Inducing durable, protective immune memory against malaria

项目摘要 目标是生产一种获得许可的疫苗，能够提供对感染的长期免疫力 恶性疟原虫是导致最致命形式疟疾的原生动物寄生虫，目前还没有认识到这一点。 目前，经过最广泛临床试验的疟疾疫苗候选是RTS，S是一名 基于环子孢子蛋白(CSP)的亚单位疫苗，在感染性细胞表面表达 寄生虫的子孢子期。然而，正如许多其他疫苗策略所见，由 接种RTS，S不仅次优，而且消退快，临床预防微不足道 在免疫后四年测量疾病。保护性疟疾产生的关键瓶颈 因此，疫苗正在了解如何产生长寿的、疟疾特异性的免疫记忆，特别是 在疟疾流行国家的人身上。一种有希望的方法是更深入地了解免疫 对整个减毒子孢子疫苗的反应，这可能导致高水平的发展 (&gt；60%)疟疾幼稚受试者在使用受控人类进行挑战时的无菌免疫力 疟疾感染(CHMI)，并首次显示出对接触疟疾的人的感染具有保护作用 非洲的受试者。在本应用程序中，我们将重点关注三个主要问题，这三个问题对于增强我们的 了解全程接种子孢子后如何维持免疫力：1)先天免疫是如何 接种子孢子后的免疫反应如何影响长寿适应性记忆的发展 以前的疟疾感染是否改变了子孢子疫苗诱导的记忆的产生？3)我们如何 Harness最近描述了血液中记忆细胞的特征，以了解长寿的维持 接种子孢子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，他们进行了 目前正在进行子孢子疫苗试验，并将采取一种全面综合的办法来解决这些问题。回答 在这些问题上，我们将使用从疟疾获得的相关人体样本-幼稚和预先暴露的疟疾 受试者接受不同模式的全子孢子疫苗接种，以及小鼠疟疾模型，其中 允许免疫系统受到干扰并进入目标器官。我们将把我们独特的专业知识与 新的工具和技术，为如何保持免疫记忆提供关键见解 免疫接种，这将为疟疾和其他传染病的疫苗接种战略提供广泛的信息 目前还没有疫苗可供使用。

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.