Project 2: Current Good Manufacture Practices (CGMP) Production of Nucleoside-Modified mRNAs Encoding HIV-1 Envelopes

项目 2：编码 HIV-1 包膜的核苷修饰 mRNA 的现行良好生产规范 (CGMP) 生产

• 批准号: 10338060
• 负责人: Frederick Porter
• 金额: $ 527.44万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-08 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10338060
• 关键词: Address; Animal Model; Animals; Antibodies; Antibody Response; Antigens; B-Lymphocytes; Categories; Cell Lineage; Characteristics; Chemicals; Clinic; Clinical Research; Clinical Trials; Complex; Consumption; Contracts; Custom; Development; Dose; Ensure; Formulation; Glycopeptides; Goals; Grant; HIV; HIV immunization; HIV vaccine; HIV-1; HIV-1 vaccine; Human; Immunity; Knowledge; Messenger RNA; Methods; Modification; Mosaicism; Nucleic Acids; Nucleosides; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Polysaccharides; Positioning Attribute; Pre-Clinical Model; Process; Production; Proteins; RNA; RNA vaccine; Recombinants; Regimen; Rivers; Safety; Site; System; T cell response; Techniques; Technology; Testing; Time; TimeLine; Toxic effect; Toxicology; Vaccine Design; Vaccines; Viral Vector; Work; Zika Virus; base; cost effectiveness; design; env Gene Products; expectation; falls; flexibility; immunogenicity; neutralizing antibody; nonhuman primate; novel; novel vaccines; plasmid DNA; preclinical study; programs; protein expression; research clinical testing; stability testing; vaccination strategy; vaccine candidate; vaccine immunogenicity; vaccine platform; vector

Project 2: Current Good Manufacture Practices (CGMP) Production of Nucleoside-Modified mRNAs Encoding HIV-1 Envelopes This IPCAVD grant seeks to develop and evaluate mRNA as an HIV-1 vaccine platform. Project 2 will oversee the manufacture of two nucleoside-modified mRNAs by current good manufacturing practices (CGMP) for a Phase I clinical trial to begin in year 5. To execute this project, we will select contract development and manufacturing organizations (CDMOs) as commercial partners to manufacture two mRNA immunogens to induce V3-glycan envelope site-targeted bnAb precursors. The scope of this work will span knowledge transfer to the selected CDMO through successful IND filing for the final vaccine candidate. A technical CDMO management team, including Drs. Haynes, Weissman and Porter will be assembled to oversee the process and ensure successful delivery of the program. The following specific aims are proposed for the project. • Aim 1. Facilitate knowledge transfer for selected mRNA immunogens to CDMOs. • Aim 2. Deliver final drug substances and drug products for toxicology studies and clinical testing. • Aim 3. Develop and deliver regulatory strategy to enable Phase I proof of concept clinical studies. Project 2 will advance modified mRNA as a platform for HIV immunization and establish the regulatory framework for its use. CGMP production of an mRNA V3-glycan mimetope vaccine will allow this vaccine platform to be evaluated in humans for comparison to other vaccination strategies and to assess the induction of V3-glycan bnAb precursors. Once developed, this platform could be rapidly applied to other HIV-1 immunogens with little additional development since the production process and the majority of release methods are not sequence dependent. These features of modified mRNA position the platform to address the complexity, safety, and cost effectiveness of HIV-1 vaccine regimens.

项目2：核苷修饰mRNA的现行良好生产规范（CGMP）生产 编码HIV-1包膜 IPCAVD的这项资助旨在开发和评估mRNA作为HIV-1疫苗平台。项目2将监督 通过现行良好生产规范（CGMP）生产两种核苷修饰的mRNA， I期临床试验将于第5年开始。为了执行这个项目，我们将选择合同开发， 生产组织（CDMO）作为商业合作伙伴生产两种mRNA免疫原， 诱导V3-聚糖包膜位点靶向bnAb前体。这项工作的范围将涵盖知识转让 通过最终候选疫苗的IND申请成功提交给选定的CDMO。技术CDMO 包括海恩斯博士、韦斯曼博士和波特博士在内的管理团队将负责监督这一过程 确保项目顺利实施。为该项目提出了以下具体目标。 ·目标1。促进向CDMO转移选定mRNA免疫原的知识。 ·目标2。交付最终原料药和制剂用于毒理学研究和临床试验。 目标3。制定并实施监管策略，以实现I期概念验证临床研究。 项目2将推进修饰的mRNA作为HIV免疫的平台，并建立监管机制。 的框架使用。mRNA V3-聚糖疫苗的CGMP生产将允许这种疫苗 在人类中进行评估的平台，用于与其他疫苗接种策略进行比较，并评估诱导 的V3-聚糖bnAb前体。一旦开发出来，这个平台可以迅速应用于其他HIV-1 由于生产过程和大部分的释放， 方法不依赖于序列。修饰的mRNA的这些特征定位了平台，以解决 复杂性、安全性和成本效益。