RNA Vaccine Innovations for TB: Targeting the Mucosa

结核病 RNA 疫苗创新：针对粘膜

• 批准号: 10612954
• 负责人: STEVEN GREGORY REED
• 金额: $ 53.81万
• 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/10612954
• 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; Coupled; Development; Dose; Formulation; Generations; Goals; Human; Immune response; Immunity; Immunization; India; Innate Immune Response; Intellectual Property; Intramuscular; Kinetics; Lipids; Lung; 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 replication; 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; clinical development; clinically relevant; cost; cost effective; design; disorder prevention; immunogenicity; improved; in vivo; innovation; large scale production; manufacture; 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.

项目总结/摘要 我们的团队与其他疫苗开发人员合作，积极参与结核病（TB） 在过去的三十年里，他一直致力于疫苗的发现，并领导了开发M72疫苗的团队， 有效亚单位结核疫苗的概念验证。限制M72商业部署的障碍包括 有限的功效（~50%的疾病预防）和大规模生产的商品成本。与这些 考虑到这些因素，我们的研究小组开发了第二代亚单位疫苗ID 93，它由四个亚单位组成。 蛋白抗原（M72有两种）与合成的靶向TLR 4的佐剂制剂一起配制，而不是 M72疫苗中含有的天然产物佐剂。ID 93已进展至2期人类临床 试验，取得了可喜的成果，目前正在进一步发展。测量的人体免疫反应 针对ID 93组分的抗原优先化已经是有益的，并且已经允许进一步的抗原优先化， 与M72的抗原互补。 我们同时开发了一种新的RNA疫苗平台，目前正处于COVID-19的临床开发阶段。 该疫苗可能于2021年夏季在印度获得批准，该疫苗可诱导有效的细胞免疫， 以具有成本效益的方式扩展。使用一组选定的抗原，我们将应用我们的RNA技术诱导 在小鼠和非人灵长类动物中有效的全身和粘膜免疫应答。此外，我们的每一个 基于RNA的佐剂、TLR 3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，我们的创新主要来自三个重点领域：首先是RNA的优化 通过使用新的复制子和传递系统的疫苗技术。第二种是应用RNA疫苗， 亚基蛋白/佐剂加强，使用已知功效的佐剂（TLR 4激动剂）与新的免疫增强剂相比， 通过TLR-3或RIG-I途径传递信号的佐剂。这两种方法都没有被广泛利用， 传染病疫苗-特别是在粘膜免疫领域。第三个领域来自创新 在生产和供应方面：我们有新的TBRNA生产工艺， 印度（Gennova）和巴西（CIMATEC）。Gennova已经生产了100万剂，目标是100 到今年年底，该公司已在印度完成了1期和2期临床试验。同样，我们也收购了大量的- 我们的佐剂分子（TLR 4，TLR 3，RIG-I），所有合成的，从而避免了知识产权 M72遭遇路障