Preclinical development of human CMV vaccines

描述（由申请人提供）： 人巨细胞病毒（CMV）是美国出生缺陷的主要感染原因。最近证明，糖蛋白B（gB）/MF 59疫苗在保护妇女免受原发性CMV感染方面具有50%的功效，这是CMV疫苗研究中的一个里程碑。然而，50%的效力不足以获得疫苗许可。因此，现在的挑战是确定可以添加到基于gB的疫苗中以将效力提高到可接受的水平。我们实验室最近的工作表明，体液免疫的一个重要组成部分是缺乏从人抗体反应的gB/MF 59疫苗。我们发现，CMV血清阳性的人有高水平的抗体，中和病毒进入上皮细胞。然而，gB/MF 59疫苗远远不能诱导血清阳性血清中发现的上皮进入中和活性水平。我们假设能够引发gB特异性抗体和中和上皮进入的抗体的疫苗在预防原发性感染方面将具有比gB/MF 59疫苗显著更高的效力。在人CMV血清阳性血清中发现的上皮入口特异性中和抗体靶向的表位尚不清楚，但最近发现的由gH、gL、UL 128、UL 130和UL 131组成的病毒体糖蛋白复合物（gH/gL/UL 128 -131）内的表位是一个强有力的例子。该复合物对于病毒有效进入上皮和内皮细胞是必需的，但对于进入成纤维细胞是必需的，并且针对UL 128、UL 130或UL 131内的表位产生的动物抗体特异性地中和上皮和/或内皮细胞的进入。因此，我们提出，疫苗策略，以引发抗体的gH/gL/UL 128 -131复合物内的表位将导致有效的上皮进入中和反应。我们与Vical Inc.合作。开发和评估包含DNA表达载体、重组亚单位蛋白/复合物和灭活病毒粒子的免疫策略。我们将评估这些方法在小动物中引起有效上皮进入中和反应的相对能力。将进一步评价最佳候选策略与已建立的基于gB的疫苗方法的兼容性。拟议研究的结果将产生可用于临床开发的候选药物。人巨细胞病毒（CMV）是美国出生缺陷的主要感染原因。我们最近发现，自然感染CMV激发中和抗体，阻止病毒进入成纤维细胞和上皮细胞，而目前的候选疫苗缺乏激发抗体，阻止上皮细胞进入。该项目的目的是开发候选疫苗，在动物中引发抗体，阻止CMV进入两种细胞类型。预计这些候选疫苗的疗效将优于现有的候选疫苗，并将适用于后续的临床开发。

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 would be insufficient for vaccine licensure. Thus, the challenge now is to determine what can be added to a gB-based vaccine to increase efficacy to an acceptable level. Recent work from our laboratory indicates that an important component of humoral immunity is lacking from human antibody responses to the gB/MF59 vaccine. We showed that CMV seropositive people have high levels of antibodies that neutralize viral entry into epithelial cells. The gB/MF59 vaccine, however, fell far short of inducing the levels of epithelial entry neutralizing activities found in seropositive sera. We hypothesize that a vaccine capable of eliciting both gB- specific antibodies and antibodies that neutralize epithelial entry will have a significantly higher efficacy in preventing primary infection than that of the gB/MF59 vaccine. The epitopes that are targeted by the epithelial entry-specific neutralizing antibodies found in human CMV seropositive sera are unknown, but a strong case can be made for epitopes within a recently discovered virion glycoprotein complex consisting of gH, gL, UL128, UL130, and UL131 (gH/gL/UL128-131). This complex is essential for efficient viral entry into epithelial and endothelial cells but dispensable for entry into fibroblasts, and animal antibodies raised to epitopes within UL128, UL130, or UL131 specifically neutralize epithelial and/or endothelial entry. We therefore propose that vaccine strategies to elicit antibodies to epitopes within the gH/gL/UL128-131 complex will result in potent epithelial entry neutralizing responses. We have partnered with Vical Inc. to develop and evaluate immunization strategies that incorporate DNA expression vectors, recombinant subunit proteins/complexes, and inactivated virions. We will evaluate these approaches for their relative ability to elicit potent epithelial entry neutralizing responses in small animals. Optimal candidate strategies will be further evaluated for compatibility with established gB-based vaccine approaches. The results of the proposed studies will produce candidates ready for clinical development. Human cytomegalovirus (CMV) is the major infectious cause of birth defects in the United States. We recently found that natural infection by CMV elicits neutralizing antibodies that block viral entry into both fibroblasts and epithelial cells, while current candidate vaccines are deficient in eliciting antibodies that block epithelial cell entry. The aim of this project is to develop vaccine candidates that in animals elicit antibodies that block CMV entry into both cells types. Such candidates are anticipated to have improved efficacy over existing candidate vaccines and will be suitable for subsequent clinical development.