THERAPEUTIC VACCINES TO REDUCE OCULAR HSV RECURRENCE

复发性眼部单纯疱疹病毒1型（HSV-1）感染是一种主要的 病毒性失明的原因利用兔子，我们有第一个 在任何动物模型中的时间证明疫苗和佐剂组合 产生统计学上显著的治疗效果， 复发性眼部HSV-1脱落。这是使用MF 59 +MTP-PE作为 佐剂，表达和高度纯化的HSV-2糖蛋白gD 2 + gB 2， 抗原和局部眼周接种途径。我们计划（1） 通过使用同源I型糖蛋白使治疗效果最大化 而不是疫苗中的2型糖蛋白;（2）确定是否全身性 接种可替代眼周（结膜下） 疫苗接种;以及（3）将佐剂改变为可能更适合于疫苗接种的形式。 它是有效的，并有望被批准用于人类。都减少 复发性角膜疾病和减少的自发脱落将被用作 端点。 我们的具体目标包括： 1.确定类型特异性的重要性（HSV-1与HSV-2） 用于局部眼部疫苗接种的糖蛋白 兔眼内HSV-1散毒。我们以前的实验使用HSV-2 糖蛋白作为预防单纯疱疹病毒-1复发的疫苗。同型HSV-1 糖蛋白应该更有效。 2.确认治疗性眼周局部接种 有效对抗HSV-1眼部复发。我们将确定眼周是否 接种疫苗是绝对必要的，或者全身接种疫苗是否可能 提供类似的效果。 3.证明MF 59 +MTP-PE脂质体制剂与 (or甚至更有效）针对复发性HSV-1的疫苗佐剂 眼部疾病的治疗效果优于原始MF 59 +MTP-PE制剂。标准 MF 59 +MTP-PE制剂在人体中耐受性不佳。 然而当 掺入脂质体制剂MF 59 +MTP-PE中的脂质体制剂MF 59 +MTP-PE非常好地 在人类中是耐受的，并且也已被证明保留其有效性， 豚鼠的一种佐剂。

Recurrent ocular herpes simplex virus type 1 (HSV-1) infection is a major cause of viral induced blindness. Using the rabbit, we have for the first time in any animal model demonstrated a vaccine and adjuvant combination that produces a statistically significant therapeutic effect against recurrent ocular HSV-1 shedding. This was done using MF59+MTP-PE as adjuvant, expressed and highly purified HSV-2 glycoproteins gD2+gB2 as antigens, and a local periocular route of inoculation. We plan to (1) maximize the therapeutic efficacy by using homologous type I glycoprotein rather than type 2 glycoprotein in the vaccine; (2) determine if systemic inoculation can be substituted for periocular (subconjunctival) vaccination; and (3) alter the adjuvant to a form that might be more effective and that is expected to be approved for human use. Both reduced recurrent corneal disease and reduced spontaneous shedding will be used as endpoints. Our specific aims include: 1. Determine the importance of type specific (HSV-1 versus HSV-2) glycoprotein for local ocular vaccination in therapeutic protection against HSV-1 ocular shedding in rabbits. Our previous experiments employed HSV-2 glycoproteins as a vaccine against HSV-1 recurrence. Homotypic HSV-1 glycoprotein should be more efficacious. 2. Confirm that local periocular vaccination is required for therapeutic efficacy against HSV-1 ocular recurrence. We will determine if periocular vaccination is absolutely required, or whether systemic vaccination might provide similar effectiveness. 3. Demonstrate that the MF59+MTP-PE liposome formulation is as efficacious (or even more efficacious) a vaccine adjuvant against recurrent HSV-1 ocular disease than the original MF59+MTP-PE formulation. The standard MF59+MTP-PE formulation is not well tolerated in humans. However, when incorporated into a liposome formulation MF59+MTP-PE is extremely well tolerated in humans and has also been shown to retain its effectiveness as an adjuvant in guinea pigs.