Combination Vaccines to Interrupt Malaria Transmission

摘要 疟疾疫苗的开发侧重于在生命周期的不同阶段表达的抗原。 寄生虫的。疟疾的传播依赖于红细胞内有性期的发育， 雌性按蚊的摄食和随后的性发育 形成子孢子。一只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，旨在阻止疾病发展的免疫干预措施 肝脏阶段(红细胞前期-PE)和性阶段预计都会提供更多 预防疟疾的有效战略。靶向传播阻断疫苗(TBV)方法 性阶段(即雄配子和雌配子和配子)和蚊子阶段的抗原 寄生虫的数量(即受精卵和卵母细胞)被认为在消除疟疾方面具有核心重要性。 努力。在恶性疟原虫中，TBV靶抗原包括Pfs25、Pfs48/45和Pfs230，已知 间日疟原虫中的同源物。而PE期疫苗会阻止或减少血液期的发展 寄生虫，包括感染者的配子体，TBV会阻止有性繁殖 蚊子体内的配子体。针对PE和性/中肠阶段的疫苗的组合是 预计将为阻断疟疾传播提供有效方法，这对实现消除目标至关重要。 利用从我们发表的关于Pfs25、Pvs28和Pfs48/45的研究中获得的知识，现在可以 系统地评估这些抗原与PfCSP的组合，PfCSP已经建立了 PE期疫苗抗原。我们建议合理发展和评估多阶段(体育和性)， 多抗原(Pfs25、Pvs25、Pfs48/45、Pvs48/45和PfCSP)和多种(恶性疟原虫和恶性疟原虫)。 间日疟原虫)疫苗组合以阻断疟疾传播，这是我们的长期和最终目标 研究。利用体内电穿孔(EP)提供的重组蛋白质和DNA疫苗，我们 将确定由来自PE和性别的靶抗原组成的疫苗组合的效力 恶性疟原虫分期(目标1)。在目标2中，我们将评估和比较靶向疫苗的组合 两种主要疟原虫的传播。(恶性疟原虫和间日疟原虫)。目标3中学习的目标 是通过增强DNA质粒的传递来确定DNA疫苗的结果和免疫效力 体内抗原提呈细胞对抗原的摄取。拟议的研究预计将确定 最有效的疫苗组合(S)，为提高有效率提供了合理的途径 联合(S)阻断疟疾传播，这是消除疟疾战略的一个重要目标。

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.