RNA Vaccine Innovations for TB: Targeting the Mucosa

项目摘要/摘要 我们的团队与其他疫苗研发人员合作，积极参与了结核病(TB)的研究 在过去的三十年里发现了疫苗，并领导了开发M72疫苗的团队，提供了 有效亚单位结核病疫苗的概念验证。限制M72商业化部署的障碍包括 有限的疗效(约50%的疾病预防)和大规模生产的商品成本。有了这些 考虑到这一点，我们团队开发了第二代亚单位疫苗ID93，它由四个部分组成 蛋白质抗原(M72有两个)是用合成的TLR4靶向佐剂配方配制的，而不是 M72疫苗中所含的天然产品佐剂。ID93已进展到人类临床第二阶段 试验结果令人振奋，目前正在进一步开发中。测量的人体免疫反应 针对ID93的组件一直具有启发性，并允许进一步确定抗原优先顺序，目标是 补充M72的抗原。 我们同时开发了一个新的RNA疫苗平台--新冠肺炎，目前正在进行临床开发 可能于2021年夏天在印度获得批准的疫苗--它可以诱导强大的细胞免疫，可以 以具有成本效益的方式进行扩展。使用一组精选的抗原，我们将应用我们的RNA技术来诱导 小鼠和非人类灵长类动物的有效系统和粘膜免疫反应。此外，我们的每个人 基于RNA的佐剂，TLR3和RIG-I激动剂，都是天然和适应性的有效诱导剂 免疫反应增加了一个创新的方面。 在这个方案中，我们的创新主要来自三个方面：一是RNA的优化 通过使用新的复制物和递送系统来开发疫苗技术。第二种是应用RNA疫苗接种 亚基蛋白/佐剂增强，使用已知疗效的佐剂(TLR4激动剂)与新的 通过TLR-3或RIG-I通路发出信号的佐剂。这两个方面都没有被广泛开发用于 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：我们拥有生产TBRNA的新工艺，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 到年底，已经完成了印度的1期和2期临床试验。同样，我们也收购了大型- 大规模获取我们的佐剂分子(TLR4、TLR3、RIG-I)，全部是合成的，从而避免了知识产权 在M72公路上遇到路障。

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.