Immunogen design to enhance the efficacy of Plasmodium vivax vaccine

项目摘要 间日疟原虫是东南亚和拉丁美洲许多地区临床疟疾的主要原因，在发展中国家造成巨大的发病率和经济损失。间日疟原虫主要侵袭年轻的红细胞，并高度依赖人类Duffy抗原趋化因子受体(DARC)蛋白的侵袭。缺乏DARC的个体对入侵具有很高的抵抗力，那些红细胞表面Duffy蛋白含量只有一半的人寄生虫血症感染较低，这表明这种相互作用可能对疫苗干预非常敏感。间日疟原虫通过Duffy结合蛋白II区(PvDBPII)与DARC结合。PvDBPII抗体可抑制寄生虫入侵，并与保护性免疫相关，但疫苗开发的主要障碍是产生可预防疾病的高滴度功能性抗体。对PvDBPII的同系物的三维结构进行了求解，并确定了关键的结合残基。本项目将使用合理的基于结构的免疫原修饰和蛋白质多聚体相结合的方法来增强PvDBPII的免疫原性，以诱导出高滴度的功能性抗体来阻止间日疟原虫的入侵，从而提高疫苗的效力。

Project Summary Plasmodium vivax is a major cause of clinical malaria in many parts of Southeast Asia and Latin America and causes substantial morbidity and economic loss in the developing world. P. vivax mainly invades young red blood cells and is highly dependent on the human Duffy antigen receptor for chemokines (DARC) protein for invasion. Individuals lacking DARC are highly resistant to invasion, and those having half the amount of Duffy protein on the erythrocyte surface have lower parasitemia infections, indicating this interaction may be very sensitive to vaccine interventions. P. vivax binds to DARC through the Duffy binding protein region II (PvDBPII). Antibodies to PvDBPII inhibit parasite invasion and are correlated with protective immunity, but the main obstacle to vaccine development is generating high titer functional antibodies that will prevent disease. The three dimensional structure has been solved for a homolog of PvDBPII and critical binding residues have been identified. This project will use rational structure-based immunogen modifications in combination with protein multimerization to enhance the immunogenicity of PvDBPII to elicit high titer functional antibodies that block P. vivax invasion and facilitate vaccine efficacy.