Live nasal recombinant B. pertussis vaccine against tuberculosis

摘要：结核重组百日咳活疫苗鼻腔接种 一种有效的结核病疫苗，可阻止感染并阻断受感染青少年的结核病传播 成人迫切需要作为对全球婴儿使用卡介苗的补充。尽管卡介苗是 在预防传播形式的结核病方面适度有效，新的疫苗战略是必要的 改善结核病的控制和预防，结核病每年感染1000多万人。真正的关联性 保护性免疫尚未确定。然而，局部的、驻留在肺中的记忆T细胞 在许多先前的动物模型研究中被认为与预防肺型结核病有关。此外， 最近的证据表明，IL-17分泌的T细胞在感染人的肺组织中丰富 可能与肺部感染的免疫控制有关。需要新的疫苗策略 可以诱导粘膜反应，更好地诱导肺内保护性T细胞。我们的疫苗战略 将推出基于B-Tech的活疫苗平台，B-Tech是百日咳杆菌的减毒株，它 已完成第二阶段临床试验，并已证明有能力诱导持久和特异的 粘膜和全身免疫反应。我们计划开发平台细菌载体(称为 B-Tech-Mtb)用于鼻腔接种。B-Tech菌株在鼻咽粘膜中的瞬时定植 动物模型与人和诱导粘膜(包括分泌型IgA和常驻记忆性T细胞) 以及针对百日咳抗原的全身(包括血清抗体和循环T细胞)反应。 此外，B-Tech疫苗是冷冻干燥的，在25摄氏度下具有2年的稳定性，可以由大多数人生产 即使不是所有发展中国家，也是低成本的。在小鼠研究中，短暂的殖民诱导了一种常驻 记忆T细胞反应，与预防百日咳杆菌感染有关。事实上，这是短暂的 百日咳杆菌在鼻咽粘膜的定植导致粘膜树突状细胞的靶向， Th17T细胞反应的诱导和IL-17的高表达与 肺中强大的分泌型免疫球蛋白A和常驻T细胞记忆的发展。我们建议设计一款 我们实验室开发的用于表达和分泌几种结核分枝杆菌的转基因细菌系统 已被临床测试为非肠道疫苗的混合抗原。我们将建造和测试B-Tech- 在小鼠和非人灵长类动物模型上鼻腔给药后的MTB候选疫苗，分泌 在粘膜诱导部位附近连续筛选结核分枝杆菌抗原。通过发展B. 百日咳菌株分泌一种或多种Mtb抗原，我们推测Th1/Th17扭曲T细胞 与之前的其他黏膜或肠外疫苗研究中观察到的反应相比，反应将更加强劲 给候选结核病疫苗接种。如果成功，该计划将使增强型结核分枝杆菌- 特异性粘膜免疫反应，包括常驻记忆T细胞反应，导致保护 结核病挑战模型。

ABSTRACT: Live nasal recombinant B. pertussis vaccine against tuberculosis An effective TB vaccine that blocks infection and interrupts transmission of TB from infected adolescents and adults is urgently needed as a complement to the worldwide use of BCG in infants. Although BCG is moderately effective in preventing disseminated forms of TB, new vaccine strategies are necessary for improved control and prevention of TB which infects over 10 million people annually. True correlates of protective immunity have not been identified. However, local, lung-resident memory T cells have been implicated in protection against pulmonary forms of TB in many prior animal model studies. Furthermore, recent evidence shows that IL-17 secreting T cells that are enriched in the lung tissue of infected humans are likely involved with immunological control of pulmonary infections. New vaccine strategies are needed that can induce mucosal response and better induce protective T cells in the lungs. Our vaccine strategy will advance a live vaccine platform based on B-Tech, an attenuated strain of Bordetella pertussis, which has already completed Phase 2 clinical trials and has demonstrated ability to induce durable and specific mucosal and systemic immune responses. We propose to develop the platform bacterial vector (called B-Tech-Mtb) for intranasal vaccination. B-Tech strains transiently colonize the nasopharyngeal mucosa in animal models and humans and induce mucosal (including secretory IgA and resident memory T cells) and systemic (including serum antibodies and circulating T cells) responses against pertussis antigens. In addition, B-Tech vaccines are lyophilized, have >2-year stability at 25°C, and can be produced by most if not all developing countries at low cost. In murine studies, transient colonization induces a resident memory T cell response that is associated with protection against B. pertussis infection. Indeed, transient colonization of the nasopharyngeal mucosa by B. pertussis results in targeting of mucosal dendritic cells, the induction of Th17 T cell responses, and high expression of IL-17 that is associated with the development of robust secretory IgA and resident T cell memory in the lungs. We propose to engineer genetically modified bacterial systems developed in our labs for expression and secretion of several Mtb hybrid antigens that have been tested clinically as parenteral vaccines. We will construct and test B-Tech- Mtb vaccine candidates after intranasal administration in mice and non-human primate models, secreting selected M. tuberculosis antigens continuously in the vicinity of mucosal inductive sites. By developing B. pertussis strains secreting one or more Mtb antigens, we anticipate that Th1/Th17 skewed T cell responses will be more robust than observed in prior vaccine studies with other mucosally or parenterally administered TB vaccine candidates. With success, this program will enable production of enhanced Mtb- specific mucosal immune responses, including resident memory T cell responses, leading to protection in TB challenge models.