Age; Amino Acid Sequence; Animals; Attenuated; Attenuated Vaccines; Biodistribution; Biological Assay; COVID-19; COVID-19 pandemic; COVID-19 vaccine; Cells; Clinical Data; Codon Nucleotides; Communication; Computational algorithm; County; Coupled; Dose; Ensure; Enzyme-Linked Immunosorbent Assay; Epitopes; Excipients; Excretory function; Exhibits; FDA approved; Formulation; Freezing; Genes; Genetic Drift; Genome; Goals; Growth; Hematology; Histopathology; Human; Immune; Immune Targeting; Immune response; Immune system; Immunoglobulin G; Knowledge; Late Effects; Licensing; Liquid substance; Medical; Mesocricetus auratus; Molecular Conformation; Mutation; Pathogenicity; Patients; Phase I Clinical Trials; Phenotype; Pre-Clinical Model; Preclinical Testing; Preparation; Production; Proteins; Protocols documentation; Recommendation; Recovery; SARS-CoV-2 immunity; SARS-CoV-2 infection; Safety; Serum; Shipping; Ships; Testing; Time; Tissues; Toxic effect; Translating; Translations; United States; Vaccine Production; Vaccines; Viral; Viral Antigens; Virus; Work; attenuation; base; cost; design; fight against; fighting; immunogenic; immunogenicity; in vivo; influenza epidemic; interest; pandemic disease; pre-clinical; preclinical study; response; stability testing; synthetic biology; vector vaccine

PROJECT SUMMARY There is a critical need for effective SARS-CoV-2 vaccines that can be rapidly produced at large scale. Given our rudimentary understanding of the immunological responses to the virus, a vaccine that engenders a broad-based response (innate, humoral, and cellular), is particularly appealing. Further, with little or no a priori knowledge of key immunological targets, a vaccine that can present all of a virus’ antigens to the host is ideal. In response, using its unique computational algorithm, Codagenix has designed and completed initial pre-clinical testing of an intranasal, live-attenuated SARS-CoV-2 vaccine, CDX-005, that 1) activates innate, humoral, and cellular immune responses, 2) presents every viral antigen in its natural conformation to the inoculated host, and 3) will be inexpensive, fast, and easy to produce at scale. This is the only LAV being developed for the US market. The vaccine grows robustly in fully characterized GMP cells and pre-clinical data suggest that a single, low, intranasal dose in the range of 104-106 PFU will be protective. Pre-clinical testing in Syrian Golden hamsters demonstrated the safety, attenuation, and efficacy of CDX-005 in vivo, and a Phase I clinical trial will be beginning in the UK in 2020 using product manufactured overseas. Our goal is to produce and distribute the CDX-005 SARS-CoV-2 vaccine in the United States. To this end, Codagenix has had pre-IND communications with and guidance from the FDA. We propose to complete additional pre- clinical studies in response to FDA recommendations and to develop a formulation that is stable for extended periods at 4°C to reduce shipping costs, simplify end-user storage, and make it easier to administer the vaccine. Accordingly, in Aim 1, we will develop a CDX-005 formulation that is stable for extended periods at 2°-8°C. Starting with our frozen formulation as a base, we will test excipients for their ability to stabilize a liquid vaccine using forced degradation, accelerated stability testing, and long-term stability testing protocols. In Aim 2, we will determine the toxicity, immunogenicity, biodistribution, attenuation, and efficacy of late passage CDX-005 in Syrian Golden hamsters. In preparation for an IND filing, we will 1) assess toxicity by histopathology and hematology after inoculation with CDX-005, 2) examine CDX-005 immunogenicity by serum IgG ELISA, plaque reduction neutralization, and Th1/Th2 response by qPCR, 3) determine CDX-005 biodistribution and attenuation by qPCR and TCID50 in tissues and excretions, and 4) assess CDX-005 efficacy by SARS-CoV-2 challenge. In parallel with the proposed work, we will bring CDX-005 manufacturing capabilities to the US, conduct a Phase I clinical trial in the UK, and sequence the virus from tissues in these patients to test for possible reversion. We recognize that other SARS-CoV-2 vaccines may reach the market before CDX-005. While these will be a tremendous boon short term in the fight against SARS-CoV-2, the are expected to be only partially protective. In contrast, we anticipate that CDX-005, as an LAV, will provide a much more robust and longer lasting protection making it a more attractive choice in the long term market.

项目摘要 目前迫切需要能够大规模快速生产的有效SARS-CoV-2疫苗。给定 我们对这种病毒的免疫反应的初步了解， 基础广泛的反应（先天的、体液的和细胞的）尤其吸引人。此外，很少或没有a 关键免疫靶点的先验知识，可以将所有病毒抗原呈递给宿主的疫苗， 理想.作为回应，Codagenet利用其独特的计算算法，设计并完成了初始 鼻内SARS-CoV-2减毒活疫苗CDX-005的临床前测试，其1）激活先天性， 体液和细胞免疫应答，2）将每种病毒抗原以其天然构象呈递给免疫原， 接种的宿主，和3）将是廉价的，快速的，并且易于大规模生产。这是唯一一辆 为美国市场开发。该疫苗在充分表征的GMP细胞中稳健生长， 数据表明，104-106 PFU范围内的单次低鼻内剂量将具有保护作用。临床前 在叙利亚金仓鼠中的测试证明了CDX-005在体内的安全性、减毒和功效， 第一阶段临床试验将于2020年在英国开始，使用海外生产的产品。我们的目标是 在美国生产和分发CDX-005 SARS-CoV-2疫苗。为此，Codagrant已 在IND前与FDA进行了沟通并获得了FDA的指导。我们建议完成额外的预- 临床研究，以响应FDA的建议，并开发一种制剂，是稳定的延长 在4°C的时间，以降低运输成本，简化最终用户的存储，并使管理更容易 疫苗因此，在目标1中，我们将开发一种CDX-005制剂，其在100 ℃下长时间稳定。 2 - 8 ℃。从我们的冷冻制剂作为基础开始，我们将测试赋形剂稳定 使用强制降解、加速稳定性试验和长期稳定性试验方案的液体疫苗。 在目标2中，我们将确定晚期免疫球蛋白的毒性、免疫原性、生物分布、减毒和疗效。 叙利亚金仓鼠中的CDX-005传代。在准备IND申请时，我们将1）通过以下方式评估毒性： 组织病理学和血液学，2）通过以下方法检测CDX-005免疫原性： 血清IgG ELISA、空斑减少中和和通过qPCR的Th 1/Th 2应答，3）测定CDX-005 通过qPCR和组织和排泄物中的TCID 50测定的生物分布和减毒，以及4）评估CDX-005功效 SARS-CoV-2挑战。在拟议的工作的同时，我们将带来CDX-005制造 在英国进行I期临床试验，并对这些组织中的病毒进行测序。 患者进行可能的逆转试验。我们认识到其他SARS-CoV-2疫苗可能会进入市场 在CDX-005之前虽然这些在短期内对抗击SARS-CoV-2将是一个巨大的布恩，但 预计只能起到部分保护作用。相比之下，我们预计CDX-005作为LAV，将提供 更强大和更持久的保护，使其成为长期市场上更具吸引力的选择。