An Effector Memory T Cell-Inducing Subunit Vaccine against Malaria

项目描述（申请人提供）：本项目的最终目标是开发一种抗疟疾的杀菌疫苗。在这个提议中测试的具体假设是，针对疟疾的杀菌免疫可以通过诱导针对疟原虫寄生虫的肝脏阶段的持久效应记忆T细胞（TEM）应答来实现。已知用活的或经辐照的子孢子重复免疫可保护接种个体免受疟疾攻击。最近的证据表明，这种保护与频繁的多能TEM的存在相关，这表明对疟疾的永久性杀菌免疫需要通过接种疫苗诱导高水平的长寿TEM。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CMV是诱导长寿命TEM的原型病毒，不显示T细胞耗竭的迹象。CMV-载体的这种独特能力最近被应用于诱导针对猿猴免疫缺陷病毒的长寿命TEM，导致针对SIV-攻击的保护，其在功效和持续时间方面远远上级常规异源初免/加强疫苗。由于使用异源初免/加强疫苗时，对诺氏疟原虫寄生虫的灭菌保护仅是部分的且短暂的，因此我们将研究CMV衍生的疫苗载体是否同样赋予针对诺氏疟原虫（Pk）子孢子攻击的持久有效的免疫力。我们建议产生表达先前用于异源初免加强疫苗接种的四种Pk抗原的重组RhCMV：环子孢子蛋白（CSP）、子孢子表面蛋白2或血小板反应蛋白相关粘附蛋白（SSP 2或TRAP）、顶端裂殖子抗原-1（AMA 1）和裂殖子表面蛋白1（MSP 1c）的C末端。我们将用这组四种重组RhCMV/Pk载体感染动物，并监测血液、肺和肝脏中TEM的发展。为了确定RhCMV/Pk 4疫苗是否具有保护性，我们将用诺氏疟原虫子孢子进行攻击。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针对疟原虫的亚单位疫苗诱导的杀菌免疫的水平和持续时间。

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.