Developing a multi-component vaccine harnessing potent antibody and cellular responses against the blood-stage of Plasmodium falciparum

开发一种多成分疫苗，利用针对恶性疟原虫血液阶段的有效抗体和细胞反应

• 批准号: 10366749
• 负责人: Prakash Srinivasan
• 金额: $ 68.38万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366749
• 关键词: Address; Adjuvant; Age; Amino Acids; Antibodies; Antigenic Diversity; Antigens; Aotus primate; Binding; Blood; CD4 Positive T Lymphocytes; Cations; Cells; Cellular Immunity; Cessation of life; Child; Clinical; Clinical Trials; Complex; Country; Data; Development; Disease; Dose; Drug resistance; Formulation; Generations; Genetic Polymorphism; Goals; Human; Immune; Immune response; Immune system; Immunity; Immunology procedure; In Vitro; Individual; Infection; Interferon Type II; Life; Liposomes; Malaria; Malaria Vaccines; Mediating; Memory B-Lymphocyte; Modeling; Molecular Conformation; Monkeys; Morbidity - disease rate; Mus; Parasite resistance; Parasites; Plasmodium; Plasmodium falciparum; Primates; Proteins; Role; Structure; Subunit Vaccines; Swiss Mice; System; T cell response; Technology; Testing; Transcend; Vaccine Antigen; Vaccines; Vulnerable Populations; Whole Blood; apical membrane; arm; base; biological sex; clinical development; design; efficacy evaluation; fight against; human model; immunogenicity; insight; mortality; multimodality; neutralizing antibody; nonhuman primate; novel; parasite invasion; phase III trial; pre-clinical; preclinical efficacy; preservation; prevent; protective efficacy; response; single-cell RNA sequencing; success; vaccine candidate; vaccine-induced immunity

PROJECT SUMMARY The malaria parasite P. falciparum continues to cause significant morbidity and mortality, with 228 million clinical cases and 405,000 deaths in 2019. With progress towards controlling malaria stalling in many high burden countries and the continuing spread of drug resistant parasites, an effective malaria vaccine is urgently needed. RTS,S, a vaccine currently under implementation, has modest efficacy (~30%) and immunity waning rapidly. Importantly, this vaccine does not target the disease-causing forms of the parasite. An efficacious vaccine targeting Plasmodium blood-forms is required to reduce parasite burden, clinical disease and sequelae to severe disease. Our proposal aims to address this gap by developing a multi-modal P. falciparum vaccine targeting the blood-stage parasite and evaluating its efficacy using a relevant primate model of human malaria. We will build this multi-modal vaccine by incorporating two vaccine candidates with distinct effector mechanisms. The individual components have been tested rigorously and reproducibly in pre-clinical efficacy models. The first is a sub-unit vaccine candidate (AMA1-RON2L complex), designed to enhance antibody quality by increasing the proportion of neutralizing antibodies targeting AMA1. Using a structure-based approach we have now designed this subunit vaccine to cover AMA1 polymorphisms and generate strain-transcending, neutralizing antibodies. The second is a whole blood-stage parasite vaccine that induces a strain-transcending, anti-parasite response through direct cell-mediated killing. This multi-modal vaccine will be formulated with a novel cationic liposomal adjuvant that potently activates both the humoral and cell-mediated arms of the immune system, thereby providing a human-compatible adjuvant platform. We will perform dosing studies to optimize the P. falciparum multi-component vaccine in mice and evaluate impact of biological sex on the vaccine-induced immune response. We will also assess memory B cell and T cell responses induced by the multi-modal P. falciparum vaccine (Aim 1). Next, we will assess immunogenicity and protective efficacy of this multi-modal vaccine against homologous and heterologous P. falciparum in Aotus nancymaae and evaluate the persistence of the immune responses using a delayed re-challenge model (Aim2). Lastly, we will use validated immunological assays and apply cutting-edge technology (single-cell RNASeq) to help inform our understanding of immune correlates of protection. The major deliverable of this project will be a novel, pre-clinically validated, multi-modal P. falciparum blood-stage vaccine in a human-compatible liposomal adjuvant that can be progressed towards clinical trials.

项目概要 疟原虫恶性疟原虫继续造成显着的发病率和死亡率，2.28 亿临床患者 2019 年有 405,000 例病例和 405,000 人死亡。随着控制疟疾的进展，许多高负担国家陷入停滞 各国和耐药寄生虫的持续传播，迫切需要一种有效的疟疾疫苗。 RTS,S 是一种目前正在实施的疫苗，其功效有限（约 30%），并且免疫力迅速减弱。 重要的是，这种疫苗并不针对致病的寄生虫。有效的疫苗 需要针对疟原虫血型来减少寄生虫负担、临床疾病和重症后遗症 疾病。我们的提案旨在通过开发一种针对恶性疟原虫的多模式疫苗来弥补这一差距 血液阶段寄生虫并使用人类疟疾的相关灵长类动物模型评估其功效。我们将建设 这种多模式疫苗结合了两种具有不同效应机制的候选疫苗。这 各个成分均已在临床前功效模型中经过严格且可重复的测试。第一个是 一种亚单位候选疫苗（AMA1-RON2L 复合物），旨在通过增加 针对 AMA1 的中和抗体的比例。使用我们现在设计的基于结构的方法 该亚单位疫苗可覆盖 AMA1 多态性并产生超越菌株的中和抗体。 第二种是全血阶段寄生虫疫苗，可诱导超越菌株的抗寄生虫反应 通过直接细胞介导的杀伤。这种多模式疫苗将采用新型阳离子脂质体配制而成 有效激活免疫系统的体液和细胞介导的臂的佐剂，从而 提供人类兼容的佐剂平台。我们将进行剂量研究以优化恶性疟原虫 小鼠多成分疫苗并评估生物性别对疫苗诱导免疫的影响 回复。我们还将评估由多模式恶性疟原虫诱导的记忆 B 细胞和 T 细胞反应 疫苗（目标 1）。接下来，我们将评估这种多模式疫苗的免疫原性和保护功效 Aotus nancymaae 中的同源和异源恶性疟原虫并评估免疫的持久性 使用延迟再挑战模型（Aim2）进行响应。最后，我们将使用经过验证的免疫学测定法 应用尖端技术（单细胞 RNASeq）来帮助我们了解免疫相关性 保护。该项目的主要成果将是一种新型的、临床前验证的、多模式的恶性疟原虫 人类相容性脂质体佐剂中的血液阶段疫苗可以进行临床试验。