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: 10084807
• 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/10084807
• 关键词: Address; Africa; Antibodies; Area; Attenuated; B-Lymphocytes; Blood; Blood Circulation; Capsid Proteins; Cells; Chemicals; 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; Lead; Lymphocyte; Maintenance; Malaria; Malaria Vaccines; Measures; Mediating; Memory; Modeling; Mus; Organ; Outcome; Parasites; Parasitology; 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; base; 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 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.

项目概要 目标是生产一种获得许可的疫苗，可以提供针对感染的长期免疫力 恶性疟原虫是一种导致最致命的疟疾的原生动物寄生虫，但人们尚未意识到这一点。 目前，经过最广泛临床测试的候选疟疾疫苗是 RTS,S，一种 基于环子孢子蛋白 (CSP) 的亚单位疫苗，表达于感染体表面 然而，正如许多其他疫苗策略所见，由寄生虫的子孢子阶段引起的保护。 RTS,S 疫苗接种不仅效果不佳，而且效果迅速减弱，临床上的预防效果可以忽略不计。 免疫后四年测量的疾病是产生保护性疟疾的关键瓶颈。 因此，疫苗正在了解如何产生长期的、疟原虫特异性的免疫记忆，特别是 一种有希望的方法是更深入地了解疟疾流行国家的人们的免疫情况。 对全减毒子孢子疫苗的反应，这可能导致高水平的发展 当使用受控人体进行攻击测试时，未患疟疾的受试者具有 (>60%) 的无菌免疫力 疟疾感染（CHMI），并首次显示出对疟疾暴露者的感染保护作用 在本申请中，我们将重点关注对于提高我们的能力至关重要的三个主要问题。 了解整个子孢子疫苗接种后如何保持免疫力：1）先天性如何 子孢子疫苗接种后的免疫反应影响长期适应性记忆的发展，2）如何影响 以前的疟疾感染是否会改变子孢子疫苗诱导的记忆的产生？3）我们怎样才能 利用最近表征的血液中的记忆细胞特征来了解长寿的维持 子孢子接种后组织中的免疫细胞。 我们的团队由免疫学、疫苗学、寄生虫学专家和合作者组成，他们进行 子孢子疫苗试验，并将寻求一种完全综合的方法来回答这些问题。 这些问题，我们将使用从疟疾初治者和疟疾预暴露者获得的相关人体样本 接受不同模式的全子孢子疫苗接种以及小鼠疟疾模型的受试者， 允许免疫系统扰动并进入目标器官，我们将结合我们独特的专业知识。 新颖的工具和技术为免疫记忆如何在术后维持提供重要见解 免疫接种，这将为疟疾以及其他传染病的疫苗接种策略提供广泛的信息 目前尚无疫苗。