Antibody and viral determinants of protection against CMV infection following gB/MF59 vaccination

gB/MF59 疫苗接种后针对 CMV 感染的抗体和病毒决定因素

基本信息

批准号：
9420470
负责人：
Cody S Nelson
金额：
$ 3.58万
依托单位：
DUKE 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：
2017-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9420470
关键词：
Address Adjuvant Amino Acids Antibodies Antibody Repertoire Antibody Response Binding Biological Assay Brain Injuries CMV glycoprotein B Centers for Disease Control and Prevention (U.S.)Child Chimeric Proteins Clinical Clinical Trials Cognitive deficits Collaborations Crystallization Cytomegalovirus Cytomegalovirus Infections Cytomegalovirus Vaccines Data Development Disease Doctor of Philosophy Down Syndrome Engineering Enzyme-Linked Immunosorbent Assay Epitopes Exhibits Failure Fetal Alcohol Syndrome Future Genetic Polymorphism Glycoproteins Hour Human Immune Immune Evasion Immune Targeting Immune response Immunization Immunologic Factors Incidence Individual Infant Infection Institute of Medicine (U.S.)Intervention Knowledge Laboratories Licensure MF59 Macaca mulatta Maps Mediating Mediator of activation protein Membrane Glycoproteins Modeling Modification Mutagenesis Mutation Neural Tube Defects Neurologic Newborn Infant Peptides Phase Phase II Clinical Trials Placebos Plasma Play Population Postpartum Women Predisposition Pregnancy Pregnant Women Prevention Proteins Regimen Research Priority Risk Role Sampling Site Specificity Structure Subunit Vaccines TYRP1 gene Techniques Tertiary Protein Structure Testing United States United States National Institutes of Health Vaccinated Vaccination Vaccines Validation Variant Vertical Disease Transmission Viral Virus Woman Work adverse outcome base cohort congenital cytomegalovirus congenital infection deafness deep sequencing defined contribution design disability efficacy trial fetal fetal infection hearing impairment human monoclonal antibodies immunogenicity improved in utero insight neutralizing antibody next generation sequencing nonhuman primate novel novel strategies phase II trial prevent protein B protein expression research clinical testing response transmission process unborn child vaccine candidate vaccine development vaccine efficacy vaccine trial vaccinology young woman

项目摘要

PROJECT SUMMARY/ABSTRACT Vertical transmission of cytomegalovirus (CMV) is the single most common cause of congenital infection worldwide, often resulting in deafness and neurodevelopmental delay for afflicted children. CMV related neurologic complications are more frequent and severe following primary maternal infection during pregnancy, and therefore a vaccine to prevent maternal acquisition of CMV during pregnancy is a potential strategy to reduce the incidence of infant congenital disease. The most successful maternal immunization regimen tested to date is a subunit vaccine consisting of CMV glycoprotein B (gB) combined with MF59 adjuvant, which achieved a promising 50% efficacy in multiple phase II clinical trials. However efforts to improve this vaccine have been slowed by an incomplete understanding of the determinants of protection against CMV infection. Previous studies have revealed a direct correlation between magnitude of the maternal CMV neutralizing antibody response and risk of congenital CMV infection. Concordant with these earlier studies, our laboratory has generated compelling data using both clinical cohorts and a novel nonhuman primate model of congenital CMV transmission, demonstrating that antibodies with the ability to neutralize CMV viruses may protect against in utero transmission. Yet it remains unclear whether antibody responses targeting the gB protein alone, and not other CMV glycoproteins, are sufficient for an effective vaccine to prevent congenital CMV. Recent discovery of the CMV gB crystal structure and identification of distinct protein domains targeted by neutralizing antibodies have made it possible to investigate gB/MF59-elicited protective antibody responses. Importantly, CMV surface glycoproteins such as gB have a high degree of structural diversity, suggesting that mutation of these proteins may be a mechanism to evade vaccine-elicited immune responses. I hypothesize that vaccine efficacy of a maternal gB immunization strategy is dependent upon 1) neutralizing antibodies targeting gB domains and 2) viral immune evasion from these protective immune responses. Over the next two years as a component of my Ph.D. dissertation project, I propose to employ novel approaches and cutting- edge vaccinology techniques to assess both antibody and viral determinants of vaccine protection using two independent gB/MF59 phase II trial cohorts. First, I will assess whether neutralizing antibodies predict CMV acquisition risk and define the epitope specificities of those protective antibodies. Secondly, through deep sequencing of viral variants and subsequent viral “sieve analysis,” I will investigate sequence diversity at the loci of gB domains to determine if viral immune evasion of vaccine-elicited immune responses is associated with vaccine failure. Finally, I will engineer and characterize chimeric rhesus CMV viruses containing human gB neutralizing domains for validation of viral immune evasion at identified polymorphic sites. These chimeric viruses will be used in the future in a nonhuman primate model developed by our laboratory, setting the stage for rational design and testing of a glycoprotein-based vaccine for the elimination of congenital CMV infection.

项目摘要/摘要巨细胞病毒（CMV）的垂直传播是先天性感染的最常见原因在全球范围内，经常导致患病儿童的死亡和神经发育延迟。 CMV相关神经系统并发症在怀孕期间原发性孕产妇感染后更频繁，严重，因此，预防孕产妇在怀孕期间获得CMV的疫苗是一种潜在的策略减少婴儿先天性疾病的发生率。测试的最成功的母体免疫方案迄今在多个II期临床试验中，实现了有希望的50％效率。但是要改善这种疫苗的努力对保护CMV感染的保护剂的不完全了解使人们放慢了脚步。先前的研究表明，母体CMV中和之间的直接相关性抗体反应和先天性CMV感染的风险。与这些早期研究一致，我们的实验室已经使用临床队列和一种新型的非人类私人模型生成了引人注目的数据 CMV传输，证明具有中和CMV病毒能力的抗体可能会预防在子宫内传输中。然而，尚不清楚是否仅针对GB蛋白的抗体反应，并且没有其他CMV糖蛋白足以使有效的疫苗预防先天性CMV。 CMV GB GB晶体结构的最新发现以及针对由中和抗体使研究GB/MF59引起的保护抗体反应成为可能。重要的是，CMV表面糖蛋白（例如GB）具有高度的结构多样性，表明这些蛋白质的突变可能是逃避疫苗引诱的免疫反应的机制。我假设主要GB免疫策略的疫苗效率取决于1）中和抗体靶向GB结构域和2）从这些受保护的免疫反应中的病毒免疫进化。在接下来的两个多年来作为我博士学位的组成部分论文项目，我建议员工新颖的方法和削减 - 使用两种疫苗的边缘疫苗学技术，以评估疫苗保护的抗体和病毒决定剂独立的GB/MF59 II期试验队列。首先，我将评估中和抗体是否预测CMV 获取风险并定义这些受保护抗体的表位特异性。其次，通过深处病毒变异的测序和随后的病毒“筛分分析”，我将研究序列多样性 GB结构域的基因座，以确定疫苗引起的免疫调查的病毒免疫驱除是否相关与疫苗衰竭。最后，我将设计并表征含有人类的嵌合恒河神CMV病毒 GB中和结构域在鉴定的多态性位点验证病毒免疫进化。这些嵌合将来将在我们实验室开发的非人类私人模型中使用病毒，设置舞台用于理性设计和基于糖蛋白的疫苗，以消除先天性CMV感染。