Defining the effect of Plasmodium infection on Ebola virus vaccine efficacy

项目摘要 扎伊尔埃博拉病毒（EBOV）感染仍然是中非和西非的一个新出现的威胁， 高达90%。FDA批准的一种称为ERVEBO的减毒活重组疫苗显示， 在2016年几内亚和2019年刚果民主共和国最近爆发的疫情期间， ERVEBO刺激针对EBOV糖蛋白（GP）的抗体应答。"环疫苗"是 目前的紧急免疫战略，重点是免疫直接接触者和地理 EBOV爆发中心附近的人群。然而，刚果民主共和国的新数据显示， 环形疫苗接种可能是高度多孔的;在最近的一项抗病毒试验中， 刚果民主共和国是ERVEBO疫苗的优先接受者。这些疫苗失败的机制基础不是 知道的 这个多PI，跨学科项目探讨了急性疟疾损害EBOV的假设 免疫诱导的B和T细胞反应。为了支持这一假设，EBOV爆发主要发生在 在那里恶性疟原虫感染是地方性的;疟疾在整个中非和西非都很常见。 此外，我们的合作团队还开发了实验性疟原虫感染和EBOV疫苗接种， 系统生成的初步数据显示，疟疾极大地削弱了EBOV疫苗诱导的病毒， 特异性抗体反应。我们还确定了可能的战略，以克服与疟疾有关的 疫苗效力的损害。在这个项目中，我们协同应用易处理的，高分辨率的，抗原特异性的 系统，以确定疟原虫感染影响EBOV疫苗诱导的体液免疫的机制， 和细胞免疫。这些新方法有助于我们确定疟原虫影响的长期目标 感染对EBOV疫苗诱导的免疫应答的效力。我们的目标是通过三个具体的 旨在测试：1）疟原虫感染如何影响疫苗诱导的病毒特异性B细胞反应; 2）如何 疟原虫感染影响促进抗体应答所需的辅助性T细胞亚群的功能; 以及3）疟疾如何影响EBOV疫苗诱导的针对强毒小鼠适应的BSL-4 EBOV的保护 挑战.这些研究的成功完成将揭示疟原虫感染的机制 削弱EBOV疫苗应答并提供临床上可应用的方法来克服这种损害。等 获得的知识将为疫苗战略提供信息，这些战略必须在EBOV期间迅速有效地实施。 爆发。

PROJECT SUMMARY Zaire Ebola virus (EBOV) infections remain an emerging threat in Central and West Africa with case fatality rates reaching as high as 90%. An FDA-approved, live-attenuated, recombinant vaccine called ERVEBO has shown promise during recent outbreaks in Guinea in 2016 and Democratic Republic of the Congo (DRC) in 2019. ERVEBO stimulates antibody responses directed against the EBOV glycoprotein (GP). “Ring vaccination” is the current emergency immunization strategy that focuses on immunizing direct contacts and geographically proximal populations surrounding the epicenter of an EBOV outbreak. However, emerging data in the DRC show that ring vaccination can be highly porous; nearly 30% of EBOV-infected participants in a recent antiviral trial in the DRC were prior recipients of the ERVEBO vaccine. The mechanistic bases for these vaccine failures are not known. This multi-PI, interdisciplinary project explores the hypothesis that acute malaria impairs EBOV immunization-induced B and T cell responses. In support of this hypothesis, EBOV outbreaks largely occur where Plasmodium falciparum infections are endemic; malaria is common throughout Central and West Africa. Moreover, our collaborative team has developed experimental Plasmodium infection and EBOV vaccination systems to generate preliminary data showing that malaria dramatically impairs EBOV vaccine-induced, virus- specific antibody responses. We have also identified potential strategies to overcome the malaria-associated impairments in vaccine efficacy. In this project we synergistically apply tractable, high-resolution, antigen-specific systems to determine the mechanisms by which Plasmodium infections impact EBOV vaccine-induced humoral and cellular immunity. These new approaches facilitate our long-term goal to define the impact of Plasmodium infection on the efficacy of EBOV vaccine-induced immune responses. Our goal is addressed by three specific aims that test: 1) how Plasmodium infections impact vaccine-induced, virus specific B cell responses; 2) how Plasmodium infections influence the function of helper T cell subsets required for promoting antibody responses; and 3) how malaria affects EBOV vaccine-induced protection against virulent mouse adapted, BSL-4 EBOV challenge. Successful completion of these studies will reveal the mechanisms by which Plasmodium infections impair EBOV vaccine responses and provide clinically applicable approaches to overcome this impairment. Such knowledge gained will inform vaccine strategies that must be rapidly and effectively implemented during EBOV outbreaks.