A Cytomegalovirus-based Vaccine Targeting the Pre-erythrocytic Stage of Malaria

摘要 疟疾灭菌疫苗的开发仍然是全球卫生的最高优先事项之一。 研究。虽然针对疟疾寄生虫的实验性疫苗在进入血液阶段之前已经 表现出巨大的希望，到目前为止还不可能获得维持所需的长期豁免权 随着时间的推移得到保护。我们建议将一种全新的疫苗工具应用于疟疾疫苗研究： 基于巨细胞病毒(CMV)的持久效应记忆T细胞激发疫苗通过利用 巨细胞病毒诱导和维持高频、不衰竭、终生细胞免疫的天然能力 证明了基于CMV的疫苗可以保护人们免受强毒病原体的侵袭，例如猿猴免疫-- 缺乏病毒和结核分枝杆菌。我们的工作重新燃起了根除艾滋病的希望，我们正在 目前正在临床上开发巨细胞病毒/艾滋病疫苗。在前期工作中，我们现在还展示了基于CMV 含有一组有限疟疾抗原的疟疾疫苗减少了血液阶段前的寄生虫负担 发展。这项提案的中心目标是进一步改善这一保护，以便产生 消毒免疫力。我们将通过以下方式应用巨细胞病毒疫苗的独特免疫学特性 设计CMV疫苗，招募不同类型的细胞毒性T细胞来消除寄生虫肝脏阶段。 具体地说，我们将讨论常规的、MHC-I限制的CD8+T细胞与非传统的CD8+T细胞的作用 MHC-II和MHC-E限制性CD8+T细胞处于保护状态。我们还将拓宽寄生虫的范围 通过纳入一套针对疟疾红细胞前阶段的新疫苗靶标，我们可以获得更多的抗原性。这些新疫苗 靶点的选择是基于对人类T细胞免疫的系统评估和小鼠的验证 疟疾模型。最后，我们将扩大异源病毒引起的免疫反应和保护作用。 巨细胞病毒载体加强免疫诱导MHC-I限制性CD8+T细胞识别 既有免疫优势表位，也有亚优势表位。我们预计这个项目将验证CMV为新的 预防疟疾的疫苗接种方法。

SUMMARY The development of a sterilizing vaccine against malaria remains one of the highest priorities for global health research. While experimental vaccines targeting the malaria parasite prior to entering the blood stage have shown great promise, it has so far not been possible to elicit the longterm immunity required to maintain protection over time. We propose to apply a fundamentally new vaccine tool to malaria vaccine research: persistent effector memory T cell-eliciting vaccines based on cytomegalovirus (CMV). By taking advantage of the natural ability of CMV to elicit and maintain high frequency, non-exhausted, life-long cellular immunity we demonstrated that CMV-based vaccines protect against highly virulent pathogens such as simian immune- deficiency virus and mycobacterium tuberculosis. Our work has renewed hope for AIDS eradication and we are now in clinical development of CMV/HIV vaccines. In preliminary work we now also show that CMV-based malaria vaccines containing a limited set of malaria antigens reduce the parasite burden prior to blood stage development. The central goal of this proposal is to further improve this protection in order to generate sterilizing immunity. We will apply the unique immunological characteristics of CMV-based vaccines by designing CMV-vaccines that recruit different types of cytotoxic T cells to eliminate the parasite liver stage. Specifically, we will address the role of conventional, MHC-I restricted CD8+ T cells versus unconventional MHC-II and MHC-E-restricted CD8+ T cells in protection. We will additionally broaden the spectrum of parasite antigens by including a new set of vaccine targets for the pre-erythrocytic stage of malaria. These new vaccine targets were selected based on systematic evaluation of T cell immunity in humans and validation in murine malaria models. Finally we will extend the immune responses and protective effects elicited by heterologous prime/boost immunization by boosting with CMV-vectors eliciting MHC-I restricted CD8+ T cells recognizing both immunodominant and subdominant epitopes. We anticipate that this project will validate CMV as new method to vaccinate against malaria.