Immunogen design to enhance the efficacy of Plasmodium vivax vaccine

项目摘要 间日疟原虫（Plasmodium vivax）是东南亚和拉丁美洲许多地区临床疟疾的主要原因，并在发展中国家造成严重的发病率和经济损失。间日疟原虫主要侵袭年轻的红细胞，并且高度依赖于趋化因子的人达菲抗原受体（DARC）蛋白进行侵袭。缺乏DARC的个体对入侵具有高度抵抗力，而红细胞表面有一半达菲蛋白的个体具有较低的寄生虫血症感染，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结合蛋白区域II（PvDBPII）与DARC结合。PvDBPII的抗体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。的三维结构已经解决了PvDBPII的同系物和关键的结合残基已被确定。该项目将使用合理的基于结构的免疫原修饰与蛋白质多聚化相结合，以增强PvDBPII的免疫原性，从而引发高滴度的功能性抗体，阻断间日疟原虫入侵并促进疫苗效力。

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.