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.

项目总结/文摘