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

总结 研制疟疾杀菌疫苗仍然是全球卫生的最高优先事项之一 research.虽然针对进入血液阶段之前的疟疾寄生虫的实验性疫苗， 尽管显示出巨大的希望，但迄今为止还不可能获得维持免疫力所需的长期免疫力。 保护时间。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细胞引发疫苗。通过利用 CMV引发和维持高频率、非耗竭、终身细胞免疫天然能力， 证明了基于CMV的疫苗可以预防高毒力病原体，如猿猴免疫- 缺乏病毒和结核分枝杆菌。我们的工作为根除艾滋病带来了新的希望，我们正在 CMV/HIV疫苗的临床开发。在初步工作中，我们现在还表明，基于CMV的 含有一组有限的疟疾抗原的疟疾疫苗在血液阶段之前减少寄生虫负担 发展这项建议的中心目标是进一步改善这种保护， 消除免疫力我们将利用CMV疫苗的独特免疫学特性， 设计CMV疫苗，募集不同类型的细胞毒性T细胞，以消除寄生虫肝脏阶段。 具体来说，我们将讨论传统的MHC-I限制性CD 8 + T细胞与非传统细胞的作用 MHC-II和MHC-E限制性CD 8 + T细胞的保护作用。我们还将扩大寄生虫的范围 通过包括一组针对疟疾红细胞前期阶段的新疫苗靶点，这些新疫苗 基于对人类T细胞免疫的系统评价和对小鼠的验证来选择靶点 疟疾模型最后，我们将扩大免疫反应和保护作用引起的异源 通过用CMV载体加强的初次/加强免疫，其引发MHC-I限制性CD 8 + T细胞识别 免疫显性和亚显性表位。我们预计，该项目将确认CMV为新的 预防疟疾的疫苗。

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.