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率和死亡率最重要的原因之一。研究儿童的麻疹和良好的恒河猕猴模型表明野生型的清除率（wt）麻疹病毒（MEV）RNA在清除感染性病毒并持续的情况下持续了多个月在外周血单核细胞和淋巴组织中。 RNA持久性伴随着免疫刺激，持续产生MEV特异性浆体，抗体（AB）成熟和功能上不同的T细胞多波。这些免疫反应导致对麻疹的终身免疫力，但是可比较的数据无法用于现场衰减的MEV疫苗。 MEV疫苗是开发的通过通过鸡肉细胞中的传递来衰减WT MEV分离物，从经验上。由此产生的现场衰减疫苗于1963年获得授权为持续的高覆盖范围造成了障碍，这可能会通过呼吸道输送来缓解。它的安全记录，结合负链病毒的反向遗传学的进步，导致了重组版本作为针对其他感染的免疫的向量，作为一种多样性的溶瘤剂肿瘤。但是，对体内生物学中MEV疫苗病毒基本方面的基本方面的了解有限发展。例如，对疫苗病毒复制的位置几乎没有知识毒力的衰减或免疫反应与WT感染诱导的免疫反应如何不同除了注意到抗体滴度较低，保护效果较低。我们假设一个中心疫苗和WT菌株感染之间的差异是复制和持续存在的能力组织。该建议将通过以下方面解决此知识差距：1）识别疫苗病毒的靶细胞复制不如WT病毒。我们假设减弱的复制是细胞类型特异性的，并且 MEV的疫苗菌株在髓样，内皮和上皮细胞中很好地复制，但在淋巴样细胞中很差。 2）确定效率低下的MEV疫苗病毒复制的病毒决定因素。我们假设血凝素（H）和基质（M）蛋白是淋巴细胞中效率低下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疫苗的重组菌株将在淋巴细胞中测试复制。 3）确定体内部位恒河猕猴中疫苗病毒复制和病毒RNA清除率的动力学。我们假设这一点 MEV的疫苗菌株不会从感染的淋巴部位有效扩散，并且两者都是感染性病毒和病毒RNA迅速清除。 4）确定CD4+ T细胞的差异和AB对感染的反应与疫苗和WT MEV一起使用。我们假设疫苗菌株会诱导更少的MEV特异性AB分泌细胞与WT相比，与较少稳健和多功能CD4+ T细胞响应相关的时间较短菌株。