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.

项目概要/摘要 我们的团队与其他疫苗开发商合作，一直积极参与结核病 (TB) 的研究 过去三十年在疫苗发现方面取得了巨大成就，并领导了开发 M72 疫苗的团队，该疫苗提供了 有效亚单位结核病疫苗的概念验证。限制 M72 商业部署的障碍包括 功效有限（约 50% 预防疾病）和大规模生产的商品成本。有了这些 考虑到这一点，我们课题组开发了第二代亚单位疫苗ID93，它由四个 蛋白质抗原（M72 有两种）采用合成 TLR4 靶向佐剂配方配制而成，而不是 M72 疫苗中含有的基于天然产物的佐剂。 ID93已进入2期人体临床 试验已取得可喜的结果，目前正在进一步开发中。测量人体免疫反应 针对 ID93 成分的研究具有指导意义，并允许进一步确定抗原优先顺序，目标是 补充M72的抗原。 我们同时开发了一种新的 RNA 疫苗平台 - 目前正在作为 COVID-19 进行临床开发 疫苗可能会于 2021 年夏季在印度获得批准，并且能够诱导有效的细胞免疫，并且可以 以具有成本效益的方式进行扩展。使用精选的抗原组，我们将应用我们的 RNA 技术来诱导 在小鼠和非人类灵长类动物中产生有效的全身和粘膜免疫反应。此外，我们的每一位 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剂 免疫反应增加了一个创新的方面。 在这个提案中，我们的创新来自三个主要重点领域：首先是RNA的优化 使用新的复制子和递送系统的疫苗技术。其次是应用 RNA 疫苗接种 亚基蛋白/佐剂增强，使用已知功效的佐剂（TLR4激动剂）与新型佐剂相比 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——特别是在粘膜免疫领域。第三个领域来自创新 在制造和供应方面：我们拥有用于生产 TBRNA 的新颖工艺，这些工艺已转移到 印度 (Gennova) 和巴西 (CIMATEC)。 Gennova 已经生产了 100 万剂，目标是 100 剂 截至年底，已完成1、2期临床试验。同样，我们已经获得了大量 大规模获得我们的佐剂分子（TLR4、TLR3、RIG-I），全部是合成的，从而避免了知识产权 M72 遇到障碍。