An HBC-vectored peptide-based cytomegalovirus vaccine

描述(申请人提供)：人类巨细胞病毒(CMV)是美国出生缺陷的主要感染原因。最近证明，糖蛋白B(GB)/MF59疫苗在保护妇女免受原发CMV感染方面具有50%的效力，这是CMV疫苗研究的一个里程碑。然而，50%的有效率可能不足以获得疫苗许可证。因此，挑战是确定可以在基于GB的疫苗中添加什么，以将效力提高到可接受的水平。PI实验室最近的工作表明，CMV血清阳性的人具有高水平的抗体，这些抗体可以中和病毒进入上皮细胞，而GB/MF59疫苗无法达到类似的水平。上皮细胞进入特异性中和表位位于由Gh、g1、UL128、UL130和UL131(Gh/gl/UL128-131)组成的病毒粒子糖蛋白复合体中。研究人员的实验室最近发现了两个多肽表位，一个来自UL130，另一个来自UL131，能够引发强大的上皮细胞进入特异性中和反应。Co-PI开发了一种新的平台，用于激发抗体对多肽表位的反应。所需的多肽被改造成乙肝病毒核心抗原(HBcAg)蛋白的外环。修饰后的蛋白质自组装成病毒样颗粒(VLP)，作为强大的免疫原，并引发对插入的多肽表位的强烈抗体反应。我们建议设计包含UL130和UL131多肽表位的嵌合HBcAg蛋白，并评估嵌合VLP在小鼠体内诱导上皮细胞进入特异性中和活性的能力。将进一步评估最佳嵌合VLP与GB亚单位疫苗的兼容性。建议的研究结果可能为临床开发提供一种新的疫苗策略。 公共卫生相关性：在美国，人类巨细胞病毒是导致出生缺陷的主要感染原因。我们最近发现，两种多肽表位可以激发高水平的抗体，从而阻止病毒进入上皮细胞。基于这些结果，将研究一种新的疫苗策略，即在乙肝病毒核心蛋白的背景下表达这些多肽。建议的研究结果可能为临床开发提供一种新的疫苗策略。

DESCRIPTION (provided by applicant): Human cytomegalovirus (CMV) is the major infectious cause of birth defects in the United States. Recent demonstration that the glycoprotein B (gB)/MF59 vaccine has 50% efficacy in protecting women against primary CMV infection is a landmark in CMV vaccine research. However, 50% efficacy may be insufficient for vaccine licensure. Thus, the challenge is to determine what can be added to a gB-based vaccine to increase efficacy to an acceptable level. Recent work from the PI's laboratory showed that CMV seropositive people have high levels of antibodies that neutralize viral entry into epithelial cells and that comparable levels are not achieved by the gB/MF59 vaccine. Epithelial entry-specific neutralizing epitopes reside within a virion glycoprotein complex consisting of gH, gL, UL128, UL130, and UL131 (gH/gL/UL128-131). The investigator's laboratory recently identified two peptide epitopes, one from UL130 and one from UL131, that are capable of eliciting potent epithelial entry-specific neutralizing responses. The co-PI has developed a novel platform for eliciting antibody responses to peptide epitopes. The desired peptides are engineered into an external loop of the hepatitis virus B core antigen (HBcAg) protein. The modified proteins self- assemble into virus-like particles (VLPs), which serve as potent immunogens and elicit strong antibody responses to the inserted peptide epitopes. We propose to engineer chimeric HBcAg proteins that contain the UL130 and UL131 peptide epitopes and evaluate the chimeric VLPs for their ability to elicit epithelial entry- specific neutralizing activities in mice. Optimal chimeric VLPs will be further evaluated for compatibility with the gB subunit vaccine. The results of the proposed studies may provide a novel vaccine strategy for advancement to clinical development. PUBLIC HEALTH RELEVANCE: Human cytomegalovirus is the major infectious cause of birth defects in the United States. We recently found that two peptide epitopes elicit high levels of antibodies that block viral entry into epithelial cells. Based on these results, a new vaccine strategy of expressing these peptides in the context of the hepatitis B virus core protein will be investigated. The results of the proposed studies may provide a novel vaccine strategy for advancement to clinical development.