ADARC PROGRAM PROJECT SIV & HIV VACCINE DEVELOPMENT

我们先前证明，恒河猴接种福尔马林灭活（FI）制备的呼吸道合胞病毒（FI-RSV）和挑战活RSV后，肺组织病理学增强。 这些结果类似于20世纪60年代在一组FI-RSV疫苗接种的儿童中自然感染后的结果。 这些不良反应被认为是基于免疫学的，但机制尚不清楚。 我们使用Praxis Biologics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只血清阴性恒河猴分为4组，每组5只动物。 两组接受高剂量或低剂量FI-RSV疫苗制剂的IM注射。 第三组接受安慰剂疫苗，第四组鼻内感染活RSV。 感染组在感染的最初过程中进行了高度和感染持续时间以及抗体应答。 在第21天对组1-3进行加强接种。 最后，在第56天对所有动物进行活RSV攻毒。 监测动物的感染动力学，然后在病毒攻击后第8天人道处死以评估肺病理学。与低剂量疫苗组相比，高剂量疫苗组对疫苗的抗体应答最大，预计上呼吸道中的病毒水平最低，低剂量疫苗组在上呼吸道中无抗体应答且病毒滴度较高。 该低疫苗组中的这些病毒滴度也比安慰剂对照组中证明的低一到两个对数。 这些结果表明疫苗在这些动物中存在剂量效应。 正如预期的那样，第四次再感染组在攻毒时受到保护。 攻毒后第8天，在感染和拟定免疫增强高峰期，对动物进行尸检。 收获每个肺叶的切片，并对肺病变进行评分，如组织病理学所示。 高剂量FI-RSV疫苗接受者的平均肺评分比低剂量动物增加两倍。 然而，这些高剂量疫苗动物的平均评分与安慰剂疫苗组以及感染/再感染组相当，表明FI-RSV疫苗未产生免疫接种。 细胞因子水平和流式细胞术也未表明任何组中存在任何重大差异。 认为缺乏免疫增强作用是由于Praxis疫苗制剂所致。制剂表征正在进行中。 一

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