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

• 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
• 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

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 我们的总体目的是通过识别PFSEA-1作为小儿恶性疟疾的疫苗候选者 广泛反应性的PFSEA-1特异性T卵泡辅助器（TFH）表位，这对于长寿命抗体至关重要 回答。 在先前的R01资助研究中，我们发现了Schizont Egress Antigen-1（PFSEA-1），一种244 kDa寄生虫 抗原是抗体的靶标的抗体，可在Schizont阶段捕获寄生虫。主动疫苗接种 RPBSEA-1导致寄生虫血症的3倍降低，挑战P挑战后的生存时间更长2倍。 Berghei Anka寄生虫（P = 0.001）。我们坦桑尼亚出生队列的孩子（n = 785）经历了 在无法检测到的抗PFSEA-1抗体的时期，严重疟疾的发生率急剧增加 与可检测到的抗体水平（0例/1,688个儿童）相比，水平（45例/23,806个儿童周） 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）， 与可检测的抗PFSEA-1 IgG抗体的个体相比，寄生虫密度降低了50％ 在18周的高传播中，具有无法检测到的抗PFSEA-1 IgG抗体（P <0.04）的个体 季节。这项工作最终导致了科学的全面全长研究文章。 疟疾疫苗发育的主要障碍是产生与 诱导长期血浆和记忆B细胞。在过去的10年中，TFH细胞被认为是 对于躯体过高，同种型切换，生发中心形成，长期活的浆细胞至关重要 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 感染，在急性疟疾感染期间观察到TFH细胞的CXCR3-子集的效率低下 在儿童中，这种缺陷可能是造成早期抗疟疾抗体反应的差的原因 童年3。基于TFH细胞的已知功能及其在产生保护抗体中的作用 对疫苗抗原4、5的反应，鉴定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中的MHC II类细胞表位映射TFH刺激 重组蛋白以及重叠的肽都接近。我们最初将确定所有可能的 半免疫成年人的横截面样品中的肽特异性表位。然后，我们将联系抗体， 细胞因子和T细胞子集对这些表位的反应，并在纵向队列中抗性感染 在居住在肯尼亚西部的全部地区地区的2 - 7年龄的儿童中进行的研究。 这项研究的可交付成果将是新出口阻塞中经过验证的T细胞表位的列表 疫苗候选PFSEA-1以及对抗体之间关系的全面，前瞻性分析， 细胞因子和T细胞子集对这些表位的反应以及对恶性疟原虫感染的抗性。这些 数据将使我们能够通过包括 来自侧面区域的广泛反应性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，这些结果将大大提高我们对角色的理解 小儿疟疾感染期间TFH细胞反应的动力学。