Immunological characterization of the P. vivax DBP

项目总结/摘要 间日疟原虫Duffy结合蛋白配体结构域（DBPII）是一种领先的间日疟原虫疫苗候选物， 这取决于其在致病血液阶段对寄生虫存活的相对重要性。然而，DBPII是 天然弱免疫原性并诱导菌株特异性免疫。我们解决问题的方法 毒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中的功能区域是已证实的保护性免疫目标。在一项概念验证研究中， 我们证明了缺乏显性变异B细胞表位的工程化DBPII免疫原保留了 具有良好的免疫原性，诱导的抑制性抗体（BIAbs）更广泛。DBPII的结果- 工程疫苗是有希望的，下一个关键步骤将是确定诱导 靶向保守中和表位的长寿命抗体和记忆B细胞（MBC）应答。的 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。 这些细胞在对间日疟有保护性免疫力的人体内扩增。我们的假设是人们能够 产生广泛自然获得的DBPII BIAb（精英应答者），建立有效和长期的DBPII- 特异性记忆B细胞（MBC），这可以通过接种疫苗复制。我们将从表型和 功能性表征免疫个体中的B细胞亚群，以优化新型DBPII疫苗的设计 其可以诱导对不同DBPII具有特异性的MBCs细胞。为此，我们将利用巴西 横断面和队列研究，其中确定了DBPII应答者的不同特征，包括 具有应变超越DBPII-BIAB的持续应答者。DBPII预计将成为一个重要的 这是一种多阶段、多价疫苗的组成部分，用于预防间日疟。该提案建立在 巴西和美国合作者之间建立了坚实和成功的合作， 优势寄生虫学，免疫学和结构生物学，以优化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.