B7 Costimulation Molecules Encoded by Replication-Defective, vhs-Deficient HSV-1 Improve Vaccine-Induced Protection against Corneal Disease

Herpes simplex virus 1 (HSV-1) causes herpes stromal keratitis (HSK), a sight-threatening disease of the cornea for which no vaccine exists. A replication-defective, HSV-1 prototype vaccine bearing deletions in the genes encoding ICP8 and the virion host shutoff (vhs) protein reduces HSV-1 replication and disease in a mouse model of HSK. Here we demonstrate that combining deletion of ICP8 and vhs with virus-based expression of B7 costimulation molecules created a vaccine strain that enhanced T cell responses to HSV-1 compared with the ICP8−vhs− parental strain, and reduced the incidence of keratitis and acute infection of the nervous system after corneal challenge. Post-challenge T cell infiltration of the trigeminal ganglia and antigen-specific recall responses in local lymph nodes correlated with protection. Thus, B7 costimulation molecules expressed from the genome of a replication-defective, ICP8−vhs− virus enhance vaccine efficacy by further reducing HSK.

单纯疱疹病毒1型（Herpes simplex virus 1, HSV-1）可引发疱疹性基质性角膜炎（herpes stromal keratitis, HSK）——一种威胁视力的角膜疾病，目前尚无可用疫苗。一种在编码ICP8和病毒粒子宿主关闭（virion host shutoff, vhs）蛋白的基因中存在缺失的复制缺陷型HSV-1原型疫苗，可在HSK小鼠模型中抑制HSV-1复制并减轻疾病症状。本研究证实，将ICP8与vhs基因缺失与以病毒为载体的B7共刺激分子表达相结合，所构建的疫苗株相较于ICP8⁻vhs⁻亲本株，可增强机体针对HSV-1的T细胞免疫应答，并在角膜攻毒后降低角膜炎的发生率以及神经系统急性感染风险。攻毒后三叉神经节（trigeminal ganglia）的T细胞浸润与局部淋巴结内的抗原特异性回忆应答，与保护效应显著相关。综上，在复制缺陷型ICP8⁻vhs⁻病毒基因组中表达的B7共刺激分子，可通过进一步减轻疱疹性基质性角膜炎，提升该疫苗的保护效力。