Inducing durable, protective immune memory against malaria

诱导针对疟疾的持久、保护性免疫记忆

• 批准号: 10545746
• 负责人: Stefan HI Kappe
• 金额: $ 80.27万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-16 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545746
• 关键词: Address; Africa; Antibodies; Area; Attenuated; B-Lymphocytes; Blood; Capsid Proteins; Cells; Chemicals; Circulation; Clinical; Clinical Trials; Communicable Diseases; Country; Cues; Data; Development; Disease; Effector Cell; Future; Generations; Goals; Human; Immune; Immune response; Immune system; Immunity; Immunization; Immunologic Memory; Immunology; Individual; Infection; Inflammatory Response; Innate Immune Response; Innate Immune System; Licensing; Lymphocyte; Maintenance; Malaria; Malaria Vaccines; Measures; Mediating; Memory; Modeling; Mus; Organ; Outcome; Parasites; Parasitology; Persons; Plasmodium; Plasmodium falciparum; Population; Prevention; Process; Research; Residencies; Sampling; Sentinel; Sporozoite vaccine; Sporozoites; Sterility; Subunit Vaccines; Surface; System; T-Lymphocyte; Techniques; Testing; Time; Tissues; Vaccination; Vaccine Design; Vaccines; adaptive immune response; circumsporozoite protein; clinically relevant; experience; insight; malaria infection; mouse model; novel; programs; research clinical testing; response; tool; vaccination strategy; vaccine candidate; vaccine development; vaccine efficacy; vaccine strategy; vaccine trial; vaccinology

Project Summary The goal of generating a licensed vaccine that can provide long-lived immunity against infection with Plasmodium falciparum, the protozoan parasite that causes the most lethal form of malaria, is yet unrealized. Currently, the malaria vaccine candidate that has undergone the most extensive clinical testing is RTS,S, a subunit vaccine based on the circumsporozoite protein (CSP), expressed on the surface of the infectious sporozoite stage of the parasite. Yet, as seen with many other vaccine strategies, protection induced by vaccination with RTS,S is not only suboptimal, it also wanes rapidly and there is negligible prevention of clinical disease measured four years after immunization. A critical bottleneck for the generation of a protective malaria vaccine is therefore understanding how to generate long-lived, Plasmodium-specific immune memory, especially in people in malaria endemic countries. One promising approach is to gain greater insight into the immune response to whole attenuated sporozoite vaccines, which can lead to the development of high levels (>60%) of sterile immunity in malaria naïve subjects when tested by challenge using controlled human malaria infection (CHMI) and has shown for the first time protection against infection in malaria-exposed subjects in Africa. In this application, we will focus on three major questions that are critical to enhancing our understanding of how immunity can be maintained after whole sporozoite vaccination: 1) how does the innate immune response after sporozoite vaccination influence the development of long-lived adaptive memory, 2) how does previous malaria infection alter the generation of sporozoite vaccine-induced memory and 3) how can we harness recently characterized memory cell signatures in the blood to understand the maintenance of long-lived immune cells in the tissues after sporozoite vaccination. Our team consists of experts in immunology, vaccinology, parasitology and collaborators that conduct sporozoite vaccine trials, and will pursue a fully integrated approach to address these questions. To answer these questions, we will use both relevant human samples obtained from malaria-naïve and malaria pre-exposed subjects who received different modes of whole sporozoite vaccination, as well as murine malaria models, which allow immune system perturbations and access to target organs. We will combine our unique expertise with novel tools and techniques to provide key insights into how immunological memory can be maintained after immunization, which will broadly inform vaccination strategies for malaria, as well as other infectious diseases for which vaccines are not currently available.

项目摘要 产生可以提供长寿命免疫抑制的许可疫苗的目的 恶性疟原虫是导致疟疾最致命形式的原生动物寄生虫，但仍未实现。 目前，经历了最广泛临床测试的疟疾疫苗候选者是RTS，S，A 基于电路孢子蛋白（CSP）的亚基疫苗，在传染性表面表达 寄生虫的孢子岩阶段。然而，正如许多其他疫苗策略所看到的，由 用RTS接种疫苗，S不仅是最佳的，而且还会迅速减弱，并且预防临床可以忽略不计 免疫后四年测量疾病。生成受保护疟疾的关键瓶颈 因此 在疟疾内在国家的人们。一种承诺的方法是更深入地了解免疫 对整个减毒的孢子虫疫苗的反应，这可能导致高水平的发展 当通过受控人类受控挑战测试时，疟疾受试者的无菌免疫学的（> 60％） 疟疾感染（CHMI），已显示出暴露于疟疾的首次防止感染 非洲的主题。在此应用程序中，我们将重点关注三个主要问题，这些问题对于增强我们的 了解整个孢子岩疫苗后如何维持免疫力：1）先天性如何 孢子岩疫苗后的免疫反应会影响长寿命自适应记忆的发展，2） 以前的疟疾感染会改变孢子虫疫苗诱导的记忆的产生吗？3）我们如何如何 线束最近表征了血液中的记忆细胞签名，以了解长寿的维护 孢子岩疫苗接种后的时机中的免疫细胞。 我们的团队由免疫学，疫苗学，寄生虫学和合作者组成的专家 Sporozoite疫苗试验，并将采取完全集成的方法来解决这些问题。回答 这些问题，我们将使用预先暴露的疟疾和疟疾获得的相关人类样本 接受不同模式的整个子孢子疫苗的受试者以及鼠类疟疾模型，这些模型 允许免疫系统扰动并访问目标器官。我们将结合我们独特的专业知识 新颖的工具和技术，以提供有关如何保持免疫记忆之后如何保持免疫记忆的关键见解 免疫，将广泛告知疟疾的疫苗接种策略以及其他传染病 目前尚无疫苗。