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.

项目概要 扎伊尔埃博拉病毒（EBOV）感染仍然是中非和西非的新威胁，病死率很高 FDA 批准的一种名为 ERVEBO 的减毒活重组疫苗已被证明达到高达 90%。 2016 年几内亚和 2019 年刚果民主共和国 (DRC) 最近爆发的疫情期间的承诺。 ERVEBO 刺激针对 EBOV 糖蛋白 (GP) 的抗体反应“环疫苗接种”。 当前的紧急免疫战略侧重于对直接接触和地理区域进行免疫接种 然而，刚果民主共和国的新数据显示，埃博拉病毒爆发中心周围的邻近人群。 在最近的一项抗病毒试验中，环疫苗接种可能存在很大的漏洞； 刚果民主共和国是 ERVEBO 疫苗的先前接受者 这些疫苗失败的机制基础尚不明确。 已知。 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 细胞反应支持了这一假设，埃博拉病毒的爆发主要发生。 恶性疟原虫感染流行；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埃博拉病毒疫苗接种 系统生成初步数据，表明疟疾极大地损害了埃博拉病毒疫苗诱导的、病毒- 我们还确定了克服疟疾相关的潜在策略。 在这个项目中，我们协同应用易于处理的、高分辨率的、抗原特异性的疫苗。 确定疟原虫感染影响 EBOV 疫苗诱导体液免疫的机制的系统 这些新方法有助于我们确定疟原虫影响的长期目标。 感染对埃博拉病毒疫苗诱导的免疫反应的功效的影响我们的目标是通过三个具体的目标来解决的。 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) 如何影响疫苗诱导的病毒特异性 B 细胞反应； 疟原虫感染会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 疫苗诱导的针对适应毒力小鼠 BSL-4 EBOV 的保护作用 成功完成这些研究将揭示疟原虫感染的机制。 损害埃博拉病毒疫苗反应并提供临床适用的方法来克服这种损害。 获得的知识将为在埃博拉病毒期间必须快速有效实施的疫苗策略提供信息 爆发。