Combination Vaccines to Interrupt Malaria Transmission

阻断疟疾传播的联合疫苗

• 批准号: 9750618
• 负责人: Nirbhay Kumar
• 金额: $ 52.71万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-04 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750618
• 关键词: Address; Adjuvant; Animals; Anopheles Genus; Antibodies; Antigen Targeting; Antigen-Presenting Cells; Antigens; Area; Artemisinins; Biological Assay; Blood; Cessation of life; Chemosensitization; Combined Modality Therapy; Combined Vaccines; Communicable Diseases; Culicidae; DNA; DNA Vaccines; DNA delivery; Development; Disease; Electroporation; Erythrocytes; Female; Formulation; Germ Cells; Goals; Hepatocyte; Human; Immune; Immune response; Individual; Infection; Ingestion; Insecticides; Interruption; Invaded; Knowledge; Lead; Life Cycle Stages; Liver; MF59; Macaca mulatta; Malaria; Malaria Vaccines; Mammals; Measures; Membrane; Midgut; Molecular Conformation; Mus; Muscle Cells; Orthologous Gene; Outcome; Papio; Papio anubis; Parasites; Pathway interactions; Persons; Pharmaceutical Preparations; Phase; Plasmodium; Plasmodium falciparum; Plasmodium vivax; Play; Population; Positioning Attribute; Proteins; Public Health; Publishing; Recombinant Proteins; Recombinants; Reporting; Reproduction; Research; Resistance; Role; Sexual Development; Site; Sporozoites; Testing; Transgenic Organisms; Vaccine Antigen; Vaccines; aluminum sulfate; base; feeding; immunogenic; immunogenicity; immunological intervention; in vivo; malaria infection; malaria transmission; malaria transmission-blocking vaccine; male; migration; novel strategies; plasmid DNA; prevent; protective efficacy; public health relevance; success; tool; transmission process; transmission-blocking vaccine; uptake; vaccine development; vaccine evaluation; vector; zygote

Abstract Malaria vaccine development has focused on antigens expressed during various stages of the life cycle of the parasite. Malaria transmission depends upon the development of intraerythrocytic sexual stages, ingestion by female anopheline mosquitoes and subsequent sexual development in mosquitoes leading to formation of sporozoites. An infected Anopheles mosquito initiates malaria infection cycle by injecting sporozoites which invade hepatocytes. Hence immune interventions aimed at blocking development of both the liver stage (pre-erythrocytic phase - PE) and sexual stage are expected to provide more effective strategy to protect against malaria. A transmission blocking vaccine (TBV) approach targeting antigens in the sexual stages (i.e. male and female gametocytes and gametes) and the mosquito stages of the parasite (i.e. zygote and ookinete) is believed to be of central importance in malaria elimination efforts. In Plasmodium falciparum, TBV target antigens include Pfs25, Pfs48/45 and Pfs230, with known orthologs in P. vivax. While a PE stage vaccine will prevent or reduce the development of blood stage parasites including gametocytes in an infected person, a TBV will block sexual reproduction of the gametocytes in the mosquito. A combination of vaccines targeting both PE and sexual/midgut stages, is expected to provide effective ways for interruption of malaria transmission, critical for elimination goal. Using knowledge gained from our published studies on Pfs25, Pvs28 and Pfs48/45, it is now possible to systematically evaluate a combination of these antigens along with PfCSP, an already well-established PE stage vaccine antigen. We propose to rationally develop and evaluate multi-stage (PE and sexual), multi-antigen (Pfs25, Pvs25, Pfs48/45, Pvs48/45 and PfCSP) and multi-species (P. falciparum and P. vivax) vaccine combinations to interrupt malaria transmission, a long-term and ultimate goal of our research. Using recombinant proteins, and DNA vaccines delivered by in vivo electroporation (EP), we will determine the potency of vaccine combinations comprised of target antigens from PE and sexual stages of P. falciparum (aim 1). In aim 2, we will evaluate and compare combination of vaccines targeting transmission of the two major Plasmodium spp. (P. falciparum and P. vivax). The goal of studies in aim 3 is to determine outcome and immune potency of DNA vaccines by enhancing delivery of DNA plasmids and uptake of antigen by antigen presenting cells in vivo. The proposed studies are expected to identify most potent vaccine combination(s) and provide a rational approach for advancing effective combination(s) to interrupt transmission of malaria, an important goal of malaria elimination strategies.

抽象的 疟疾疫苗的开发重点关注生命周期各个阶段表达的抗原 寄生虫。疟疾传播取决于红细胞内性阶段的发育， 雌性按蚊的摄入以及随后蚊子的性发育导致 以形成子孢子。受感染的按蚊通过注射启动疟疾感染周期 侵入肝细胞的子孢子。因此，免疫干预旨在阻止 肝脏阶段（红细胞前阶段 - PE）和性阶段预计会提供更多 预防疟疾的有效战略。一种针对传播阻断疫苗 (TBV) 的方法 性阶段（即雄性和雌性配子细胞和配子）和蚊子阶段的抗原 寄生虫（即受精卵和动合体）被认为对于消除疟疾至关重要 努力。在恶性疟原虫中，TBV靶抗原包括Pfs25、Pfs48/45和Pfs230，已知 间日疟原虫中的直系同源物。虽然 PE 阶段疫苗可以预防或减少血液阶段的发展 如果感染者体内存在包括配子细胞在内的寄生虫，TBV 将阻止配子体的有性繁殖 蚊子的配子细胞。针对 PE 和性/中肠阶段的疫苗组合是 预计将为阻断疟疾传播提供有效方法，这对于消除疟疾目标至关重要。 利用我们已发表的 Pfs25、Pvs28 和 Pfs48/45 研究中获得的知识，现在可以 系统地评估这些抗原与 PfCSP 的组合，PfCSP 是一种已经完善的 PE阶段疫苗抗原。我们建议合理开发和评估多阶段（PE和性）， 多抗原（Pfs25、Pvs25、Pfs48/45、Pvs48/45 和 PfCSP）和多物种（恶性疟原虫和疟原虫） vivax）疫苗组合可阻断疟疾传播，这是我们的长期和最终目标 研究。使用重组蛋白和通过体内电穿孔 (EP) 提供的 DNA 疫苗，我们 将确定由PE和性的目标抗原组成的疫苗组合的效力 恶性疟原虫的阶段（目标 1）。在目标 2 中，我们将评估和比较针对不同目标的疫苗组合 两种主要疟原虫属的传播。 （恶性疟原虫和间日疟原虫）。目标3的研究目标 是通过增强 DNA 质粒的递送来确定 DNA 疫苗的结果和免疫效力 以及体内抗原呈递细胞对抗原的摄取。拟议的研究预计将确定 最有效的疫苗组合，并为推进有效疫苗提供合理的方法 阻断疟疾传播的联合用药，这是消除疟疾战略的一个重要目标。