Infection-blocking antibody targets for malaria

 描述（由申请方提供）：能够靶向和中和子孢子（通过蚊子叮咬注射的疟原虫的感染阶段）的疫苗仍然是预防疟疾感染和传播的有希望的靶点。对疟疾疫苗试验的分析表明，抗体可以中和子孢子，防止肝脏感染。然而，基于环子孢子蛋白（CSP）的临床上最先进的红细胞前候选疫苗仅提供部分保护，这表明有必要添加新的抗原靶点以提高疫苗效力。本提案的总体目标是评估新的恶性疟原虫红细胞前抗原候选者，可以引起感染的保护性免疫。基于我们最近对恶性疟原虫子孢子表面/分泌蛋白质组的前所未有的表征，我们已经鉴定了许多有希望的表面/分泌抗原，这些抗原作为新的疫苗候选物值得询问。基于这些证据，我们将在最先进的重组蛋白表达平台中开发15种恶性疟原虫子孢子表面/分泌抗原，并评估它们是否可以引发针对蚊子叮咬子孢子感染的保护性免疫。我们将采用转基因疟原虫寄生虫技术、B细胞克隆技术和人源化啮齿动物模型的创新组合来开发用于分析抗体介导的保护的全面的红细胞前抗原开发管道。此外，我们将评估疫苗引起的保护性体液免疫对寄生虫的机制，并加深我们对B细胞介导的保护性免疫的理解。我们在完全人源化的体液免疫原性小鼠模型和肝脏人源化小鼠攻击模型中研究人类病原体恶性疟原虫的实验系统将确保我们的结果提供人类中疫苗接种引发的应答的最接近的可能近似。我们的目标的结果将提供一个基于证据的选择新的候选疫苗，并将加快他们的途径，人类临床试验使用恶性疟原虫挑战模型。如果成功，可以考虑将鉴定的新型非CSP疫苗免疫原纳入下一代多抗原亚单位疟疾疫苗。

 DESCRIPTION (provided by applicant): A vaccine capable of targeting and neutralizing sporozoites, the infectious stage of the malaria parasites injected by mosquito bite, remains a promising target for preventing malaria infection and transmission. Analysis of malaria vaccine trials has shown that antibodies can neutralize the sporozoite and prevent infection of the liver. However, the most clinically advanced pre-erythrocytic vaccine candidate based on the circumsporozoite protein (CSP) confers only partial protection, indicating that it is necessary to add new antigen targets to increase vaccine efficacy. The overall goal of this proposal is to evaluate novel Plasmodium falciparum pre-erythrocytic antigen candidates that can elicit protective immunity from infection. Building on our recent unprecedented characterization of the P. falciparum sporozoite surface/secreted proteome, we have identified a number of promising surface/secreted antigens that warrant interrogation as new vaccine candidates. Based on this evidence, we will develop 15 P. falciparum sporozoite surface/secreted antigens in a state-of-the-art recombinant protein expression platform and evaluate whether they can elicit protective immunity against mosquito bite sporozoite infection. We will employ an innovative combination of transgenic Plasmodium parasite technology, B cell cloning techniques and humanized rodent models to develop a comprehensive pre-erythrocytic antigen development pipeline for analysis of antibody-mediated protection. In addition, we will evaluate the mechanisms of vaccine-elicited protective humoral immunity against the parasite and deepen our understanding of B cell-mediated protective immunity. Our experimental systems to study the human pathogen P. falciparum in a fully humanized humoral immunogenicity mouse model and a liver- humanized mouse challenge model will ensure our results provide the closest possible approximation of vaccination-elicited responses in humans. The outcomes of our aims will provide an evidence-based selection of novel vaccine candidates and will accelerate their pathway toward human clinical trials using the P. falciparum challenge model. If successful, novel non-CSP vaccine immunogens identified can be considered for inclusion into next generation multi-antigen subunit malaria vaccines.