Tfh responses to novel vaccine candidates and protection from pediatric falciparum malaria

Tfh 对新型候选疫苗的反应以及对小儿恶性疟疾的保护

基本信息

批准号：
9977935
负责人：
Jonathan D. Kurtis
金额：
$ 65.55万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-11 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9977935
关键词：
2 year old Acute Adult Age Algorithms Antibodies Antibody Response Antigens Antimalarials Area BLR1 gene Biological Assay Birth Blocking Antibodies CXCR3 gene Child Childhood Clinical Data Defect Dependence Disease Epitopes Erythrocytes Falciparum Malaria Flow Cytometry Formulation Funding Generations Helper-Inducer T-Lymphocyte Hepatocyte Human Immune Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin Somatic Hypermutation Incidence Individual Infection Kenya Kinetics Knowledge Length Longitudinal cohort study MHC Class II Genes Malaria Malaria Vaccines Maps Measures Memory B-Lymphocyte Merozoite Surface Protein 1 Methods Parasitemia Parasites Peptides Peripheral Blood Mononuclear Cell Planets Plasma Plasma Cells Plasmodium falciparum Production Proteins Proteome Publishing Recombinant Proteins Reporting Research Resistance Resistance to infection Role Sampling Science Seasons Sentinel Structure of germinal center of lymph node T-Lymphocyte Epitopes T-Lymphocyte Subsets Tanzania Time Vaccination Vaccine Antigen Vaccines Work aged base cohort cytokine density early childhood epidemiologic data experience immunogenicity interleukin-21 malaria infection male novel novel vaccines programmed cell death protein 1 prospective response screening transmission process vaccine candidate vaccine development

项目摘要

ABSTRACT Our overall aim is to advance PfSEA-1 as a vaccine candidate for pediatric falciparum malaria by identifying broadly reactive, PfSEA-1 specific T follicular helper (Tfh) epitopes, which are critical for long-lived antibody responses. In previous R01 funded studies, We discovered Schizont Egress Antigen-1 (PfSEA-1), a 244-kDa parasite antigen that is the target of antibodies which arrest parasites at the schizont stage. Active vaccination with rPbSEA-1 results in a 3-fold reduction in parasitemia and a 2 fold longer survival time after challenge with P. berghei ANKA parasites (P = 0.001). Children in our Tanzanian birth cohort (N=785) experienced a dramatically increased incidence of severe malaria during periods with undetectable anti-PfSEA-1 antibody levels (45 cases/23,806 child weeks) compared to periods with detectable antibody levels (0 cases/1,688 child weeks; adjusted OR 4.4; Type III fixed effects P < 0.01). In our cohort of Kenyan males (12-35 yrs old, N= 138), individuals with detectable anti-PfSEA-1 IgG antibodies had 50% decreased parasite density compared to individuals with undetectable anti-PfSEA-1 IgG antibodies (P < 0.04) over an 18-week high transmission season. This work has culminated in a comprehensive, full length Research Article in Science 1. A major obstacle to malaria vaccine development is the generation of high-titer functional antibodies with the induction of long-lived plasma and memory B-cells. In the past 10 yrs, Tfh cells have been recognized as essential for somatic hypermutation, isotype switching, germinal center formation, long lived plasma cell formation as well as memory B cell formation 2. Intriguingly, in the only report of Tfh cells in human malaria infection, inefficient activation of the CXCR3- subset of Tfh cells was observed during acute malaria infections in children, and this defect may be responsible for the poor anti-malarial antibody responses seen in early childhood 3. Based on the known function of Tfh cells and their role in generating protective antibody responses to vaccine antigens 4, 5, identifying Tfh epitopes is essential for malaria vaccine optimization. In the current application, we propose to map Tfh stimulating, MHC Class II T cell epitopes in PfSEA-1 using both recombinant protein as well as overlapping peptide approaches. We will initially identify all possible peptide specific epitopes in a cross-sectional sample of semi-immune adults. We will then relate antibody, cytokine, and T-cell subset responses to these epitopes with resistance to infection in a longitudinal cohort study conducted in 2-7 yr old children living in a holoendemic region of western Kenya. The deliverables from this study will be a list of validated T cell epitopes within the novel egress blocking vaccine candidate PfSEA-1 and a comprehensive, prospective analysis of the relationship between antibody, cytokine and T-cell subset responses to these epitopes and resistance to infection with P. falciparum. These data will allow us to enhance the immunogenicity of second generation rPfSEA-1A based vaccines by including broadly reactive T cell epitopes from the flanking regions, or increasing the copy number of T-cell epitopes within the aa 810-1083 region. In addition, these results will significantly increase our understanding of the role and kinetics of Tfh cell responses during pediatric malaria infections.

