Physiological and immunological responses to measles vaccine

麻疹疫苗的生理和免疫反应

基本信息

批准号：
10200638
负责人：
Diane E Griffin
金额：
$ 66.16万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-06 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10200638
关键词：
Address Amino Acid Substitution Antibodies Antibody Response Antibody titer measurement Attenuated Attenuated Vaccines Avidity B-Lymphocytes Biological Biology Blood Bone Marrow CD4 Positive T Lymphocytes Cause of Death Cells Characteristics Chicken Cells Child Communicable Diseases Data Development Dose Endothelial Cells Epithelial Cells Exanthema Gene Proteins Genetic Determinism Hemagglutinin Immune response Immunity Immunization Immunoglobulin-Secreting Cells Infection Inhalation Injections Knowledge Lymphocyte Lymphoid Lymphoid Cell Lymphoid Tissue Macaca Macaca mulatta Measles Measles Vaccine Measles virus Modeling Morbidity - disease rate Myeloid Cells Oncolytic Pattern Peripheral Blood Mononuclear Cell Physiological Plasmablast Population Process Production Productivity Proteins RNA Recombinants Rest Safety Sampling Signal Transduction Site Structure of respiratory epithelium T cell response T-Cell Immunologic Specificity T-Lymphocyte TLR2 gene Testing Time Vaccines Viral Viremia Virulence Virulent Virus Virus Assembly Virus Replication attenuated measles virus attenuation cancer therapy cell type citrate carrier in vivo mortality novel vaccines respiratory response reverse genetics tumor vector viral RNA

项目摘要

Summary Measles remains one of the most important causes of child morbidity and mortality worldwide. Studies of measles in children and in a well-characterized rhesus macaque model have shown that clearance of wild type (WT) measles virus (MeV) RNA is ongoing for many months after clearance of infectious virus with persistence in peripheral blood mononuclear cells and lymphoid tissues. RNA persistence is accompanied by ongoing immune stimulation with continued production of MeV-specific plasmablasts, antibody (Ab) maturation and multiple waves of functionally distinct T cells. These immune responses result in lifelong immunity to measles, but comparable data are not available for the live attenuated MeV vaccine. The MeV vaccine was developed empirically by attenuation of a WT MeV isolate by passage in chicken cells. The resultant live attenuated vaccine was licensed in 1963 and has been remarkably safe and successful although delivery by injection creates hurdles to sustained high coverage that might be alleviated with respiratory delivery. Its safety record, combined with advances in reverse genetics for negative strand viruses, have led to development of recombinant versions as vectors for immunization against other infections and as oncolytic agents for a variety of tumors. However, limited understanding of fundamental aspects of MeV vaccine virus in vivo biology hinders development. For instance, there is little knowledge of where the vaccine virus replicates, the mechanism(s) of attenuation of virulence or how the immune responses induced differ from those induced by WT infection except to note that antibody titers are lower and protection is less durable. We hypothesize that a central difference between infection with vaccine and WT strains is the ability to replicate and persist in lymphoid tissues. This proposal will address this knowledge gap by: 1) Identifying the target cell(s) in which vaccine virus replicates less well than WT virus. We hypothesize that attenuated replication is cell type-specific and that vaccine strains of MeV replicate well in myeloid, endothelial and epithelial cells, but poorly in lymphoid cells. 2) Identifying the viral determinants of inefficient MeV vaccine virus replication. We hypothesize that the hemagglutinin (H) and matrix (M) proteins are the primary determinants of inefficient replication in lymphocytes through effects on TLR2 signaling, virus assembly and release and will test the hypothesis by constructing recombinant strains of EZ vaccine that will tested for replication in lymphocytes. 3) Determining the in vivo sites of vaccine virus replication and dynamics of viral RNA clearance in rhesus macaques. We hypothesize that vaccine strains of MeV do not spread efficiently from lymphoid sites of infection and that both infectious virus and viral RNA are cleared quickly. 4) Identifying differences in the CD4+ T cell and Ab responses to infection with vaccine and WT MeV. We hypothesize that vaccine strains induce fewer MeV-specific Ab-secreting cells for a shorter period of time associated with a less robust and less polyfunctional CD4+ T cell response than WT strains.

概括麻疹仍然是全世界儿童发病和死亡的最重要原因之一。研究儿童麻疹和特征明确的恒河猴模型表明，野生型麻疹的清除 (WT) 麻疹病毒 (MeV) RNA 在清除传染性病毒后持续数月存在于外周血单核细胞和淋巴组织中。 RNA 持久性伴随着持续的通过持续产生 MeV 特异性浆母细胞、抗体 (Ab) 成熟和多波功能不同的 T 细胞。这些免疫反应导致对麻疹的终生免疫力，但 MeV 减毒活疫苗没有可比数据。 MeV疫苗研制成功根据经验，通过在鸡细胞中传代来减毒 WT MeV 分离株。由此产生的活衰减疫苗于 1963 年获得许可，尽管通过注射给药，但仍然非常安全和成功这对持续高覆盖率造成了障碍，而这些障碍可以通过呼吸输送来缓解。其安全记录，结合负链病毒反向遗传学的进展，导致了重组版本作为针对其他感染的免疫载体以及作为多种溶瘤剂肿瘤。然而，对 MeV 疫苗病毒体内生物学基本方面的了解有限阻碍了发展。例如，人们对疫苗病毒的复制地点、复制机制知之甚少。毒力减弱或诱导的免疫反应与 WT 感染诱导的免疫反应有何不同但要注意的是，抗体滴度较低且保护效果较不持久。我们假设一个中央疫苗和 WT 毒株感染之间的区别在于在淋巴中复制和持续的能力组织。该提案将通过以下方式解决这一知识差距：1）识别疫苗病毒所在的靶细胞复制能力不如 WT 病毒。我们假设复制减弱是细胞类型特异性的，并且 MeV 疫苗株在骨髓细胞、内皮细胞和上皮细胞中复制良好，但在淋巴细胞中复制较差。 2）确定 MeV 疫苗病毒复制效率低下的病毒决定因素。我们假设血凝素 (H) 和基质 (M) 蛋白是淋巴细胞低效复制的主要决定因素通过对 TLR2 信号传导、病毒组装和释放的影响，并将通过构建来检验该假设 EZ 疫苗的重组菌株将测试其在淋巴细胞中的复制情况。 3) 体内位点的确定恒河猴中疫苗病毒复制和病毒 RNA 清除动力学的研究。我们假设 MeV 疫苗株不能从感染的淋巴部位有效传播，并且这两种传染性病毒病毒RNA被快速清除。 4) 识别 CD4+ T 细胞和抗体对感染反应的差异与疫苗和 WT MeV。我们假设疫苗株诱导较少的 MeV 特异性抗体分泌细胞与 WT 相比，持续时间更短，且 CD4+ T 细胞反应的稳健性和多功能性较差菌株。