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: 10614511
• 负责人: Prakash Srinivasan
• 金额: $ 67.24万
• 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/10614511
• 关键词: Acceleration; Address; Adjuvant; Age; Amino Acids; Antibodies; Antigen Presentation; Antigenic Diversity; Antigens; Aotus primate; Binding; Blood; CD4 Positive T Lymphocytes; Cells; Cellular Immunity; Cessation of life; Child; Clinical; Clinical Trials; Complex; Country; Data; Development; Disease; Dose; Drug resistance; 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; Reproducibility; Role; Structure; Subunit Vaccines; Swiss Mice; System; T cell response; Technology; Testing; Transcend; Vaccine Antigen; Vaccines; Vulnerable Populations; Whole Blood; apical membrane; arm; biological sex; clinical development; design; efficacy evaluation; fighting; human model; immunogenicity; insight; liposomal formulation; 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; synergism; 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.

项目摘要 恶性疟原虫疟原虫继续引起明显的发病率和死亡率，有2.28亿个临床 案件和2019年405,000例死亡。在控制疟疾中陷入困境的进展许多高负担 迫切需要国家和耐药寄生虫的持续扩散，有效的疟疾疫苗是急需的。 RTS，S是目前正在实施的疫苗，具有适度的功效（约30％），免疫力迅速降低。 重要的是，该疫苗不瞄准寄生虫的引起疾病形式。有效的疫苗 需要靶向疟原虫形式来减轻寄生虫负担，临床疾病和后遗症 疾病。我们的建议旨在通过开发针对的多模式恶性疟原虫疫苗来解决这一差距 血液阶段的寄生虫并使用人类疟疾相关的灵长类动物模型评估其功效。我们将建造 这种多模式疫苗是通过掺入具有不同效应机制的两种疫苗的。这 在临床前功效模型中，已经对单个组件进行了严格和可重复的测试。第一个是 亚单位疫苗候选者（AMA1-RON2L复合物），旨在通过增加抗体质量 靶向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 该亚基疫苗覆盖AMA1多态性并产生应变转移，中和抗体。 第二个是一种全血阶段寄生虫疫苗 通过直接细胞介导的杀戮。这种多模式疫苗将用一种新型的阳离子脂质体配制 有效激活免疫系统的体液和细胞介导的臂的佐剂，从而 提供与人兼容的辅助平台。我们将进行剂量研究以优化恶性疟原虫 小鼠中的多组分疫苗，并评估生物性别对疫苗诱导的免疫的影响 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（AIM 1）。接下来，我们将评估该多模式疫苗针对的免疫原性和保护性 Nancymaae中的同源性和异源性恶性疟原虫，并评估免疫的持久性 使用延迟重新挑战模型的响应（AIM2）。最后，我们将使用经过验证的免疫学分析和 应用尖端技术（单细胞RNASEQ），以帮助我们了解我们对免疫相关性的理解 保护。该项目的主要可交付方式将是一种新颖的，经过限制的，多模式的恶性疟原虫 可以在临床试验中进展的人类兼容脂质体辅助剂中的血级疫苗。

项目成果

Structure guided mimicry of an essential P. falciparum receptor-ligand complex enhances cross neutralizing antibodies.

恶性疟原虫必需受体-配体复合物的结构引导模拟增强了交叉中和抗体。

• DOI: 10.21203/rs.3.rs-2733434/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Srinivasan,Prakash;Yanik,Sean;Venkatesh,Varsha;Parker,Michelle;Diouf,Ababacar;Sarkar,Deepti;Miura,Kazutoyo;Long,Carole;Boulanger,Martin
• 通讯作者: Boulanger,Martin