Combination Vaccines to Interrupt Malaria Transmission

阻断疟疾传播的联合疫苗

• 批准号: 9381629
• 负责人: Nirbhay Kumar
• 金额: $ 58.19万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 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/9381629
• 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; Injectable; 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.

摘要 疟疾疫苗的开发集中在生命周期各个阶段表达的抗原上 的寄生虫。疟疾的传播取决于红细胞内性阶段的发展， 雌性按蚊的摄食和随后蚊子的性发育导致 子孢子的形成受感染的按蚊通过注射 孢子侵入肝细胞。因此，免疫干预旨在阻止发展， 肝期（红细胞前期- PE）和性期都有望提供更多的 预防疟疾的有效战略。传播阻断疫苗（TBV）， 性阶段（即雄性和雌性配子母细胞和配子）和蚊阶段的抗原 寄生虫（即受精卵和动合子）被认为是消灭疟疾的核心重要性 努力在恶性疟原虫中，TBV靶抗原包括Pfs 25、Pfs 48/45和Pfs 230，其中已知 间日疟原虫中的直系同源物。虽然PE阶段疫苗将预防或减少血液阶段的发展， 当感染者体内存在包括配子母细胞在内的寄生虫时，TBV会阻断寄生虫的有性生殖。 蚊子体内的配子体靶向PE和性/中肠阶段的疫苗组合， 预计将提供阻断疟疾传播的有效途径，这对实现消灭疟疾目标至关重要。 利用我们发表的关于Pfs 25、Pvs 28和Pfs 48/45的研究中获得的知识，现在可以 系统地评价这些抗原沿着PfCSP的组合，PfCSP是一种已经很好建立的 PE阶段疫苗抗原。我们建议合理开发和评估多阶段（体育和性）， 多抗原（Pfs 25、Pvs 25、Pfs 48/45、Pvs 48/45和PfCSP）和多种（恶性疟原虫和疟原虫）。 间日疟）疫苗组合阻断疟疾传播，这是我们的长期和最终目标。 research.使用重组蛋白和通过体内电穿孔（EP）递送的DNA疫苗，我们 将决定由来自PE和性的靶抗原组成的疫苗组合的效力 恶性疟原虫的阶段（目的1）。在目标2中，我们将评估和比较针对 传播两种主要的疟原虫属。(P.恶性疟原虫和间日疟原虫）。目标3中的研究目标 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，并提供合理的方法， 联合用药阻断疟疾传播是消除疟疾战略的一个重要目标。