Mechanisms and protective efficacy of nanovaccines against Chlamydia trachomatis

描述（由申请人提供）：沙眼衣原体是一种引起公共卫生关注的性传播细菌，因为它会引起发病率和社会经济负担，如不孕症、异位妊娠和慢性腹痛。尽管经过多年的疫苗开发工作，仍没有针对沙眼衣原体的疫苗，这可能部分源于无效的递送系统或配方，不能增强免疫反应以实现持久的保护性免疫。因此，有必要探索其他可能有效提高疫苗效力的递送系统。可生物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品，因为它们通过向免疫系统提供抗原的可控和持续释放，有效地增强了免疫原性。我们开发了两种新型沙眼衣原体纳米疫苗，分别采用PLGA （Poly D， l -乳酸-羟基乙酸）和PLA-PEG （Poly D， l -乳酸-聚乙二醇）作为重组主要外膜蛋白（rMOMP）和肽衍生物（命名为M278）的递送系统。命名的PLGA-rMOMP和PLA-PEG-M278纳米疫苗具有免疫原性、免疫增强性，并在小鼠体内引发了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；Th1相关保护性免疫反应的T细胞和B细胞介导的效应物，以及免疫相关物是否能对小鼠沙眼衣原体感染提供完全保护性免疫。为实现我们的目标，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在受体介导的识别、细胞摄取、加工和T细胞亚群激活方面的相互作用，以产生Th1保护性免疫反应。在SA2中，我们将用纳米疫苗对小鼠进行免疫，以测量Th1细胞和体液保护性免疫相关物，并评估这些相关物是否可以为小鼠沙眼衣原体感染提供短期和长期保护性免疫。实现这一提议的目标将对沙眼原体疫苗的研究产生积极影响，并改善我们开发抗衣原体疫苗的努力。

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.