抽象的我们的总体目标是通过确定 PfSEA-1 作为儿童恶性疟疾候选疫苗的地位广泛反应性的 PfSEA-1 特异性滤泡辅助性 T (Tfh) 表位，对于长寿命抗体至关重要回应。在之前的 R01 资助的研究中，我们发现了 Schizont Egress Antigen-1 (PfSEA-1)，一种 244 kDa 的寄生虫抗原是在裂殖体阶段阻止寄生虫的抗体的目标。积极接种疫苗 rPbSEA-1 可使寄生虫血症减少 3 倍，并且在受到疟原虫攻击后，存活时间延长 2 倍。 berghei ANKA 寄生虫 (P = 0.001)。我们坦桑尼亚出生队列中的儿童 (N=785) 经历了在抗 PfSEA-1 抗体检测不到的时期，严重疟疾的发病率急剧增加水平（45 例/23,806 儿童周）与可检测到抗体水平的时期（0 例/1,688 儿童几周；调整或4.4； III 型固定效应 P < 0.01）。在我们的肯尼亚男性队列中（12-35 岁，N= 138），与相比，具有可检测到的抗 PfSEA-1 IgG 抗体的个体的寄生虫密度降低了 50% 在 18 周的高传播期内具有检测不到的抗 PfSEA-1 IgG 抗体 (P < 0.04) 的个体季节。这项工作最终在 Science 1 上发表了一篇全面、完整的研究文章。疟疾疫苗开发的一个主要障碍是产生高滴度功能性抗体诱导长寿命血浆和记忆 B 细胞。在过去的10年里，Tfh细胞被认为是对于体细胞超突变、同种型转换、生发中心形成、长寿浆细胞至关重要形成以及记忆 B 细胞形成 2。有趣的是，在人类疟疾中 Tfh 细胞的唯一报告中在急性疟疾感染期间，观察到 Tfh 细胞 CXCR3 子集的低效激活在儿童中，这种缺陷可能是早期儿童中抗疟疾抗体反应较差的原因。童年3.基于Tfh细胞的已知功能及其在产生保护性抗体中的作用针对疫苗抗原 4、5 的反应，识别 Tfh 表位对于疟疾疫苗优化至关重要。在当前的应用中，我们建议使用 PfSEA-1 来绘制 Tfh 刺激的 MHC II 类 T 细胞表位重组蛋白和重叠肽方法。我们将首先确定所有可能的半免疫成人横截面样本中的肽特异性表位。然后我们将关联抗体，在纵向队列中，细胞因子和 T 细胞亚群对这些表位的反应具有抗感染性对生活在肯尼亚西部大流行地区的 2-7 岁儿童进行的研究。这项研究的成果将是新型出口阻断中经过验证的 T 细胞表位列表候选疫苗 PfSEA-1 与抗体之间关系的全面、前瞻性分析，细胞因子和 T 细胞亚群对这些表位的反应以及对恶性疟原虫感染的抵抗力。这些数据将使我们能够通过包括以下内容来增强第二代 rPfSEA-1A 疫苗的免疫原性来自侧翼区域的广泛反应性 T 细胞表位，或增加 T 细胞表位的拷贝数在 aa 810-1083 区域内。此外，这些结果将显着增加我们对该角色的理解以及儿科疟疾感染期间 Tfh 细胞反应的动力学。