Project 2 - GMP Manufacturing of mRNA Immunogens

项目2 - mRNA免疫原的GMP生产

• 批准号: 10355429
• 负责人: Thomas Denny
• 金额: $ 643.28万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-11 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355429
• 关键词: ALVAC; Address; Animal Model; Animals; Antibodies; Antibody Response; Antigens; B-Lymphocytes; Categories; Characteristics; Chemicals; Clinic; Clinical Research; Clinical Trials; Complex; Consumption; Contracts; Development; Dose; Ensure; Goals; Grant; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV-1; Human; Immunity; Immunization; Knowledge; Messenger RNA; Mosaicism; Mus; Nature; Nucleic Acids; Nucleosides; Performance; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Positioning Attribute; Pre-Clinical Model; Process; Production; Proteins; RNA; RNA vaccination; RNA vaccine; Recombinants; Regimen; Rivers; Safety; System; T cell response; Technology; Testing; Time; TimeLine; Toxic effect; Toxicology; Vaccine Design; Vaccines; Viral Vector; Work; Zika Virus; base; cGMP production; cost effectiveness; design; env Gene Products; expectation; falls; flexibility; immunogenicity; lipid nanoparticle; neutralizing antibody; nonhuman primate; novel; novel vaccines; plasmid DNA; preclinical study; programs; research clinical testing; stability testing; vaccine candidate; vaccine platform; vaccine strategy; vector

HIV vaccine candidates entering into clinical testing generally fall into three categories: 1) recombinant envelope (Env) protein immunogens, 2) viral vectors, and 3) plasmid DNA. Numerous vaccine Env designs are being tested in clinical trials. Likewise, numerous HIV vaccine inserts, such as mosaic sequences, have been designed to induce broad, protective T-cell responses. However, to date, no specific vaccine regimen has been able to initiate and expand broadly neutralizing antibody (bnAb) lineages in non-human primates or humans, nor have induced durable antibody responses. Furthermore, the current platforms have multiple challenges; the manufacturing processing for sequential protein vaccines may be complex and time- consuming, viral vectors may have potential pitfalls of anti-vector immunity, and plasmid DNA may have the need for complex delivery systems to enhance immunogenicity. These potential hurdles highlight the need for a next generation vaccine platform that possesses favorable production, safety, and immunogenicity characteristics such as nucleoside-modified messenger (m) RNAs in lipid nanoparticles (LNPs). To execute this project, we will select CDMO partners to manufacture two non-neutralizing antibody(NNAb)-inducing gp120 mRNA immunogens (ADCC Mosaic or WT Env) chosen in overall Aim 1 for use in a Phase I clinical trial that will start at the mid- to end of year 5 of this grant. By leveraging the existing expertise for this novel platform, we will accelerate the timeline for evaluating a vaccine in the clinic. 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 CDMO project leaders and Haynes, Weissman, Maughan and Denny 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. Transfer pre-production knowledge and processes for mRNA immunogens to contract development and manufacturing organizations (CDMOs). • Aim 2. Deliver final drug substances and drug products for toxicology studies and clinical testing. • Aim 3. Develop and deliver regulatory strategies to enable Phase I proof of concept clinical studies.

进入临床试验的HIV候选疫苗一般分为三类：1）重组 包膜（Env）蛋白免疫原，2）病毒载体，和3）质粒DNA。多种疫苗Env设计 正在进行临床试验同样地，许多HIV疫苗插入物，如嵌合序列， 旨在诱导广泛的保护性T细胞反应。然而，到目前为止，没有特定的疫苗方案， 已经能够在非人灵长类动物中启动和扩增广泛中和抗体（bnAb）谱系，或 人类，也没有诱导持久的抗体反应。此外，当前平台具有多个 挑战;连续蛋白质疫苗的制造过程可能是复杂的和耗时的- 消耗性的病毒载体可能具有抗载体免疫的潜在缺陷，而质粒DNA可能具有抗载体免疫的潜在缺陷。 需要复杂的递送系统以增强免疫原性。这些潜在的障碍突出表明， 具有良好生产性、安全性和免疫原性的下一代疫苗平台 脂质纳米颗粒（LNP）中的核苷修饰的信使（m）RNA等特征。 为了执行这个项目，我们将选择CDMO合作伙伴， 在总体目标1中选择抗体（NNAb）诱导gp 120 mRNA免疫原（ADCC Mosaic或WT Env）， 在第一阶段临床试验中使用，该试验将在本补助金的第5年中期至年底开始。通过利用现有的 我们将利用这一新平台的专业知识，加快在临床上评估疫苗的时间轴。范围 这项工作的一部分将通过成功的IND申请将知识转移到选定的CDMO， 候选疫苗CDMO技术管理团队，包括CDMO项目负责人和Haynes， Weissman，Maughan和Denny将被召集起来监督这一过程，并确保成功交付 节目为该项目提出了以下具体目标。 ·目标1。转移mRNA免疫原的生产前知识和流程， 开发和制造组织（CDMO）。 ·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。制定并交付监管策略，以实现I期概念验证临床 问题研究