新型肺炎链球菌全合成糖脂疫苗的设计、合成与免疫生物活性评价

Streptococcus pneumoniae (SP) infections cause severe threat to human health. The pneumococcal vaccines based on capsular polysaccharide and/or glycoprotein conjugates have been played the important roles on prevention and treatment of pneumococcal infection diseases. However, with the insurgence of high drug-resistant pneumococci and the lower efficiency of immune responds for some SP bacteria, the development of safe and efficient pneumococcal vaccines still remain new challenges and difficulties to be solved. The fully synthetic, self-adjuvanting glycoconjugate vaccines with monophosphoryl lipid A (MPLA ) as carrier molecule have been recently received more concerns. This research project aims at developing of novel fully synthetic anti-pneumococcal glycolipid vaccines based on the artificial oligosaccharide antigens of pneumococci type 3 and 23F and MPLA carrier. For this purpose, the structurally well-defined pneumococcal oligosaccharide antigens with different chain lengths will be first chemically synthesized using preactivation-based iterative one-pot and/or highly convergent glycosylation strategies, followed by incorporation with MPLA carrier via a bifunctional activated ester as linker, to furnish the fully synthetic MPLA-pneumococcal oligosaccharide conjugates. Moreover, the immunobiological studies on the these fully synthetic MPLA conjugates will be detailedly investigated by mice immunization, by antiserum titration and binding, by antibody-mediated complement-dependent cytotoxicity, and by the protection of mice against pneumococci infections, so as to find the effective anti-pneumococcal glycolipid vaccines. This research will not only yield novel fully synthetic MPLA conjugates or promising lead compounds worthy further investigations but also provide with the structure-activity relationships (SARs) of pneumococcal oligosaccharides as target antigens to guide further optimization of the anti-pneumococcal vaccine design. The result will have a major impact on antibacterial research.

肺炎链球菌（Streptococcus pneumoniae，SP）感染严重危害着人类的健康。基于SP细胞表面荚膜多糖抗原研制的多糖疫苗和糖蛋白疫苗在预防和治疗SP感染疾病方面发挥了重要作用。然而，随着耐药或多重耐药等高抗药性SP菌的出现，以及某些SP菌存在有效免疫应答率较低等问题，使得SP疫苗研制工作依然面临许多新的挑战和困难亟待解决。本项目结合最新发展的单磷酰类脂A（MPLA）为载体和免疫佐剂的全合成糖脂疫苗策略，以肺炎链球菌血清3和23F型为研究对象，采用MPLA为载体、人工合成的SP荚膜多糖重复片段为抗原，研发新型、高效和具有明确结构的全合成抗SP糖脂疫苗。项目研究方法采用化学法合成系列具有明确结构的各种长度不一的SP寡糖半抗原，通过双活化酯连接臂与MPLA进行缀合，获取制备系列具有确定结构的新型SP寡糖脂复合物，并进行相应免疫生物学和抗菌活性的研究，从而发现新型抗SP糖脂疫苗。