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.

项目总结 疟疾寄生虫恶性疟原虫继续造成显著的发病率和死亡率，临床病例为2.28亿人。 2019年病例和死亡人数为40.5万人。随着控制疟疾的进展在许多沉重的负担中停滞不前 鉴于许多国家的疟疾疫情和抗药性寄生虫的持续传播，迫切需要一种有效的疟疾疫苗。 目前正在实施的疫苗RTS、S的效力不大(~30%)，免疫力迅速下降。 重要的是，这种疫苗不针对这种寄生虫的致病形式。有效的疫苗 需要以疟原虫血型为目标，将寄生虫负担、临床疾病和后遗症减少到严重 疾病。我们的建议旨在通过开发一种针对恶性疟原虫的多模式疫苗来解决这一差距 利用人类疟疾的相关灵长类动物模型评估其疗效。我们将建造 这种多模式疫苗结合了两种具有不同效应器机制的候选疫苗。这个 个别成分已经在临床前疗效模型中进行了严格和可重复性的测试。第一个是 一种亚单位候选疫苗(AMA1-RON2L复合体)，旨在通过增加 针对AMA1的中和抗体比例。使用基于结构的方法，我们现在已经设计了 这种亚单位疫苗可以覆盖AMA1基因的多态性，并产生跨越菌株的中和抗体。 第二种是全血液期寄生虫疫苗，它能诱导一种跨菌株的抗寄生虫反应。 通过直接的细胞介导的杀戮。这种多模式疫苗将由一种新型阳离子脂质体制成 有效地激活免疫系统的体液和细胞介导臂的佐剂，从而 提供一种人体相容的佐剂平台。我们将进行剂量研究，以优化恶性疟原虫 小鼠多组分疫苗接种及生物性别对疫苗诱导免疫的影响 回应。我们还将评估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效果。 南美姬鼠体内同源和异源恶性疟原虫及其免疫持久性评价 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分析和 应用尖端技术(单细胞RNAseq)帮助我们了解免疫相关因素 保护。该项目的主要成果将是一种新的、经过临床前验证的多模式恶性疟原虫。 血液阶段疫苗是一种与人类相容的脂质体佐剂，可以进行临床试验。