Immunogen Design to enhance the efficacy of Plasmodium vivax vaccine

描述（由申请人提供）：间日疟原虫是非洲以外临床疟疾的主要原因，在发展中国家造成严重的发病率和经济损失。 间日疟原虫为侵入阻断疫苗方法提供了独特的机会，因为寄生虫对网织红细胞具有高度选择性，并且依赖于人DARC蛋白进行侵入。这种选择性将间日疟原虫与恶性疟原虫区分开来，并为开发侵袭阻断疫苗提供了相当大的优势。间日疟原虫通过间日疟原虫Duffy结合蛋白（PvDBPII）中的区域II与DARC结合。PvDBPII的抗体抑制寄生虫入侵，但疫苗开发的主要障碍是产生预防疾病的高滴度功能性抗体。在这个项目中，我们将确定PvDBPII免疫原性是否可以通过与HepB核心抗原颗粒缀合来增强，并研究是否可以通过将重组蛋白定向为具有暴露的预测DARC相互作用位点并覆盖脱靶多态性表位来进一步集中抗体应答。 公共卫生相关性：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。该项目的目标是使用合理的免疫原设计，通过将PvDBPII重组蛋白缀合在病毒样颗粒（VLP）上并使蛋白定向以使抗体与预测的DARC相互作用位点的反应性最大化来增强间日疟原虫疫苗的效力。

DESCRIPTION (provided by applicant): Plasmodium vivax is a major cause of clinical malaria outside of Africa and causes substantial morbidity and economic loss in the developing world. P. vivax presents unique opportunities for invasion blocking vaccine approaches because the parasite is highly selective for reticulocytes and depends on the human DARC protein for invasion. This selectivity differentiates P. vivax from P. falciparum, and provides considerable advantages for development of invasion blocking vaccines. P. vivax binds to DARC via the region II in the P. vivax Duffy binding protein (PvDBPII). Antibodies to PvDBPII inhibit parasite invasion, but the main obstacle to vaccine development is generating high titer functional antibodies that will prevent disease. In this project, we will determine if PvDBPII immunogenicity can be enhanced by conjugating to HepB core antigen particles and investigate whether the antibody response can be further focused by orienting the recombinant protein with the predicted DARC interaction site exposed and covering up off-target polymorphic epitopes. PUBLIC HEALTH RELEVANCE: 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. The goal of this project is to use rational immunogen design to enhance the efficacy of a P. vivax vaccine by conjugating PvDBPII recombinant protein on virus-like particles (VLP) and orienting the protein so as to maximize antibody reactivity to the predicted DARC interaction site.