Defining the effect of Plasmodium infection on Ebola virus vaccine efficacy

确定疟原虫感染对埃博拉病毒疫苗功效的影响

• 批准号: 10681616
• 负责人: Noah Sullivan Butler
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-11 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681616
• 关键词: Acute; Address; Affect; Affinity; Africa; Antibodies; Antibody Affinity; Antibody Response; Antibody titer measurement; Antigens; Area; Attenuated; B-Lymphocytes; Blood; CD4 Positive T Lymphocytes; Case Fatality Rates; Cellular Immunity; Data; Democratic Republic of the Congo; Development; Disease Outbreaks; Dose; Ebola Vaccines; Ebola virus; Emergency Situation; Event; FDA approved; Failure; Family; Filovirus; Geography; Glycoproteins; Goals; Guinea; Helper-Inducer T-Lymphocyte; Human; Humoral Immunities; Immune; Immune response; Immunization; Immunize; Immunoglobulin Class Switching; Immunoglobulin G; Impairment; Infection; Knowledge; Malaria; Memory; Memory B-Lymphocyte; Mus; Participant; Pathogenicity; Plasma Cells; Plasmodium; Plasmodium falciparum; Population; Porosity; Public Health; Recombinant Vaccines; Resolution; Structure of germinal center of lymph node; System; T cell response; T-Lymphocyte Subsets; Testing; Time; Vaccination; Vaccines; Viral; Viral Hemorrhagic Fevers; Virulent; Virus; Virus Diseases; Zaire Ebola virus; base; clinical application; clinically relevant; design; immunogenicity; in vivo; member; mortality; novel strategies; protective efficacy; response; transmission process; vaccination protocol; vaccination strategy; vaccine delivery; vaccine efficacy; vaccine failure; vaccine response; vaccine strategy; vaccine-induced immunity

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.

项目总结 扎伊尔埃博拉病毒(EBOV)感染仍然是中非和西非的一个新威胁，病死率很高 高达90%。FDA批准的一种名为ERVEBO的重组减毒活疫苗显示 2016年几内亚和2019年刚果民主共和国最近疫情期间的承诺。 ERVEBO刺激针对EBOV糖蛋白(GP)的抗体反应。“环形疫苗接种”是 目前的紧急免疫战略，重点是对直接接触者和地理位置进行免疫 EBOV暴发中心周围的近距离人群。然而，刚果民主共和国的新兴数据显示 这种环形疫苗接种可以高度渗透；在最近的一项抗病毒试验中，近30%的EBOV感染参与者 刚果民主共和国人以前是ERVEBO疫苗的接受者。这些疫苗失败的机制基础并不是 为人所知。 这个多PI、跨学科的项目探索了急性疟疾损害EBOV的假说 免疫诱导B细胞和T细胞反应。为了支持这一假设，EBOV疫情在很大程度上发生了 在那里恶性疟原虫感染是地方病；疟疾在中非和西非很常见。 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 系统产生的初步数据显示，疟疾极大地损害了EBOV疫苗诱导的病毒- 特异性抗体反应。我们还确定了克服疟疾相关疾病的潜在战略 疫苗效力受损。在这个项目中，我们协同使用了易处理的、高分辨率的、抗原特异性的 确定疟原虫感染影响EBOV疫苗诱导的体液的机制的系统 和细胞免疫。这些新方法有助于我们确定疟疾影响的长期目标。 感染对EBOV疫苗免疫效果的影响。我们的目标是通过三个具体的 测试的目的是：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反应所需的辅助T细胞亚群的功能； 3)疟疾如何影响EBOV疫苗诱导的对适应BSL-4 EBOV的强毒小鼠的保护 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疫苗的反应，并提供临床适用的方法来克服这种损害。是这样的 所获得的知识将为疫苗战略提供依据，这些战略必须在EBOV期间迅速有效地实施 疫情爆发。