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

• 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
• 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

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，使用噬菌体多肽展示文库，我们的团队已经鉴定了疟原虫寄生虫配体和 哺乳动物肝脏中对子孢子-库普弗细胞相互作用至关重要的相应宿主细胞受体。 使用类似的方法，我们鉴定了hp1肽，这是一种模仿子孢子的配体的结构。 用来感染肝细胞。HP1多肽免疫小鼠可保护约50%的小鼠免受伯氏肺孢子虫感染 挑战。利用抗HP1抗体，我们鉴定了疟原虫磷脂扰乱酶(PLS)是 肝细胞的子孢子配体和潜在的疫苗抗原。我们提出了1)鉴定偏最小二乘蛋白 在肝细胞识别中起作用的表位，用作疫苗抗原；以及2)开发三种表位。 功能疫苗抗原，包括1)针对肝脏的子孢子环子孢子蛋白(CSP)表位 正弦结合，ii)子孢子GAPDH相关表位，靶向子孢子通过 Kupffer细胞遍历，以及iii)子孢子的PLS表位，靶向肝细胞感染。我们预计这一次 方法将导致增强最先进的RTS，S/AS01中的保护效力 疟疾疫苗。