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 疟疾寄生虫恶性疟原虫继续导致显著的发病率和死亡率， 2019年有405，000例病例和405，000例死亡。随着控制疟疾的进展在许多高负担地区停滞不前， 由于疟疾在许多国家蔓延，抗药性寄生虫不断蔓延，因此迫切需要有效的疟疾疫苗。 RTS，S是目前正在实施的一种疫苗，具有适度的效力（约30%），免疫力迅速减弱。 重要的是，这种疫苗不针对寄生虫的致病形式。有效的疫苗 需要针对疟原虫血型，以减少寄生虫负担、临床疾病和后遗症， 疾病我们的提案旨在通过开发针对以下人群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，并评估其疗效使用相关的灵长类动物模型的人类疟疾。我们将建立 这种多模式疫苗通过结合具有不同效应机制的两种疫苗候选物来实现。的 在临床前功效模型中对各个组分进行了严格和可重复的测试。一是 一种亚单位候选疫苗（AMA 1-RON 2L复合物），旨在通过增加 靶向AMA 1的中和抗体的比例。使用我们现在设计的基于结构的方法 这种亚单位疫苗覆盖AMA 1多态性并产生超越菌株的中和抗体。 第二种是全血阶段的寄生虫疫苗，诱导超越菌株的抗寄生虫反应 通过直接的细胞介导的杀伤。这种多模式疫苗将与新型阳离子脂质体一起配制 佐剂，有效激活免疫系统的体液和细胞介导的武器，从而 提供人相容的佐剂平台。我们将进行剂量研究，以优化恶性疟原虫 多组分疫苗在小鼠体内的免疫反应，并评价生物学性别对疫苗诱导免疫的影响 反应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细胞应答 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效力， 同源和异源恶性疟原虫在Aotus nancymaae和评估的持久性的免疫 使用延迟再激发模型（Aim 2）的响应。最后，我们将使用经过验证的免疫学检测方法， 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 在人类相容的脂质体佐剂中的血液阶段疫苗，其可以进展到临床试验。

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