ADARC PROGRAM PROJECT SIV & HIV VACCINE DEVELOPMENT

ADARC 计划 SIV 项目

• 批准号: 6116176
• 负责人: DAVID D HO
• 金额: $ 5.31万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6116176
• 关键词: AIDS; Mammalia; animal tissue; communicable diseases; immunology; inflammation; lymphatic system; vaccines; virus

We previously demonstrated that rhesus monkeys develop enhanced pulmonary histopathology after vaccination with a formalin inactivated (FI) preparation of respiratory syncytial virus (FI-RSV) and challenge with live RSV. These results were similar to those that followed natural infection in a group of FI-RSV vaccinated children in the 1960's. These adverse effects are believed to be immunologically based but the mechanism is unknown. We conducted a large RSV vaccine study using a Praxis Biologics preparation of formalin-inactivated RSV vaccine. Twenty seronegative rhesus macaques were divided into four groups of five animals each. Two groups received IM injections of FI-RSV vaccine preparation, either high dose or low dose. A third group received placebo vaccine and the fourth group was intranasally infected with live RSV. The infection group was followed through the initial course of infection for height and duration of infection as well as antibody response. A booster vaccination was given to groups 1-3 on day 21. Finally, a live RSV challenge was administered to all animals on day 56. The animals were monitored for the dynamics of their infection and then were humanely euthanized to assess pulmonary pathology on day 8 following viral challenge. The high dose vaccine group had the greatest antibody response to vaccine and the anticipated the lowest level of virus in the upper respiratory tract as compared with the the low dose vaccine group that had no antibody response and high titers of virus in the upper respiratory tract. These virus titers in this low vaccine group were also one to two logs lower that that demonstrated in the placebo control group. These results indicated a dose effect of the vaccine in these animals. As expected, the fourth reinfection group was protected on challenge. On day 8 post challenge, at the height of infection and proposed immunopotentiation, the animals were necropsied. Sections from each of the lung lobes were harvested and scored for lung lesions, as demonstrated by histopathology. The high dose FI-RSV vaccine recipients had a two fold increase in the mean lung score of the low dose animals. However, the mean scores of these high dose vaccine animals was comparable to both the placebo vaccine group as well as the infection/reinfection group, indicating that there was no immunpotiation produced by the FI-RSV vaccine. Cytokine levels and flow cytometry also did not indicate any major differences in any of the groups. The lack of immunopotentiation is believed to be due to the Praxis vaccine preparation. Characterization of the preparation is ongoing. A

我们之前证明，恒河猴在接种福尔马林灭活呼吸道合胞病毒（FI-RSV）制剂和用活RSV攻击后，肺部组织病理学增强。这些结果与20世纪60年代接种过FI-RSV疫苗的一组儿童自然感染后的结果相似。这些不良反应被认为是基于免疫的，但其机制尚不清楚。我们使用Praxis Biologics公司制备的福尔马林灭活RSV疫苗进行了一项大型RSV疫苗研究。将20只血清阴性的恒河猴分为四组，每组5只。两组均采用高剂量或低剂量IM注射FI-RSV疫苗制剂。第三组接受安慰剂疫苗，第四组鼻内感染活RSV。感染组随访感染初期病程，观察感染高度、感染持续时间及抗体反应。1 ~ 3组在第21天进行加强免疫。最后，在第56天对所有动物进行RSV活攻毒。对这些动物进行感染动态监测，然后在病毒攻击后的第8天对其进行人道安乐死，以评估肺部病理。与低剂量疫苗组相比，高剂量疫苗组对疫苗的抗体反应最大，上呼吸道病毒水平预期最低，而低剂量疫苗组没有抗体反应，上呼吸道病毒滴度高。低剂量疫苗组的病毒滴度也比安慰剂对照组低一到两个对数。这些结果表明疫苗对这些动物有剂量效应。不出所料，第四组再感染小鼠在挑战时受到保护。在攻毒后第8天，在感染高峰和建议的免疫增强时，对动物进行尸检。从每个肺叶上取切片，并对肺病变进行评分，如组织病理学所示。高剂量FI-RSV疫苗接种者的平均肺评分是低剂量动物的两倍。然而，这些高剂量疫苗动物的平均得分与安慰剂疫苗组以及感染/再感染组相当，表明FI-RSV疫苗没有产生免疫。细胞因子水平和流式细胞术也没有显示任何组间的重大差异。缺乏免疫增强被认为是由于Praxis疫苗的制备。制备的表征正在进行中。一个