Mechanisms and protective efficacy of nanovaccines against Chlamydia trachomatis

描述(申请人提供)：沙眼衣原体是一种引起公共卫生问题的性传播细菌，因为它会导致不孕不育、宫外孕和慢性腹痛等发病率和社会经济负担。尽管进行了多年的疫苗开发工作，但仍没有针对沙眼衣原体的疫苗，这可能在一定程度上源于无效的递送系统或配方，这些制剂不能增强免疫反应，实现持久的保护性免疫。因此，有必要探索其他可以有效提高疫苗效力的递送系统。生物可降解纳米颗粒作为佐剂和递送系统提供了有吸引力的替代方案，因为它们通过向免疫系统提供受控和持续的抗原释放而有效地增强了免疫原性。我们研制了两种新型沙眼衣原体纳米疫苗，分别以PLGA(聚D，L-乳酸-乙醇酸)和聚乙二醇(聚D，L-乳酸-聚乙二醇)作为其重组主要外膜蛋白(RMOMP)和多肽衍生物(命名为M278)的载体。命名为PLGA-rMOMP和PLA-PEG-M278的纳米疫苗具有免疫原性、免疫增强作用，并能在小鼠体内触发与沙眼衣原体相关的Th1保护性免疫反应。我们的目标是研究纳米疫苗与抗原提呈细胞相互作用激活T细胞的分子机制、T细胞和B细胞介导的Th1相关保护性免疫反应的效应物，以及免疫相关性是否能对小鼠沙眼衣原体感染提供完全的保护性免疫。为了实现我们的目标，我们提出了两个具体目标。在SA1中，我们将评估纳米疫苗与抗原提呈细胞之间的相互作用，以实现受体介导的识别、细胞摄取、加工和T细胞亚群的激活，以产生Th1保护性免疫反应。在SA2中，我们将用纳米疫苗免疫小鼠，以测量Th1细胞和体液保护性免疫相关性，并评估这些相关性是否可以提供对小鼠沙眼衣原体感染的短期和长期保护性免疫。实现这一提议的目标将对沙眼衣原体疫苗研究产生积极影响，并改善我们在开发抗衣原体疫苗方面的努力。

DESCRIPTION (provided by applicant): Chlamydia trachomatis is a sexually transmitted bacterium of public health concerns because it causes morbidity and socioeconomic burdens, such as infertility, ectopic pregnancy and chronic abdominal pain. Despite many years of vaccine development efforts, there is no vaccine against C. trachomatis, which probably stems in part from ineffective delivery systems or formulations that do not bolster immune responses to achieve long-lasting protective immunity. Therefore it is essential to explore other delivery systems that may effectively enhance the vaccine efficacy. Biodegradable nanoparticles offer attractive alternatives as adjuvants and delivery systems because they effectively enhance immunogenicity by providing controlled and sustained release of antigens to the immune system. We have developed two novel C. trachomatis nanovaccines employing PLGA (Poly D, L-lactic-co-glycolic acid) and PLA-PEG (Poly D, L-lactic acid-Polyethylene glycol), respectively as delivery systems for its recombinant major outer membrane protein (rMOMP) and peptide derivative (named M278). The named PLGA-rMOMP and PLA-PEG-M278 nanovaccines were immunogenic, immune-potentiating, and triggered profound C. trachomatis correlative Th1 protective immune responses in mice. Our goals are to investigate the molecular mechanisms by which nanovaccines interact with antigen presenting cells for T cell activation; the T and B cell-mediated effectors of the Th1 correlative protective immune responses, and whether the immune correlates can provide complete protective immunity against C. trachomatis infection in mice. Two specific aims are proposed to accomplish our goals. In SA1 we will assess the interaction of nanovaccines with antigen presenting cells for receptor-mediated recognition, cellular uptake, processing, and T cell subsets activation to produce Th1 protective immune responses. In SA2, we will immunize mice with nanovaccines to measure Th1 cellular and humoral protective immune correlates and evaluate whether these correlates can provide short- and long-term protective immunity against C. trachomatis infection in mice. Achieving this proposal's goals would positively impact C. trachomatis vaccine research and improve our efforts toward developing an anti-Chlamydia vaccine.