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

项目摘要/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 这种疾病对妇幼健康的影响。两种疫苗正处于早期临床试验阶段，两种疫苗都针对 VAR2CSA蛋白中的结构域，它是疟原虫表达的主要表面抗原 恶性疟原虫胎盘分离株。这种蛋白与胎盘中的受体结合，并介导对 感染的红细胞(IRBC)，是胎盘性疟疾发病的基础。然而，VAR2CSA 处于强烈的免疫选择之下，并且具有高度的多态；这通过限制疫苗的效力而损害了疫苗的效力 针对不同等位基因的保护广度。多态抗原是一种普遍存在的挑战 疟疾亚单位疫苗的开发。这个项目的长期目标是开发一种替代方案 以高度保守、亚显性疟疾为靶点的妊娠相关疟疾疫苗的探讨 (甚至是神秘的)表位。这种方法的独特之处在于，它利用了一种交叉的机制 物种免疫，来自一种疟原虫物种的表位引发强大的、广泛的中和 针对来自另一物种的结构相关抗原的抗体。这种机制是被发现的 最近在哥伦比亚和巴西的人群中，VAR2CSA抗体可以在国外获得 感染间日疟原虫后怀孕，这些抗体阻断了iRBC的隔离 胎盘性疟疾的体外相关性。间日疟原虫交叉反应表位被定位到亚区(Sd1) 在PvDBP和人SD1纯化的抗体中，阻止了寄生虫的粘连。这个项目的目标是 开发一种疫苗来保护孕妇免受恶性胎盘疟疾的影响，这种疫苗是基于 间日疟原虫sd1的反应性表位。这将通过合成三个互补的特定的 目标。激发功能性交叉反应抗体所需的表位将在目标1至 用鼠单抗筛选构象受限的多肽微阵列 从哥伦比亚研究人群中分离的人抗SD1单抗。表位将被合成为多肽- 结合物或在工程重组区域内，免疫原性将在目标2至 产生对寄生虫具有功能活性的抗体，这些抗体表达不同的var2csa等位基因。在 第三个目标是，这些抗体识别的VAR2CSA中的隐蔽表位将被绘制出来，以识别 SD1衍生疫苗所产生抗体的靶点。综合这些调查结果将提供 对跨物种表位识别机制的重要洞察，这将作为 一种针对恶性胎盘疟疾的间日疟疫苗，可更广泛地应用于预防疟疾的疫苗 其他疟疾抗原。

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.