A dual function TB subunit vaccine designed for non-interference with BCG and post-exposure activity

摘要 尽管广泛使用，但唯一获得许可的结核病（TB）疫苗可用于人类使用，M。牛杆菌 卡介苗（BCG）未能阻止结核病成为全球卫生紧急情况。实现 为了实现世卫组织终止结核病规划的2030年目标，需要制定新的结核病疫苗战略。为了达到最佳效果， 战略将需要在结核病初治婴儿接种疫苗后提高疗效， 在M.结核病流行地区暴露于结核病（Mtb）的青少年/成人。进展 我们对结核病免疫学和疫苗学的了解，使我们能够为这种双重疾病设计更有针对性的疫苗。 功能基于特异性抗原选择和佐剂给药，我们开发了一种新的单 疫苗具有双重用途，作为与BCG一起用于初治个体的联合疫苗，以及作为单独疫苗用于 以前接触/感染的人。设计的杂交蛋白亚单位疫苗（ESX1-Vax）由以下组成： 特别是BCG中缺失的分泌型ESX-1相关抗原，包括靶向 独特的保护，防止再生长的预先存在的感染。杂交蛋白与CAF01一起递送 在促进具有确定的TB保护性表型和功能的T细胞应答中高度有效的佐剂。 ESX1-Vax/CAF01与BCG的共同施用不妨碍BCG作用。相反，它协同作用， 以ESX-1毒力因子为靶点的诱导分化抗性T细胞的卡介苗免疫 抗原作为一种非复制型亚单位疫苗，ESX1-Vax也很容易加强。此外，行政 ESX1-Vax/CAF01在暴露后环境中对细菌再生长非常有效。在这一提议中， 我们的目标是通过分子修饰来优化这种ESX1-Vax的免疫原性和功效， 最大化针对ESAT-6表位的T细胞应答。我们将比较改良结构的功效 BCG联合疫苗接种后以及标准和新建立的暴露后疫苗接种后的免疫原性 模型来选择最佳ESX1-Vax结构。然后将开发选定的结构用于生产 作为最终GMP生产的ESX1/CAF01产品，验证疫苗活性并评估毒理学。的 因此，该产品开发的总体结果是一种独特设计的单一可加强疫苗， 在未感染的新生儿和结核分枝杆菌感染后分娩时， 暴露在潜伏感染的个人，这是准备进展到临床试验。

ABSTRACT Despite widespread use, the only licensed tuberculosis (TB) vaccine available for human use, M. bovis Bacille Calmette-Guerin (BCG), has not been able to prevent TB from becoming a global health emergency. To achieve the 2030 targets of the WHO End TB Program, a new TB vaccine strategy is needed. For optimal effect, such a strategy will need to offer both improved efficacy following vaccination of TB-naïve infants, as well as vaccine efficacy in the population of M. tuberculosis (Mtb)-exposed adolescents/adults in endemic regions. Advances in our understanding of TB immunology and vaccinology allow for a more tailored vaccine designed for this dual function. Based on specific antigen selection and adjuvanted administration, we have developed a novel single vaccine with dual use as a co-vaccine alongside BCG for naïve individuals and as a standalone vaccine for previously exposed/infected individuals. This designed hybrid protein subunit vaccine (ESX1-Vax) is composed specifically of secreted ESX-1 related antigens that are missing from BCG, including ESAT-6 whose targeting is uniquely protective against re-growth of pre-existing infection. The hybrid protein is delivered with the CAF01 adjuvant that is highly effective in promoting T cell responses with defined TB-protective phenotype and function. Co-administration of ESX1-Vax/CAF01 with BCG does not hinder BCG effects. Instead, it acts synergistically to complement BCG vaccination by priming differentiation-resistant T cells targeting ESX-1 virulence factor antigens. As a non-replicative subunit vaccine, ESX1-Vax is also readily boostable. Furthermore, administration of ESX1-Vax/CAF01 in a post-exposure setting is highly efficacious against bacterial re-growth. In this proposal, we aim to optimize the immunogencity and efficacy of this ESX1-Vax through molecular modifications to maximize the T cell response against ESAT-6 epitopes. We will compare the modified constructs for efficacy and immunogenicity after BCG co-vaccination and in standard and newly-established post-exposure vaccination models to select the optimal ESX1-Vax construct. The selected construct will then be developed for production as a final GMP-produced ESX1/CAF01 product, verified for vaccine activity and assessed for toxicology. The overall outcome of this product development is, thus, a single boostable vaccine that is uniquely designed to work both together with BCG prophylactically in non-infected neonates, as well as when delivered post Mtb exposure in latently infected individuals, and that is ready for progress to clinical trials.