Advancing Innovative Next_generation Heterologous Vaccines Against Tuberculosis

项目概要/摘要 纵观现代历史，结核病（TB）比任何其他传染病都要多 迄今为止，结核病仍在肆虐（在过去350年中，估计有超过20亿人感染）， 每天有4,000名患者。仅在2019年，世界卫生组织估计， 100万人死于结核病，800万至900万新诊断的病人。唯一被批准的疫苗，M。 卡介苗（BCG）已取得许多成功，但其保护作用是可变的， 接种BCG疫苗的结核病患者仍然传播M. tb。在整个地球仪， 并且存在疾病，使得每个现有的肺结核患者产生一个新的肺结核病例; 因此，必须重新努力降低结核病发病率。需要新的战略来打击 结核病，包括发现和发展新疫苗以控制病原体分枝杆菌 结核病（M.tb）。牢记这一最终目标，我们响应RFA AI-21-007的号召：创新 结核病疫苗发现（ITVD），在有疫苗的PI之间建立伙伴关系 发展专业知识和使用结核病动物模型的专业知识。我们提出了三种新颖的方法 to advance推进TB结核vaccines疫苗.在R61阶段，我们开发并确定性能最佳的新 候选疫苗具体地，我们（i）将ID 93蛋白抗原与新佐剂组合 旨在最大限度地提高粘膜免疫反应和持久性;（ii）利用新的RNA 该平台用于创建表达ID 93和相关结核分枝杆菌抗原的疫苗，以诱导快速和持久的结核分枝杆菌感染。 免疫力;（iii）优化异源蛋白/RNA引发-加强候选物， 粘膜、体液和细胞抗结核分枝杆菌免疫，并选择最终候选人进入 挑战研究。为了最大限度地提高早期开发，严谨性和可重复性，我们执行 在选定的一组协作杂交（CC）近交系中的免疫原性研究， 代表已知的对结核分枝杆菌感染的不同易感性。在R33阶段，即，M.tb 挑战研究，我们利用多样性远交（DO）小鼠种群的杰出表现， 与人类相同的基因型和表型多样性的代表性，这是结核病的主要障碍 疫苗研发工作至今。我们还将在豚鼠身上测试最终的候选疫苗， 结核疫苗的经典临床前模型，以确保在2种动物模型中取得成功。

PROJECT SUMMARY/ABSTRACT Throughout modern history, tuberculosis (TB) has killed more people than any other infectious disease to date (estimated > 2 billion people over the past 350 years) and TB continues to kill 4,000 patients each day. In 2019 alone, the World Health Organization estimated that ~1.4 million people died of TB and 8-9 million patients were newly diagnosed. The only approved vaccine, M. bovis Bacille Calmette-Guerin (BCG) has had many successes but its protection is variable and BCG-vaccinated TB patients still transmit M.tb. Across the globe, an equilibrium of transmission and disease exists such that one new case of pulmonary TB arises from each existing TB patient; thus, efforts must be reinvigorated to drive TB rates lower. New strategies are needed to combat TB including discovery and advancement of new vaccines to control the pathogen Mycobacterium tuberculosis (M.tb). With that end goal in mind, we answer the call for RFA AI-21-007: Innovation for Tuberculosis Vaccine Discovery (ITVD), forming partnerships between PIs with vaccine development expertise, and expertise using animal models of TB. We propose three novel means to advance TB vaccines. In the R61 phase, we develop and identify the best performing new vaccine candidates. Specifically, we (i) combine the ID93 protein antigen with new adjuvants designed to maximize mucosal immune responses and durability; (ii) capitalize on novel RNA platform to create vaccines expressing ID93 and related M.tb antigens to induce rapid and durable immunity; (iii) optimize heterologous protein/RNA prime-boost candidates for strong and durable mucosal, humoral, and cellular anti-M.tb immunity, and select the final candidates to move into challenge studies. To maximize early-stage development, rigor, and reproducibility, we perform immunogenicity studies in a selected panel of Collaborative Cross (CC) inbred strains, representing known differential susceptibility to M.tb infection. In the R33 phase, i.e., M.tb challenge studies, we exploit the Diversity Outbred (DO) mouse population for its outstanding representation of genotypic and phenotypic diversity equivalent to humans, a major hurdle in TB vaccine development efforts to date. We will also test the final vaccine candidates in guinea pigs, the classic preclinical model for TB vaccines to ensure success in 2 animal models.