A Neonatal Monkey Model for Tuberculosis Vaccination

摘要 由结核分枝杆菌(MTB)引起的结核病是导致死亡的主要原因 今天，全球有200多万人死于感染。卡介苗来源于 牛分枝杆菌是唯一被批准的人类疫苗，尽管它对 儿童和成人肺结核。由于卡介苗缺乏某些野生型结核分枝杆菌的基因，因此许多 重组卡介苗疫苗株已被制备，并在动物模型中进行了评估。基于 人新生儿在类Toll刺激下对疫苗抗原反应增强的观察 受体(TLR)佐剂，我们构建了一种新型重组卡介苗，它表达一种 刺激TLR-2的多肽(TLR-BCG)。这种疫苗比野生型卡介苗对小鼠的保护作用更好 疫苗。我们还开发了一种新的新生猴子模型来评估疫苗的效果 肺结核。该项目将验证这样的假设，即TLR-BCG疫苗将更有效 在产生更强和更持久的免疫反应方面优于野生型卡介苗 卫生保健计划中的结核病。特异性目标-1A：我们将评估野生动物诱导的TH1免疫反应 新生猴模型分型卡介苗和重组TLR-卡介苗。我们将确定TLR-BCG是否 在NHP中诱导与自然的不同的初级T细胞免疫反应 结核分枝杆菌感染及相关疫苗对气溶胶诱导的保护作用 卫生保健计划中的结核病。具体目标-2：我们将评估TLR-BCG疫苗的长期疗效 在新生猴子模型中使用主要的增强策略。这些研究很可能导致 生产更好的结核病初级疫苗和更有效的更好的加强疫苗 对于已经接种了wt-BCG的儿童。

ABSTRACT Tuberculosis due to Mycobacterium tuberculosis (MTB) is the leading cause of mortality due to infections today with more than 2 million deaths worldwide. BCG vaccine derived from Mycobacterium bovis is the only approved human vaccine although, it has a partial efficacy against childhood and adult tuberculosis. Since BCG lacks certain genes of wild type M. tuberculosis many recombinant BCG vaccine strains have been prepared and evaluated in animal models. Based on the observation that human neonates respond better to vaccine antigens when stimulated with Toll-like receptor (TLR) adjuvants, we constructed a novel recombinant BCG vaccine that expresses a peptide stimulating TLR-2 (TLR-BCG). This vaccine protected mice better than wild type BCG vaccine. We also developed a novel neonatal monkey model to evaluate vaccine effects against tuberculosis. This project will verify the hypothesis that, TLR-BCG vaccine will be more efficient than wild type BCG vaccine in generating stronger and longer lasting immune responses against tuberculosis in NHPs. Specific Aim-1A: We will evaluate TH1 immune responses induced by wild type BCG and recombinant TLR-BCG in the neonatal monkey model. We will determine if TLR-BCG induces qualitatively different primary T cell immune responses in NHPs compared with a natural infection with M. tuberculosis and correlate vaccine-induced protection against aerosol induced tuberculosis in NHPs. Specific Aim -2: We will evaluate long-term efficacy of TLR-BCG vaccines using a prime boost strategy with the neonatal monkey model. These studies are likely to lead to generate a better primary vaccine against tuberculosis, and a more efficient better booster vaccine for children already vaccinated with wt-BCG.