Immunological characterization of the P. vivax DBP

项目摘要/摘要 间日疟原虫Duffy结合蛋白配基结构域(DBPII)是一种领先的间日疟疫苗候选疫苗 在致病的血液阶段对寄生虫存活的相对重要性。然而，DBPII是 天然的弱免疫原性，并诱导菌株特异性免疫。我们解决问题的方法 菌株免疫是设计一种疫苗，将抗体反应集中在保守的B细胞表位上 DBPII内被证实为保护性免疫目标的功能区。在一项概念验证研究中， 我们证明了缺乏优势变异B细胞表位的工程化DBPII免疫原仍然存在 免疫原性好，可诱导更广泛的抑制性抗体(BIAbs)。DBPII的结果是- 工程疫苗前景看好，下一个关键步骤将是确定诱导 针对保守中和表位的长寿抗体和记忆B细胞(MBCs)反应。这个 该计划的总体目标是设计一种疫苗接种策略，以诱导不同的B-亚群。 在对间日疟具有保护性免疫力的人体内扩增的细胞。我们的假设是人们能够 生产广泛天然获得的DBPII BIAbs(精英响应者)安装有效和长期的DBPII- 特异性记忆B细胞(MBCs)，这可以通过接种疫苗来复制。我们将在表型上和 对免疫个体的B细胞亚群进行功能表征，以优化新型DBPII疫苗的设计 可以诱导出具有不同DBPII特异性的MBCs细胞。为此，我们将利用巴西人的优势 横断面和队列研究，其中确定了DBPII应答者的不同特征，包括 具有超越压力的DBPII-BIAB的持久应答者。预计DBPII将是一个重要的 多阶段、多价疫苗的组成部分，用于预防间日疟。这项提议建立在一个 巴西和美国的合作者之间建立了坚实和成功的合作关系，结合 加强寄生虫学、免疫学和结构生物学，优化DBPII作为有效的疫苗 间日疟。

Project Summary/Abstract Plasmodium vivax Duffy binding protein ligand domain (DBPII) is a leading vivax vaccine candidate based upon its relative importance for parasite survival during the disease-causing blood stage. However, DBPII is naturally weakly immunogenic and induces strain-specific immunity. Our approach to solve the problem strain immunity is to design a vaccine that focuses antibody responses onto conserved B-cell epitopes in functional regions within DBPII that are proven targets of protective immunity. In a proof-of-concept study, we demonstrated that an engineered DBPII immunogen lacking the dominant variant B-cell epitope retained good immunogenicity and induced more broadly inhibitory antibodies (BIAbs). The results for the DBPII- engineered vaccine is promising and the next critical step will be to determine the requirements to induce long-lived antibody and memory B-cell (MBCs) responses targeting conserved neutralizing epitopes. The overall goal of this program is to design a vaccination strategy to induce the distinct subpopulations of B- cells that are expanded in people with protective immunity to vivax malaria. Our hypothesis is people able to produce broadly naturally acquired DBPII BIAbs (elite responders) mount an efficient and long-term DBPII- specific memory B-cells (MBCs) and this can be replicated by vaccination. We will phenotypically and functionally characterize B cell sub-sets in immune individuals, to optimize the design of new DBPII vaccine that can induce MBCs cells with specificity for different DBPII. For that, we will take advantage of Brazilian cross-sectional and cohort studies, where different profiles of DBPII responders were identified, including persistent responders with strain-transcending DBPII-BIABs. DBPII is expected to be an important component of a multi-stage, multi-valent vaccine to protect against vivax malaria. The proposal builds on a solid and successful collaboration established between the Brazilian and US collaborators, combining strengths parasitology, immunology, and structural biology to optimize DBPII as an effective vaccine against vivax malaria.