Choi K Yeon, Root Matthew, McGregor Alistair
Department of Microbial Pathogenesis and Immunology, Texas A&M University, Health Science Center, College of Medicine, College Station, Texas, USA.
Department of Microbial Pathogenesis and Immunology, Texas A&M University, Health Science Center, College of Medicine, College Station, Texas, USA
J Virol. 2016 Aug 12;90(17):7902-19. doi: 10.1128/JVI.00283-16. Print 2016 Sep 1.
Congenital cytomegalovirus (CMV) infection is a leading cause of mental retardation and deafness in newborns. The guinea pig is the only small animal model for congenital CMV infection. A novel CMV vaccine was investigated as an intervention strategy against congenital guinea pig cytomegalovirus (GPCMV) infection. In this disabled infectious single-cycle (DISC) vaccine strategy, a GPCMV mutant virus was used that lacked the ability to express an essential capsid gene (the UL85 homolog GP85) except when grown on a complementing cell line. In vaccinated animals, the GP85 mutant virus (GP85 DISC) induced an antibody response to important glycoprotein complexes considered neutralizing target antigens (gB, gH/gL/gO, and gM/gN). The vaccine also generated a T cell response to the pp65 homolog (GP83), determined via a newly established guinea pig gamma interferon enzyme-linked immunosorbent spot assay. In a congenital infection protection study, GP85 DISC-vaccinated animals and a nonvaccinated control group were challenged during pregnancy with wild-type GPCMV (10(5) PFU). The pregnant animals carried the pups to term, and viral loads in target organs of pups were analyzed. Based on live pup births in the vaccinated and control groups (94.1% versus 63.6%), the vaccine was successful in reducing mortality (P = 0.0002). Additionally, pups from the vaccinated group had reduced CMV transmission, with 23.5% infected target organs versus 75.9% in the control group. Overall, these preliminary studies indicate that a DISC CMV vaccine strategy has the ability to induce an immune response similar to that of natural virus infection but has the increased safety of a non-replication-competent virus, which makes this approach attractive as a CMV vaccine strategy.
Congenital CMV infection is a leading cause of mental retardation and deafness in newborns. An effective vaccine against CMV remains an elusive goal despite over 50 years of CMV research. The guinea pig, with a placenta structure similar to that in humans, is the only small animal model for congenital CMV infection and recapitulates disease symptoms (e.g., deafness) in newborn pups. In this report, a novel vaccine strategy against congenital guinea pig cytomegalovirus (GPCMV) infection was developed, characterized, and tested for efficacy. This disabled infectious single-cycle (DISC) vaccine strategy induced a neutralizing antibody or a T cell response to important target antigens. In a congenital infection protection study, animals were protected against CMV in comparison to the nonvaccinated group (52% reduction of transmission). This novel vaccine was more effective than previously tested gB-based vaccines and most other strategies involving live virus vaccines. Overall, the DISC vaccine is a safe and promising approach against congenital CMV infection.
先天性巨细胞病毒（CMV）感染是新生儿智力迟钝和耳聋的主要原因。豚鼠是先天性CMV感染的唯一小动物模型。研究了一种新型CMV疫苗作为针对先天性豚鼠巨细胞病毒（GPCMV）感染的干预策略。在这种失活感染单周期（DISC）疫苗策略中，使用了一种GPCMV突变病毒，该病毒除了在互补细胞系上生长外，缺乏表达必需衣壳基因（UL85同源物GP85）的能力。在接种疫苗的动物中，GP85突变病毒（GP85 DISC）诱导了针对被认为是中和靶抗原的重要糖蛋白复合物（gB、gH/gL/gO和gM/gN）的抗体反应。该疫苗还通过新建立的豚鼠γ干扰素酶联免疫斑点试验产生了对pp65同源物（GP83）的T细胞反应。在一项先天性感染保护研究中，在怀孕期间用野生型GPCMV（10⁵ PFU）对接种GP85 DISC的动物和未接种疫苗的对照组进行攻击。怀孕动物将幼崽足月分娩，并分析幼崽靶器官中的病毒载量。基于接种疫苗组和对照组的活幼崽出生情况（94.1%对63.6%），该疫苗成功降低了死亡率（P = 0.0002）。此外，接种疫苗组的幼崽CMV传播减少，感染靶器官的比例为23.5%，而对照组为75.9%。总体而言，这些初步研究表明，DISC CMV疫苗策略能够诱导与自然病毒感染相似的免疫反应，但具有无复制能力病毒的更高安全性，这使得这种方法作为一种CMV疫苗策略具有吸引力。
先天性CMV感染是新生儿智力迟钝和耳聋的主要原因。尽管对CMV进行了50多年的研究，但有效的CMV疫苗仍然难以实现。豚鼠的胎盘结构与人类相似，是先天性CMV感染的唯一小动物模型，并在新生幼崽中重现疾病症状（如耳聋）。在本报告中，开发、表征并测试了一种针对先天性豚鼠巨细胞病毒（GPCMV）感染的新型疫苗策略。这种失活感染单周期（DISC）疫苗策略诱导了针对重要靶抗原的中和抗体或T细胞反应。在一项先天性感染保护研究中，与未接种疫苗组相比，动物受到了CMV的保护（传播减少52%）。这种新型疫苗比先前测试的基于gB的疫苗和大多数其他涉及活病毒疫苗的策略更有效。总体而言，DISC疫苗是一种针对先天性CMV感染的安全且有前景的方法。
