A Neonatal Monkey Model of Tuberculosis Vaccination

摘要 由结核分枝杆菌（MTB）引起的结核病是由于以下原因导致死亡的主要原因： 目前，全世界有超过200万人死亡。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 儿童和成人结核病。由于BCG缺乏野生型M.结核病很多 已经制备了重组BCG疫苗株并在动物模型中进行了评价。基于 观察到当用Toll样刺激时，人类新生儿对疫苗抗原的应答更好 受体（TLR）佐剂，我们构建了一种新的重组BCG疫苗， 肽刺激TLR-2（TLR-BCG）。这种疫苗比野生型BCG更能保护小鼠 疫苗我们还开发了一种新的新生猴模型，以评估疫苗对 结核本项目将验证TLR-BCG疫苗更有效的假设 与野生型BCG疫苗相比， NHP中的结核病。具体目标-1A：我们将评估野生型抗病毒药物诱导的TH 1免疫应答。 型BCG和重组TLR-BCG在新生猴模型中的作用。我们将确定TLR-BCG 与自然免疫相比， 杆菌感染结核病和相关疫苗诱导的对气溶胶诱导的 NHP中的结核病。具体目标-2：我们将评估TLR-BCG疫苗的长期有效性 使用新生猴模型的初免加强策略。这些研究可能会导致 生产出更好的结核病初级疫苗和更有效的加强疫苗 对于已经接种过卡介苗的儿童。

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.