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; 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.

项目摘要 Zaire Ebola病毒（EBOV）感染仍然是中非和西非的新兴威胁 达到90％。 FDA批准的，现场活体，重组疫苗称为Ervebo已显示 在2016年几内亚的最近爆发和刚果民主共和国（DRC）的爆发期间。 Ervebo刺激针对EBOV糖蛋白（GP）的抗体反应。 “环疫苗接种”是 当前的紧急免疫策略，重点是对直接接触和地理位置进行免疫接触 围绕EBOV爆发的中心近端人口。但是，DRC中的新兴数据显示 该环疫苗接种可能是高度多孔的。最近在最近的一项抗病毒试验中，几乎30％的EBOV感染了参与者 DRC是Ervebo疫苗的先前接受者。这些疫苗失败的机械基础不是 已知。 这个多pi的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爆发在很大程度上发生 恶性疟原虫感染是内在的；疟疾在整个中非和西非很常见。 此外，我们的协作团队已经开发了实验性疟原虫感染和EBOV疫苗接种 产生初步数据的系统，表明疟疾极大地损害了EBOV疫苗诱导的病毒 - 特定的抗体反应。我们还确定了克服疟疾相关的潜在策略 疫苗效率的障碍。在这个项目中，我们协同应用可拖动的高分辨率，抗原特异性 确定疟原虫感染影响EBOV疫苗引起的体液的机制 和细胞免疫。这些新方法促进了我们的长期目标来定义疟原虫的影响 EBOV疫苗诱导的免疫反应的效率感染。我们的目标是由三个特定的 目的是测试：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 疟原虫感染会影响促进抗体反应所需的辅助T细胞子集的功能； 3）疟疾如何影响EBOV疫苗诱导的针对病毒小鼠的保护，BSL-4 EBOV 挑战。这些研究的成功完成将揭示疟原虫感染的机制 损害了EBOV疫苗反应，并提供临床适用的方法来克服这种障碍。 获得的知识将为您在EBOV期间必须快速有效地实施的疫苗策略提供信息 爆发。