Inducing durable, protective immune memory against malaria

项目摘要 目标是生产一种许可的疫苗，可以提供针对感染的长期免疫力， 恶性疟原虫是导致最致命形式疟疾的原生动物寄生虫，但尚未发现。 目前，经过最广泛临床试验的疟疾候选疫苗是RTS，S， 基于环子孢子蛋白（CSP）的亚单位疫苗，表达在感染性细胞表面， 寄生虫的子孢子阶段。然而，与许多其他疫苗策略一样， 用RTS，S接种疫苗不仅不是最佳的，它还迅速减弱，并且对临床免疫的预防作用可以忽略不计。 免疫后四年测量的疾病。产生保护性疟疾的一个关键瓶颈 因此，疫苗是了解如何产生长寿的，疟原虫特异性免疫记忆，特别是 在疟疾流行的国家。一种有希望的方法是更深入地了解免疫系统， 对整个减毒子孢子疫苗的反应，这可能导致高水平的发展 （>60%）在疟疾初治受试者中，当使用对照人 疟疾感染（CHMI），并首次显示出对疟疾暴露者感染的保护作用。 在非洲的主题。在本应用程序中，我们将重点关注对增强我们的 了解如何免疫可以维持后，整个子孢子疫苗接种：1）如何先天 子孢子接种后的免疫应答影响长寿命适应性记忆的发展，2）如何 先前的疟疾感染是否改变子孢子疫苗诱导的记忆的产生，以及3）我们如何能够 利用血液中最近表征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， 我们将继续开展子孢子疫苗试验，并将采取全面综合的办法来解决这些问题。回答 这些问题，我们将使用从疟疾初治者和疟疾预暴露者中获得的相关人类样本。 受试者接受不同模式的完整子孢子疫苗接种，以及鼠疟疾模型， 使免疫系统受到干扰并进入靶器官。我们将联合收割机的独特专业知识与 新的工具和技术，以提供关键的见解，如何免疫记忆可以维持后， 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信息 目前还没有疫苗。

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.