Advancing Innovative Next_generation Heterologous Vaccines Against Tuberculosis

项目摘要/摘要 纵观现代历史，结核病导致的死亡人数比其他任何传染病都要多。 到目前为止，疾病(在过去350年里估计有20亿人)和结核病继续导致死亡。 每天有4000名病人。仅在2019年，世界卫生组织估计约有140万人 人们死于结核病，新诊断出800万至900万患者。唯一被批准的疫苗是M。 卡介苗(Bovis Bacille Calmette-Guerin，BCG)已经取得了许多成功，但其保护措施是多种多样的 接种卡介苗的结核病患者仍然传播结核分枝杆菌。在全球范围内，传播的均衡 疾病的存在使得每一个现有的结核病患者都会出现一个新的肺结核病病例； 因此，必须重振努力，以降低结核病发病率。需要新的战略来打击 结核病，包括控制病原体分枝杆菌的新疫苗的发现和进展 结核病(结核分枝杆菌)。考虑到这一最终目标，我们响应RFA AI-21-007的号召：创新 针对结核病疫苗发现(ITVD)，在PI与疫苗之间建立合作伙伴关系 开发专业知识，以及利用结核病动物模型的专业知识。我们提出了三种新的方法 以推动结核病疫苗的发展。在R61阶段，我们开发并确定性能最好的新 候选疫苗。具体地说，我们(I)将ID93蛋白抗原与新的佐剂结合 旨在最大限度地提高粘膜免疫反应和耐久性；(Ii)利用新型RNA 创造表达ID93和相关结核分枝杆菌抗原的疫苗平台，以诱导快速和持久的 免疫力；(Iii)优化异源蛋白质/RNA初级增强候选，强健耐用 黏膜、体液和细胞抗结核分枝杆菌免疫，并选择最终候选进入 挑战研究。为了最大限度地提高早期开发、严格性和可重复性，我们执行 在选定的合作杂交(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，我们利用多样性近交系(DO)小鼠种群的突出表现 表示等同于人类的基因和表型多样性，这是结核病的一个主要障碍 迄今为止，疫苗开发工作取得了进展。我们还将在豚鼠身上测试最终的候选疫苗， 结核病疫苗的经典临床前模型确保在2个动物模型中成功。

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.