Exploiting cross-reactive, conserved epitopes in Plasmodium vivax to develop a vaccine against falciparum placental malaria.

利用间日疟原虫中的交叉反应性保守表位开发针对恶性胎盘疟疾的疫苗。

• 批准号: 10362723
• 负责人: Stephanie Yanow
• 金额: $ 33.45万
• 依托单位: UNIVERSITY OF ALBERTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-10 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10362723
• 关键词: Adhesions; Adjuvant; Affinity; Africa South of the Sahara; African; Alleles; Anemia; Antibodies; Antigenic Diversity; Antigens; Binding; Binding Proteins; Biological; Biological Assay; Birth; Blocking Antibodies; Chondroitin Sulfate A; Clinical Research; Clinical Trials; Colombian; Data; Development; Disease; Engineering; Epitope Mapping; Epitopes; Erythrocytes; Exposure to; Falciparum Malaria; Fetal Growth Retardation; Frequencies; Genetic Polymorphism; Goals; Heterophile Antibodies; High-Risk Pregnancy; Human; Immune; Immunity; Immunization; Immunodominant Epitopes; In Vitro; Individual; Infection; Low Birth Weight Infant; Malaria; Malaria Vaccines; Maps; Maternal and Child Health; Measures; Mediating; Mediator of activation protein; Molecular; Molecular Conformation; Monoclonal Antibodies; Mothers; Multigravidities; Mus; Outcome; Parasites; Pathogenesis; Peptide Conformation; Peptides; Phase I Clinical Trials; Placenta; Plasmodium; Plasmodium falciparum; Plasmodium vivax; Population; Pregnancy; Pregnant Women; Primigravidities; Protein Engineering; Proteins; Public Health; Recombinants; Risk; South America; Specificity; Subunit Vaccines; Surface Antigens; Translating; Vaccine Antigen; Vaccine Design; Vaccines; Woman; Work; base; cohort; cross immunity; cross reactivity; genetic variant; human monoclonal antibodies; immunogenic; immunogenicity; insight; malaria infection; neutralizing antibody; novel strategies; novel vaccines; parity; placental infection; placental malaria; pre-clinical; pregnancy associated death; prevent; receptor; stillbirth; study population; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation; vaccine formulation; vaccine strategy; vaccine trial

PROJECT SUMMARY/ABSTRACT A vaccine is urgently needed to protect pregnant women from malaria infection and the devastating effects of this disease on maternal and child health. Two vaccines are in early stage clinical trials and both target domains within the protein VAR2CSA, which is the major surface antigen expressed by Plasmodium falciparum placental isolates. This protein binds to receptors in the placenta and mediates sequestration of infected red blood cells (iRBCs), underpinning the pathogenesis of placental malaria. However, VAR2CSA is under strong immune selection and is highly polymorphic; this compromises vaccine efficacy by limiting the breadth of protection against diverse alleles. Polymorphic antigens present a ubiquitous challenge in the development of malaria subunit vaccines. The long-term goal of this project is to develop an alternative approach to a vaccine against pregnancy-associated malaria that targets highly conserved, subdominant (even cryptic) epitopes. What is unique about this approach is that it exploits a mechanism of cross- species immunity, where epitopes from one Plasmodium species elicit robust, broadly neutralizing antibodies against structurally related antigens from another species. This mechanism was discovered recently in Colombian and Brazilian populations where VAR2CSA antibodies can be acquired outside of pregnancy following infection with P. vivax, and these antibodies blocked sequestration of iRBCs using in vitro correlates of placental malaria. The cross-reactive epitope in P. vivax was mapped to subdomain (SD1) in PvDBP and human SD1-purified antibodies blocked parasite adhesion. The objective of this project is to develop a vaccine to protect pregnant women from falciparum placental malaria that is based on the cross- reactive epitope in vivax SD1. This will be achieved through synthesis of three complementary Specific Aims. Epitopes required to elicit functional, cross-reactive antibodies will be identified in Aim 1 through conformationally constricted peptide microarrays screened with mouse monoclonal antibodies (mAbs) and human mAbs to SD1 isolated from Colombian study populations. Epitopes will be synthesized as peptide- conjugates or within engineered recombinant domains, and immunogenicity will be optimized in Aim 2 to produce antibodies with functional activity against parasites that express diverse alleles of var2csa. In the third Aim, the cryptic epitopes in VAR2CSA recognized by these antibodies will be mapped to identify the targets of antibodies elicited by an SD1-derived vaccine. The integration of these findings will provide important insight into the mechanism of cross-species epitope recognition, which will serve as the basis for a vivax vaccine against falciparum placental malaria and could be applied more broadly to vaccines against other malaria antigens.

项目概要/摘要 迫切需要一种疫苗来保护孕妇免受疟疾感染及其破坏性影响 该病对妇幼健康的影响。两种疫苗正处于早期临床试验阶段，并且都针对 蛋白质 VAR2CSA 内的结构域，它是疟原虫表达的主要表面抗原 恶性疟原虫胎盘分离株。这种蛋白质与胎盘中的受体结合并介导隔离 受感染的红细胞（iRBC），是胎盘疟疾发病机制的基础。然而，VAR2CSA 免疫选择强，多态性高；这会限制疫苗的功效 针对不同等位基因的保护范围。多态性抗原在免疫学领域提出了普遍存在的挑战 开发疟疾亚单位疫苗。该项目的长期目标是开发一种替代方案 针对妊娠相关疟疾的疫苗方法，其目标是高度保守的、次显性的 （甚至是神秘的）表位。这种方法的独特之处在于它利用了一种交叉机制 物种免疫，其中一种疟原虫物种的表位引发强大的、广泛的中和作用 针对其他物种的结构相关抗原的抗体。这个机制被发现了 最近在哥伦比亚和巴西人群中，可以在国外获得 VAR2CSA 抗体 感染间日疟原虫后怀孕，这些抗体阻止了 iRBC 的隔离，用于 胎盘疟疾的体外相关性。间日疟原虫中的交叉反应表位被映射到子域 (SD1) PvDBP 和人 SD1 纯化抗体可阻断寄生虫粘附。该项目的目标是 开发一种疫苗来保护孕妇免受恶性胎盘疟疾的侵害，该疫苗基于交叉研究 间日疟原虫 SD1 中的反应性表位。这将通过综合三个互补的特定目标来实现 目标。目标 1 中将通过以下方式鉴定引发功能性交叉反应抗体所需的表位： 用小鼠单克隆抗体（mAb）筛选的构象收缩肽微阵列和 从哥伦比亚研究人群中分离出针对 SD1 的人单克隆抗体。表位将被合成为肽- 缀合物或工程重组结构域内，免疫原性将在目标 2 中得到优化 产生具有针对表达 var2csa 多种等位基因的寄生虫的功能活性的抗体。在 第三个目标，这些抗体识别的 VAR2CSA 中的隐藏表位将被映射以识别 SD1 衍生疫苗引发的抗体靶标。这些发现的整合将提供 对跨物种表位识别机制的重要见解，这将作为 针对恶性胎盘疟疾的间日疫苗，可更广泛地应用于针对恶性胎盘疟疾的疫苗 其他疟疾抗原。