THERAPEUTIC VACCINES TO REDUCE OCULAR HSV RECURRENCE

减少眼部 HSV 复发的治疗性疫苗

• 批准号: 3266817
• 负责人: ANTHONY BART NESBURN
• 金额: $ 27.01万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-01-01 至 1994-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3266817
• 关键词: Freund's adjuvant; Herpesviridae vaccine; active immunization; biomarker; cell mediated lymphocytolysis test; cellular immunity; cornea disorder; cytotoxic T lymphocyte; disease /disorder model; drug administration routes; genital herpes; herpes simplex virus 1; herpes simplex virus 2; immunomodulators; laboratory rabbit; latent virus infection; liposomes; lymphocyte proliferation; nonhuman therapy evaluation; ocular herpes; protein structure; relapse /recurrence; technology /technique development; virus antigen; virus protein

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.

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 (2) 确保建议用于人类的针对 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 美国每年约有 400,000 人患有复发性眼病 单纯疱疹病毒 (HSV) 发作需要就医 药物。 不幸的是，商业 HSV 疫苗的开发是针对 生殖器HSV-2。 对抗眼部 HSV 的努力很少或根本没有 （其中 90% 是 HSV-1）。 治疗性疫苗的开发 是一种减少 HSV 眼部复发的疫苗，将大大缓解 目前美国最常见的严重病毒性眼部感染是什么 病毒性失明的主要原因。 宿主的免疫反应 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带来更好的结果 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 免疫原必须与有效的佐剂一起施用。 随着 基因工程生产新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的 复发性HSV眼部感染的免疫疗法可以成功 发达。 我们的具体工作是： 1. 治疗性疫苗的开发 减少自发性 HSV-1 眼脱落和角膜疾病 HSV-1潜伏期和复发的兔眼模型。学习意志 重点关注表达 HSV-1 糖蛋白的局部眼部疫苗接种。 尽管对自然 HSV 感染的免疫反应并不能保护 针对随后的复发，“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方法获得 佐剂可减少豚鼠生殖器 HSV-3 复发（第 17 页）。 一个 最近在患有以下疾病的人类中获得了“高于正常”的免疫反应 一种类似的 Gd 亚单位疫苗，可增加 HSV-2 抗体滴度 血清阳性个体数量是自然产生的个体数量的 20 倍 感染（1809）。 由于我们发现局部眼部疫苗接种 保护兔子在随后的眼科手术后免受角膜疾病的影响 挑战比全身疫苗接种要好得多（第 20 页），眼部 使用亚单位疫苗接种应该是有效的方法 开发针对眼部 HSV 复发的治疗性疫苗。 2. 人用候选疫苗对兔的眼部安全性筛选 HSV-1潜伏期和复发的眼部模型。 眼部安全意味着没有 自发性眼部 HSV 脱落或角膜疾病增加。 我们有 5 种 HSV-2 候选疫苗可能用于人类。安全试验 将使用尽可能接近的疫苗接种方案来完成 由特定候选人的开发人员建议在人中使用 疫苗。