THERAPEUTIC VACCINES TO REDUCE OCULAR HSV RECURRENCE

复发性眼部单纯疱疹病毒1型(HSV-1)感染是主要的 病毒致盲的原因。使用兔子，我们第一次有了 在任何动物模型中展示疫苗和佐剂组合的时间 这在统计上具有显著的治疗效果 复发性眼部单纯疱疹病毒1型脱落。这是使用MF59+MTP-PE作为 佐剂、表达和高纯度HSV-2糖蛋白GD2+GB2 AS 抗原，以及局部眼周接种途径。我们计划(1) 应用同源I型糖蛋白最大化治疗效果 而不是疫苗中的2型糖蛋白；(2)确定系统性 接种可替代眼周(结膜下)接种 接种疫苗；以及(3)将佐剂改变为可能更多的形式 有效，预计将被批准用于人类使用。两者都减少了 复发的角膜疾病和减少的自发脱落将被用作 终端。 我们的具体目标包括： 1.确定特定类型的重要性(HSV-1与HSV-2) 眼部局部接种糖蛋白对流行性出血热的治疗保护作用 兔单纯疱疹病毒1型眼球脱落模型。我们之前的实验使用的是HSV-2 糖蛋白作为预防HSV-1复发的疫苗。同型单纯疱疹病毒1型 糖蛋白应该更有效。 2.确认需要局部眼周疫苗接种才能治疗 抗单纯疱疹病毒1型眼部复发的疗效观察我们将确定眼球周围是否 接种疫苗是绝对必要的，还是系统接种疫苗可能 提供类似的有效性。 3.证明MF59+MTP-PE脂质体制剂同样有效 (或更有效的)预防HSV-1复发的疫苗佐剂 比原来的MF59+MTP-PE配方更适合眼科疾病。标准 MF59+MTP-PE制剂在人体内不能很好地耐受性。但是，当 加入脂质体配方MF59+MTP-PE非常好 在人类中是耐受的，也被证明保持了它的有效性 豚鼠用的佐剂。

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.