Development of novel malaria pre-erythrocytic vaccine antigens targeting Plasmodium sporozoite liver infection

针对疟原虫子孢子肝脏感染的新型疟疾前红细胞疫苗抗原的开发

基本信息

批准号：
10667817
负责人：
Sung-Jae Cha
金额：
$ 2.42万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-04 至 2023-03-17
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10667817
关键词：
Antibodies Antigen Targeting Antigens Binding Biological Assay Blood Circulation Blood Vessels Cd68 Cell Communication Cell surface Charge Circulation Communicable Diseases Culicidae Development Discontinuous Capillary Endothelial Cells Epitopes Erythrocytes Glyceraldehyde-3-Phosphate Dehydrogenases Glycosaminoglycans Hepatic Stellate Cell Hepatocyte Immunization Infection Invaded Kupffer Cells Libraries Ligands Liver Macrophage Malaria Malaria Vaccines Mediating Membrane Proteins Mus Parasites Parasitic infection Peptide Phage Display Library Peptides Persons Phage Display Plasmodium Plasmodium berghei Plasmodium falciparum Process Proteins Receptor Cell Reporting Skin Sporozoites Sterility Surface Testing Transgenic Organisms Vaccine Antigen Vaccines chemokine circumsporozoite circumsporozoite protein immunogenicity improved liver infection malaria infection novel phospholipid scramblase preclinical evaluation protective efficacy receptor stellate cell transcytosis

项目摘要

Previously, using a phage peptide display library, our group has identified Plasmodium parasite ligands and corresponding host cell receptors important for sporozoite-Kupffer cell interaction in the mammalian liver. Using a similar approach, we identified the HP1 peptide, a structural mimic of a ligand that the sporozoite uses to infect hepatocytes. Immunization with the HP1 peptide protects ~ 50 % mice from P. berghei challenge. Using an anti-HP1 antibody, we identified Plasmodium Phospholipid Scramblase (PLS) as the sporozoite ligand of hepatocytes and a potential vaccine antigen. We propose 1) to identify PLS protein epitopes that function in hepatocyte recognition, for use as a vaccine antigen; and 2) to develop a tri- functional vaccine antigen containing i) a sporozoite circumsporozoite protein (CSP) epitope, targeting liver sinusoid binding, ii) a sporozoite GAPDH-related epitope, targeting sporozoite exit from the circulation via Kupffer cell traversal, and iii) sporozoite PLS epitope, targeting hepatocyte infection. We expect that this approach will lead to enhancement of the moderate protective efficacy of the most advanced RTS,S/AS01 malaria vaccine.

此前，我们的团队利用噬菌体肽展示文库鉴定了疟原虫寄生虫配体和相应的宿主细胞受体对于哺乳动物肝脏中的子孢子-库普弗细胞相互作用很重要。使用类似的方法，我们鉴定了 HP1 肽，它是子孢子配体的结构模拟物。用于感染肝细胞。 HP1 肽免疫可保护约 50% 的小鼠免受伯氏疟原虫感染挑战。使用抗 HP1 抗体，我们鉴定出疟原虫磷脂扰乱酶 (PLS) 肝细胞的子孢子配体和潜在的疫苗抗原。我们建议1）鉴定PLS蛋白在肝细胞识别中起作用的表位，用作疫苗抗原； 2）开发一个三功能性疫苗抗原含有 i) 子孢子环子孢子蛋白 (CSP) 表位，靶向肝脏正弦结合，ii) 子孢子 GAPDH 相关表位，靶向子孢子通过循环退出库普弗细胞穿越，以及 iii) 子孢子 PLS 表位，针对肝细胞感染。我们期望这方法将增强最先进的 RTS,S/AS01 的中等保护功效疟疾疫苗。