Live nasal recombinant B. pertussis vaccine against tuberculosis

摘要：活的鼻重组B。结核病百日咳疫苗 一种有效的结核病疫苗，可阻断感染并阻断受感染青少年的结核病传播 迫切需要在儿童和成人中接种卡介苗，以补充全球范围内在婴儿中使用的卡介苗。虽然BCG 在预防播散型结核病方面，新的疫苗策略是必要的， 加强对结核病的控制和预防，每年有1000多万人感染结核病。真正的关联 保护性免疫尚未确定。然而，局部的，肺部驻留的记忆T细胞已经被 在许多先前的动物模型研究中，它涉及针对肺形式的TB的保护。此外，委员会认为， 最近的证据表明，IL-17分泌的T细胞在感染者的肺组织中富集， 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，更好地诱导肺中的保护性T细胞。我们的疫苗策略 将推进基于B-Tech的活疫苗平台，B-Tech是一种百日咳博德特氏菌减毒株， 已经完成了2期临床试验，并已证明有能力诱导持久和特异性的 粘膜和全身免疫反应。我们建议开发平台细菌载体（称为 B-Tech-Mtb）用于鼻内接种。B-Tech菌株瞬时定殖于鼻咽粘膜， 动物模型和人类，并诱导粘膜（包括分泌型IgA和常驻记忆T细胞） 和针对百日咳抗原的全身（包括血清抗体和循环T细胞）应答。 此外，B-Tech疫苗是冻干的，在25 ° C下具有> 2年的稳定性，并且可以由大多数人生产。 如果不是所有的发展中国家都以低成本。在鼠类研究中，短暂的定殖诱导了一个居民 记忆性T细胞应答，与抗B相关。百日咳感染的确，短暂的 B在鼻咽粘膜的定植。百日咳导致粘膜树突细胞的靶向， Th17 T细胞应答的诱导，以及与Th17 T细胞应答相关的IL-17的高表达。 在肺中发展强大的分泌型IgA和常驻T细胞记忆。我们建议设计 在我们的实验室中开发的用于表达和分泌几种Mtb的基因修饰的细菌系统 已经作为胃肠外疫苗在临床上测试的杂交抗原。我们将建造并测试B科技 在小鼠和非人灵长类动物模型中鼻内给药后， 选择M。结核抗原连续存在于粘膜诱导部位附近。通过开发B. 分泌一种或多种Mtb抗原的百日咳菌株，我们预期Th1/Th17偏斜的T细胞 应答将比先前用其他粘膜或胃肠外给药的疫苗研究中观察到的更稳健。 接种结核病候选疫苗。如果成功，该计划将使生产增强型结核分枝杆菌- 特异性粘膜免疫应答，包括常驻记忆T细胞应答，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.