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.

项目概要/摘要巨细胞病毒（CMV）垂直传播是先天性感染的最常见原因在世界范围内，经常导致受 CMV 影响的儿童耳聋和神经发育迟缓。妊娠期间原发性母亲感染后，神经系统并发症更加频繁和严重，因此，预防母亲在怀孕期间感染巨细胞病毒的疫苗是一种潜在的策略降低婴儿先天性疾病的发生率经测试最成功的孕产妇免疫方案。迄今为止，一种由 CMV 糖蛋白 B (gB) 与 MF59 佐剂组合而成的亚单位疫苗，在多项 II 期临床试验中取得了令人鼓舞的 50% 的疗效，但仍需努力改进这种疫苗。由于对 CMV 感染保护的决定因素的不完全了解而减慢了速度。先前的研究表明，母体 CMV 中和程度与母体 CMV 中和程度之间存在直接相关性。抗体反应和先天性巨细胞病毒感染的风险与这些早期研究一致，我们的实验室。使用临床队列和新型非人类灵长类动物先天性模型产生了令人信服的数据 CMV 传播，证明具有中和 CMV 病毒能力的抗体可以预防然而，目前尚不清楚抗体反应是否单独针对 gB 蛋白，以及而非其他巨细胞病毒糖蛋白，足以成为预防先天性巨细胞病毒的有效疫苗。最近发现了 CMV gB 晶体结构并鉴定了不同的蛋白质结构域中和抗体使得研究 gB/MF59 引发的保护性抗体反应成为可能。重要的是，CMV 表面糖蛋白（例如 gB）具有高度的结构多样性，这表明这些蛋白质的突变可能是逃避疫苗引发的免疫反应的机制。母体 gB 免疫策略的疫苗功效取决于 1) 中和抗体靶向 gB 结构域和 2) 在接下来的两个过程中病毒免疫逃避这些保护性免疫反应。作为我博士论文项目的一部分，我建议采用新颖的方法和切割边缘疫苗学技术，使用两种方法评估疫苗保护的抗体和病毒决定因素首先，我将评估中和抗体是否可以预测 CMV。其次，通过深入了解获得风险并定义这些保护性抗体的表位特异性。对病毒变体进行测序以及随后的病毒“筛分分析”，我将研究序列多样性 gB 结构域的位点，以确定疫苗引发的免疫反应的病毒免疫逃避是否相关最后，我将设计并表征含有人类的嵌合恒河猴 CMV 病毒。 gB 中和结构域，用于验证这些嵌合体位点上的病毒免疫逃避。病毒将来将用于我们实验室开发的非人类灵长类动物模型，为我们奠定基础合理设计和测试基于糖蛋白的疫苗，以消除先天性巨细胞病毒感染。