THERAPEUTIC VACCINES TO REDUCE OCULAR HSV RECURRENCE

描述（研究者摘要）：我们的长期目标是（1） 开发有效的治疗性疫苗以减少眼部HSV复发 及（2）确保拟供人类使用的抗HSV-2生殖器疱疹疫苗 感染不会不知不觉地增加眼部HSV疾病。 在联合 在美国，每年约有40万人患有复发性眼病。 需要看医生的单纯疱疹病毒（HSV）发作， 药 不幸的是，商业HSV疫苗的开发是针对 生殖器HSV-2 很少或根本没有努力对抗眼部HSV (90%，其中HSV-1）。 治疗性疫苗的开发， 是一种减少HSV眼部复发的疫苗， 这是目前美国最常见的严重病毒性眼部感染， 病毒性失明的主要原因。 宿主对 自然HSV感染不完全或不足以控制复发 疾病 治疗性HSV疫苗的开发基于以下前提： 接种HSV疫苗可能会增强免疫反应 特异性免疫原，从而控制复发。 最近的结果 动物表明，特异性免疫增强可以导致更好的 控制复发性HSV感染。然而， 单独使用或与明矾一起使用的疫苗，表明要有效， 免疫原必须与有效佐剂一起施用。 的到来 基因工程生产新的亚单位疫苗和共同开发 新的合成佐剂，很可能是病毒特异性 复发性HSV眼部感染的免疫治疗可以成功地 开发 我们的具体是：1. 治疗性疫苗的开发 减少自发性HSV-1眼部脱落和角膜疾病， HSV-1潜伏期和复发的兔眼模型。学习will 集中于用表达的HSV-1糖蛋白局部眼部接种。 尽管对天然HSV感染的免疫反应不能保护 对抗随后的复发，“高于正常”的免疫反应 使用表达的糖蛋白亚单位疫苗和适当的 佐剂减少豚鼠生殖器HSV-3复发（第17页）。 一 “高于正常”的免疫应答最近在患有 一种类似的Gd亚单位疫苗，它增加了HSV-2抗体滴度， 血清阳性个体产生的抗体是其天然抗体的20倍 感染（1809）。 因为我们发现局部眼部接种 保护兔在随后的眼部手术后免受角膜疾病 挑战更好地进行全身接种（第20页），眼部 使用亚单位疫苗接种应该是一种有效的方法， 开发针对眼部HSV复发的治疗性疫苗。 2. 人用候选疫苗兔眼安全性筛选 HSV-1潜伏期和复发的眼部模型。 眼部安全意味着 自发性眼部HSV脱落或角膜疾病增加。 我们有 5种候选HSV-2疫苗可能用于人类。安全性试验 将使用尽可能接近那些 由特定候选物的开发者提议用于人体 疫苗

DESCRIPTION (Investigator's Abstract): Our long term goals are to (1) develop an effective therapeutic vaccine to reduce ocular HSV recurrences and (2) ensure that vaccines proposed for human use against HSV-2 genital infections do not unknowingly increase ocular HSV disease. In the United States, approximately 400,000 people per year suffer recurrent ocular herpes simplex virus (HSV) episodes requiring doctor visits and medication. Unfortunately, commercial HSV vaccine development is directed at genital HSV-2. There are little or no efforts to combat ocular HSV (90% of which is HSV-1). The development of a therapeutic vaccine, that is, a vaccine to reduce HSV ocular recurrences, would greatly alleviate what is now the most frequent serious viral eye infection in the U.S. and a major cause of viral induced blindness. The host immune response to natural HSV infection is incomplete or inadequate to control recurrent disease. Development of a therapeutic HSV vaccine is based on the premise that the immune response might be augmented by vaccination with HSV specific immunogens, thereby controlling recurrences. Recent results in animals suggest that specific immune augmentation can result in better control of recurrent HSV infections.However, the ineffectiveness of vaccines used alone or with alum, suggests that to be effective the immunogen must be administered with potent adjuvants. With the advent of genetic engineering to produce new subunit vaccines and the co-development of new synthetic adjuvants it is very likely that virus-specific immunotherapy of recurrent HSV ocular infections can be successfully developed. Our specific are: 1. Development of a therapeutic vaccine that decreases spontaneous HSV-1 ocular shedding and corneal disease in the rabbit ocular model of HSV-1 latency and recurrences. Studied will focus on local ocular vaccination with expressed HSV-1 glycoproteins. Although the immune response to natural HSV infection does not protect against subsequent recurrences, "higher than normal" immune responses obtained using expressed glycoprotein subunit vaccines and an appropriate adjuvant reduced genital HSV-3 recurrences in guinea pigs (page 17). A "higher than normal" immune response was recently obtained in humans with a similar Gd subunit vaccine that increased HSV-2 antibody titers in seropositive individuals 20 fold over that produced by their natural infection (1809). Since we have found that local ocular vaccination protects rabbits against corneal disease following subsequent ocular challenge much better that does systemic vaccination (page 20), ocular inoculation using subunit vaccines should be an effective approach to developing a therapeutic vaccine against ocular HSV recurrences. 2. Ocular safety screening of candidate vaccines for human use in the rabbit ocular model of HSV-1 latency and recurrence. Ocular safety means no increase in spontaneous ocular HSV shedding or corneal disease. We have 5 of the candidate HSV-2 vaccines likely to be used in man. Safety trials will be done using vaccination regimens as close as possible to those proposed for use in man by the developer of the specific candidate vaccine.