An Effector Memory T Cell-Inducing Subunit Vaccine against Malaria

项目说明（由申请人提供）：该项目的最终目标是研制一种疟疾消毒疫苗。本研究的具体假设是，通过诱导针对疟原虫肝期的持久效应记忆T细胞（TEM）反应，可以实现对疟疾的灭菌免疫。已知用活的或辐照的孢子虫反复免疫可保护接种疫苗的个体免受疟疾的挑战。最近的证据表明，这种保护作用与多能瞬变电磁体的频繁存在相关，这表明对疟疾的永久绝育免疫需要通过接种疫苗诱导高水平的长期瞬变电磁体。为了验证这一假设，我们建议使用重组巨细胞病毒（CMV）作为疫苗载体，因为巨细胞病毒是一种典型的病毒，可诱导不显示T细胞衰竭迹象的长寿命透射电镜。cmv载体的这种独特能力最近被应用于诱导抗猴免疫缺陷病毒的长寿命TEM，导致对siv攻击的保护，在效力和持续时间方面远远优于传统的异源启动/增强疫苗。由于在使用异源启动/加强疫苗时，对诺氏疟原虫寄生虫的灭菌保护只是部分和短暂的，因此我们将研究巨细胞病毒衍生的疫苗载体是否同样能对诺氏疟原虫（Pk）孢子虫的攻击提供持久和有效的免疫。我们拟生成重组RhCMV，表达四种先前用于异源启动增强疫苗的Pk抗原：环孢子子蛋白（CSP）、孢子子表面蛋白2或血栓相关粘附蛋白（SSP2或TRAP）、顶端merozoite antigen-1 （AMA1）和merozoite表面蛋白1 （MSP1c）的c端。我们将用这四组重组RhCMV/Pk载体接种动物，并监测血液、肺和肝脏中TEM的发展。为了确定RhCMV/Pk4疫苗是否具有保护作用，我们将用诺氏假体进行挑战。在这个探索性项目完成后，我们将因此知道tem诱导疫苗是否可以提高亚单位疟疾寄生虫疫苗诱导的绝育免疫水平和持续时间。

DESCRIPTION (provided by applicant): The ultimate goal of this project is to develop a sterilizing vaccine against malaria. The specific hypothesis tested in this proposal is that sterilizing immunity against malaria can be achieved by induction of a lasting effector memory T cell (TEM) response targeting the liver stage of Plasmodium parasites. Repeated immunizations with live or irradiated sporozoites are known to protect vaccinated individuals against malaria challenge. Recent evidence suggests that this protection correlated with the presence of frequent pluripotent TEM, suggesting that permanent sterilizing immunity against malaria requires the induction of high levels of long-lived TEM by vaccination. To test this hypothesis, we propose to use recombinant cytomegalovirus (CMV) as a vaccine vector because CMV is the prototypical virus inducing long-lived TEM that do not show signs of T cell exhaustion. This unique capability of CMV-vectors was recently applied to induce long-lived TEM against simian immunodeficiency virus, resulting in protection against SIV-challenge that was by far superior to conventional heterologous prime/boost vaccines with respect to efficacy and duration. Since sterilizing protection against Plasmodium knowlesi parasites was only partial and shortlived when heterologous prime/boost vaccines were used, we will examine whether CMV-derived vaccine vectors will similarly confer lasting and efficacious immunity against challenge with Plasmodium knowlesi (Pk) sporozoites. We propose to generate recombinant RhCMV expressing four Pk antigens previously used for heterologous prime boost vaccination: the circumsporozoite protein (CSP), the sporozoite surface protein 2 or thrombospondin-related adhesion protein (SSP2 or TRAP), the apical merozoite antigen-1 (AMA1) and the C-terminus of the merozoite surface protein 1 (MSP1c). We will inoculate animals with this panel of four recombinant RhCMV/Pk vectors and monitor the development of TEM in blood, lung and liver. To determine whether the RhCMV/Pk4 vaccine is protective we will challenge with P. knowlesi sporozoites. Upon completion of this exploratory project, we will thus know whether a TEM-inducing vaccine can improve the level and duration of sterilizing immunity induced by subunit vaccines against malaria parasites.