Israel Institute for Biological Research, Ness-ziona, Israel.
Virol J. 2012 Jun 18;9:119. doi: 10.1186/1743-422X-9-119.
In an event of a smallpox outbreak in humans, the window for efficacious treatment by vaccination with vaccinia viruses (VACV) is believed to be limited to the first few days post-exposure (p.e.). We recently demonstrated in a mouse model for human smallpox, that active immunization 2-3 days p.e. with either VACV-Lister or modified VACV Ankara (MVA) vaccines, can rescue animals from lethal challenge of ectromelia virus (ECTV), the causative agent of mousepox. The present study was carried out in order to determine whether a single dose of the anti-viral cidofovir (CDV), administered at different times and doses p.e. either alone or in conjunction with active vaccination, can rescue ECTV infected mice.
Animals were infected intranasally with ECTV, treated on different days with various single CDV doses and monitored for morbidity, mortality and humoral response. In addition, in order to determine the influence of CDV on the immune response following vaccination, both the "clinical take", IFN-gamma and IgG Ab levels in the serum were evaluated as well as the ability of the mice to withstand a lethal challenge of ECTV. Finally the efficacy of a combined treatment regime of CDV and vaccination p.e. was determined.
A single p.e. CDV treatment is sufficient for protection depending on the initiation time and dose (2.5 - 100 mg/kg) of treatment. Solid protection was achieved by a low dose (5 mg/kg) CDV treatment even if given at day 6 p.e., approximately 4 days before death of the control infected untreated mice (mean time to death (MTTD) 10.2). At the same time point complete protection was achieved by single treatment with higher doses of CDV (25 or 100 mg/kg). Irrespective of treatment dose, all surviving animals developed a protective immune response even when the CDV treatment was initiated one day p.e.. After seven days post treatment with the highest dose (100 mg/kg), virus was still detected in some organs (e.g. lung and liver) yet all animals survived, suggesting that efficacious single CDV treatment requires a potent immune system. The combination of CDV and vaccination provided no additional protection over CDV alone. Yet, combining CDV and vaccination maintained vaccination efficacy.
Altogether, our data substantiate the feasibility of single post-exposure antiviral treatment to face orthopoxvirus infection.
如果人类中出现天花疫情，人们认为通过接种牛痘病毒（VACV）进行有效治疗的窗口期仅限于暴露后几天（p.e.）。我们最近在人类天花的小鼠模型中证明，在暴露后 2-3 天通过 VACV-Lister 或改良 VACV Ankara（MVA）疫苗进行主动免疫接种，可以使动物免受致死性的细毛病毒（ECTV）挑战，细毛病毒是小鼠痘的病原体。本研究旨在确定在不同时间和剂量的 p.e. 单独或联合主动免疫接种时，单次给予抗病毒药物更昔洛韦（CDV）是否可以挽救 ECTV 感染的小鼠。
动物经鼻腔感染 ECTV，在不同时间用不同的 CDV 单剂量治疗，并监测发病率、死亡率和体液反应。此外，为了确定 CDV 对疫苗接种后免疫反应的影响，还评估了血清中的 CDV 对“临床接种”、IFN-γ和 IgG Ab 水平的影响，以及小鼠对 ECTV 致死性挑战的抵抗力。最后，还确定了 p.e. 时 CDV 联合疫苗接种的联合治疗方案的疗效。
取决于治疗开始时间和剂量（2.5-100mg/kg），单次 p.e. CDV 治疗即可提供保护。即使在第 6 天（即感染未治疗对照小鼠死亡前约 4 天）给予低剂量（5mg/kg）CDV 治疗，也能获得可靠的保护，对照感染未治疗小鼠的平均死亡时间（MTTD）为 10.2 天。同时，通过单次给予更高剂量的 CDV（25 或 100mg/kg）治疗可获得完全保护。无论治疗剂量如何，即使在 p.e. 时开始 CDV 治疗一天后，所有幸存的动物都产生了保护性免疫反应。在接受最高剂量（100mg/kg）治疗七天后，仍可在一些器官（如肺和肝）中检测到病毒，但所有动物均存活，这表明有效的单剂 CDV 治疗需要有效的免疫系统。CDV 与疫苗接种的联合治疗并没有提供比单独使用 CDV 更多的保护。然而，CDV 和疫苗接种联合治疗维持了疫苗接种的效果。
总之，我们的数据证实了在面对正痘病毒感染时，单次暴露后抗病毒治疗的可行性。
