THERAPEUTIC VACCINES TO REDUCE OCULAR HSV RECURRENCE

描述(调查人员摘要)：我们的长期目标是(1) 开发一种有效的治疗性疫苗以减少眼部HSV复发 以及(2)确保为人类提供的针对HSV-2生殖器的疫苗 感染不会在不知不觉中增加眼部HSV疾病。在美国 在美国，每年约有40万人患有眼部复发 单纯疱疹病毒(HSV)发作需要就医和 药物治疗。不幸的是，商业HSV疫苗的开发是针对 生殖器HSV-2。抗击眼部单纯疱疹病毒的努力很少或根本没有 (其中90%为HSV-1)。一种治疗性疫苗的开发， IS，一种减少HSV眼部复发的疫苗，将极大地缓解 目前美国最常见的严重病毒性眼部感染是什么？ 病毒致盲的一个主要原因。宿主的免疫反应 单纯疱疹病毒自然感染不完全或不足以控制复发 疾病。治疗性单纯疱疹病毒疫苗的研制是基于这样一个前提 接种单纯疱疹病毒疫苗可以增强免疫反应 特定的免疫原，从而控制复发。的最新结果 动物表明，特定的免疫增强可以产生更好的效果 控制复发的单纯疱疹病毒感染。但无效的 单独使用或与明矾一起使用的疫苗表明，要有效 免疫基因必须与强效佐剂一起使用。随着……的到来 基因工程生产新型亚单位疫苗及其共同开发 在新的合成佐剂中，很可能是病毒特异性 复发性单纯疱疹病毒眼部感染的免疫治疗可以成功 发展起来的。我们的具体工作是：1.治疗性疫苗的研制 减少自发性HSV-1眼球脱落和角膜疾病 单纯疱疹病毒1型潜伏期和复发的兔眼模型。学习意志 重点是用表达的HSV-1糖蛋白进行眼部局部接种。 尽管对自然感染单纯疱疹病毒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 佐剂降低豚鼠生殖器HSV-3复发(第17页)。一个 最近在患有艾滋病的人中获得了“高于正常水平”的免疫反应 一种类似的Gd亚单位疫苗，可提高HSV-2抗体效价 血清阳性个体是其天然抗体阳性个体的20倍 感染(1809)。因为我们发现局部的眼部疫苗接种 保护兔免受后续眼球后角膜疾病的影响 挑战要好得多，做系统性疫苗接种(第20页)，眼睛 使用亚单位疫苗接种应该是有效的方法 开发预防眼部HSV复发的治疗性疫苗。2. 人用候选疫苗的兔眼安全性筛选 单纯疱疹病毒1型潜伏期和复发的眼部模型。眼睛安全意味着没有 自发性眼部单纯疱疹病毒感染增多或角膜病变。我们有 5种可能用于人类的HSV-2候选疫苗。安全性试验 将使用尽可能接近的疫苗接种方案进行 建议由特定候选者的开发商在MAN中使用 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.