RNA Vaccine Innovations for TB: Targeting the Mucosa

结核病 RNA 疫苗创新：针对粘膜

• 批准号: 10442288
• 负责人: STEVEN GREGORY REED
• 金额: $ 55.07万
• 依托单位: HDT BIO CORPORATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-22 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10442288
• 关键词: Address; Adjuvant; Aerosols; Agonist; Alphavirus; Animals; Antigens; Area; Brazil; Businesses; COVID-19 vaccine; Cellular Immunity; Clinical; Clinical Trials; Collaborations; Combined Vaccines; Communicable Diseases; Complement; Cost of Illness; Coupled; Development; Dose; Formulation; Generations; Goals; Human; Immune response; Immunity; Immunization; India; Instruction; Intellectual Property; Intramuscular; Kinetics; Lipids; Lung; Manufactured Supplies; Measures; Mind; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Natural Products; Pathway interactions; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Process; Production; Protein Subunits; Proteins; RNA; RNA vaccination; RNA vaccine; Recombinant Proteins; Regimen; Replicon; Risk; Route; Safety; Signal Transduction; Subunit Vaccines; System; T-Lymphocyte; TLR3 gene; TLR4 gene; Technology; Testing; Tuberculosis; Tuberculosis Vaccines; Vaccines; adaptive immune response; base; clinical development; clinically relevant; cost effective; design; disorder prevention; immunogenicity; improved; in vivo; innovation; large scale production; nanoparticle; nonhuman primate; novel; prevent; response; success; vaccination strategy; vaccine candidate; vaccine delivery; vaccine development; vaccine discovery; vaccine distribution; vaccine platform

PROJECT SUMMARY/ABSTRACT Our team - in collaboration with other vaccine developers - has been actively involved in tuberculosis (TB) vaccine discovery for the past three decades and led the team that developed the M72 vaccine that has provided proof of concept for effective subunit TB vaccines. Obstacles limiting commercial deployment of M72 include limited efficacy (~50% prevention of disease) and cost of goods for large-scale production. With these considerations in mind, our group developed a second-generation subunit vaccine, ID93, which consists of four protein antigens (M72 has two) formulated with a synthetic TLR4 targeted adjuvant formulation, as opposed to the natural product-based adjuvant contained in the M72 vaccine. ID93 has progressed to Phase 2 human clinical trials, with promising results and is currently in further development. Human immune responses measured against the ID93 components have been instructive and have allowed further antigen prioritization with a goal of complementing the antigens of M72. We have concurrently developed a new RNA vaccine platform - now in clinical development as a COVID-19 vaccine which may be approved in India in summer 2021 - and that induced potent cellular immunity and can be scaled in a cost-effective manner. Using a select panel of antigens, we will apply our RNA technology for inducing effective systemic and mucosal immune responses in mice and non-human primates. In addition, each of our RNA based adjuvants, TLR3 and RIG-I agonists, both being effective inducers of both innate and adaptive immune responses adds an innovative aspect. In this proposal, our innovation comes from three main areas of emphasis: First is optimization of the RNA vaccine technology by using new replicons and delivery systems. Second is applying RNA vaccination with subunit protein/adjuvant boosting, using adjuvants of known efficacy (TLR4 agonists) in comparison with novel adjuvants that signal through the TLR-3 or RIG-I pathways. Neither of these have been exploited extensively for infectious disease vaccines - particularly in the area of mucosal immunity. The third area comes from innovation in manufacturing and supply: We have novel processes for the production of TBRNA that were transferred to India (Gennova) and Brazil (CIMATEC). Gennova has already produced 1 million doses, with a target of 100 million by year-end, and has completed Phase 1 and 2 clinical trials in India. Similarly, we have acquired large- scale access to our adjuvant molecules (TLR4, TLR3, RIG-I), all synthetic, thus avoiding the intellectual property roadblock encountered with M72.

项目摘要/摘要 我们的团队与其他疫苗开发人员合作 - 一直积极参与结核病（TB） 在过去的三十年中，发现疫苗的发现，并领导了开发已提供M72疫苗的团队 有效亚基结核病疫苗的概念证明。限制M72商业部署的障碍包括 有限的疗效（预防疾病的预防）和大规模生产的商品成本。与这些 考虑到这一点，我们的小组开发了第二代亚基疫苗ID93，由四个组成 蛋白质抗原（M72具有两种），用合成TLR4靶向辅助配方制成 M72疫苗中含有基于天然产品的佐剂。 ID93已发展为第2阶段人类临床 试验，结果令人鼓舞，目前正在进一步发展中。人类免疫反应测量 反对ID93组件具有启发性，并允许进一步的抗原优先级，目的是 补充M72的抗原。 我们同时开发了一个新的RNA疫苗平台 - 现在作为Covid -19的临床开发 2021年夏季可能在印度批准的疫苗 - 诱导有效的细胞免疫力，可以是 以具有成本效益的方式缩放。使用精选的抗原面板，我们将应用RNA技术诱导 小鼠和非人类灵长类动物中有效的全身和粘膜免疫反应。此外，我们每个 基于RNA的佐剂TLR3和RIG-I激动剂，都是先天性和适应性的有效诱导者 免疫反应增加了一个创新的方面。 在该提议中，我们的创新来自重点的三个主要领域：首先是RNA的优化 疫苗技术通过使用新的复制子和输送系统。第二是使用RNA疫苗接种 与新型相比 通过TLR-3或RIG-I途径发出信号的佐剂。这些都没有被广泛利用 传染病疫苗 - 尤其是在粘膜免疫区域。第三个领域来自创新 在制造和供应中：我们有用于生产TBRNA的新过程，这些过程已转移到 印度（Gennova）和巴西（Cimatec）。 Gennova已经产生了100万剂，目标为100 到年底时数百万，并在印度完成了第1阶段和2阶段的临床试验。同样，我们获得了大型 比例访问我们的辅助分子（TLR4，TLR3，RIG-I），所有合成，因此避免了知识产权 M72遇到了障碍。