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

• 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
• 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

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.

项目总结/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 在世界范围内，这通常会导致患病儿童的耳聋和神经发育迟缓。CMV相关 神经系统并发症在妊娠期间原发性母体感染后更频繁和严重， 因此，预防孕妇在怀孕期间获得CMV的疫苗是一种潜在的策略， 降低婴儿先天性疾病的发生率。测试的最成功的孕产妇免疫方案 迄今为止是由CMV糖蛋白B（gB）与MF 59佐剂组合组成的亚单位疫苗， 在多项II期临床试验中取得了令人鼓舞的50%疗效。然而，改进这种疫苗的努力 由于对保护免受CMV感染的决定因素的不完全理解， 先前的研究已经揭示了母体CMV中和作用的大小与 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 使用临床队列和一种新的非人灵长类动物先天性心脏病模型， CMV传播，表明具有中和CMV病毒能力的抗体可以保护免受 在子宫内传播然而，目前还不清楚是否抗体反应靶向gB蛋白单独， 而不是其他CMV糖蛋白，足以作为预防先天性CMV的有效疫苗。 CMV gB晶体结构的最新发现和CMV gB靶向的不同蛋白质结构域的鉴定 中和抗体使得研究gB/MF 59引发的保护性抗体应答成为可能。 重要的是，CMV表面糖蛋白如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发的免疫应答的机制。我假设 母体gB免疫策略的疫苗效力取决于1）中和抗体 靶向gB结构域和2）病毒免疫逃避这些保护性免疫应答。在未来两 作为我博士学位的一部分。论文项目，我建议采用新的方法和切割- 边缘疫苗学技术，以评估抗体和疫苗保护的病毒决定因素， 独立的gB/MF 59 II期试验队列。首先，我将评估是否中和抗体预测CMV 获得风险并定义那些保护性抗体的表位特异性。其次，通过深入 病毒变体的测序和随后的病毒“筛选分析”，我将在 gB结构域的基因座，以确定疫苗引发的免疫应答的病毒免疫逃避是否与 疫苗失败。最后，我将工程和表征嵌合恒河猴CMV病毒含有人类 gB中和结构域，用于在鉴定的多态性位点验证病毒免疫逃避。这些嵌合 病毒将在未来用于我们实验室开发的非人类灵长类动物模型， 用于消除先天性CMV感染的基于糖蛋白的疫苗的合理设计和测试。