Benson J, Chougnet C, Robert-Guroff M, Montefiori D, Markham P, Shearer G, Gallo R C, Cranage M, Paoletti E, Limbach K, Venzon D, Tartaglia J, Franchini G
Basic Research Laboratory, National Cancer Institute, Bethesda, Maryland 20892, USA.
J Virol. 1998 May;72(5):4170-82. doi: 10.1128/JVI.72.5.4170-4182.1998.
Vaccine protection from infection and/or disease induced by highly pathogenic simian immunodeficiency virus (SIV) strain SIV(mac251) in the rhesus macaque model is a challenging task. Thus far, the only approach that has been reported to protect a fraction of macaques from infection following intravenous challenge with SIV(mac251) was the use of a live attenuated SIV vaccine. In the present study, the gag, pol, and env genes of SIV(K6W) were expressed in the NYVAC vector, a genetically engineered derivative of the vaccinia virus Copenhagen strain that displays a highly attenuated phenotype in humans. In addition, the genes for the alpha and beta chains of interleukin-12 (IL-12), as well as the IL-2 gene, were expressed in separate NYVAC vectors and inoculated intramuscularly, in conjunction with or separate from the NYVAC-SIV vaccine, in 40 macaques. The overall cytotoxic T-lymphocyte (CTL) response was greater, at the expense of proliferative and humoral responses, in animals immunized with NYVAC-SIV and NYVAC-IL-12 than in animals immunized with the NYVAC-SIV vaccine alone. At the end of the immunization regimen, half of the animals were challenged with SIV(mac251) by the intravenous route and the other half were exposed to SIV(mac251) intrarectally. Significantly, five of the eleven vaccinees exposed mucosally to SIV(mac251) showed a transient peak of viremia 1 week after viral challenge and subsequently appeared to clear viral infection. In contrast, all 12 animals inoculated intravenously became infected, but 5 to 6 months after viral challenge, 4 animals were able to control viral expression and appeared to progress to disease more slowly than control animals. Protection did not appear to be associated with any of the measured immunological parameters. Further modulation of immune responses by coadministration of NYVAC-cytokine recombinants did not appear to influence the outcome of viral challenge. The fact that the NYVAC-SIV recombinant vaccine appears to be effective per se in the animal model that best mirrors human AIDS supports the idea that the development of a highly attenuated poxvirus-based vaccine candidate can be a valuable approach to significantly decrease the spread of human immunodeficiency virus (HIV) infection by the mucosal route.
在恒河猴模型中，疫苗预防高致病性猿猴免疫缺陷病毒（SIV）毒株SIV（mac251）引起的感染和/或疾病是一项具有挑战性的任务。到目前为止，据报道，唯一能保护一部分猕猴在静脉注射SIV（mac251）后免受感染的方法是使用减毒活SIV疫苗。在本研究中，SIV（K6W）的gag、pol和env基因在NYVAC载体中表达，NYVAC载体是痘苗病毒哥本哈根株的基因工程衍生物，在人类中表现出高度减毒的表型。此外，白细胞介素-12（IL-12）的α链和β链基因以及IL-2基因在单独的NYVAC载体中表达，并与NYVAC-SIV疫苗联合或分开进行肌肉注射，接种于40只猕猴。与仅接种NYVAC-SIV疫苗的动物相比，接种NYVAC-SIV和NYVAC-IL-12的动物总体细胞毒性T淋巴细胞（CTL）反应更强，但以增殖和体液反应为代价。在免疫方案结束时，一半动物通过静脉途径用SIV（mac251）进行攻击，另一半通过直肠内暴露于SIV（mac251）。值得注意的是，11只经黏膜暴露于SIV（mac251）的疫苗接种动物中有5只在病毒攻击后1周出现病毒血症短暂峰值，随后似乎清除了病毒感染。相比之下，所有12只静脉接种的动物都被感染，但在病毒攻击后5至6个月，4只动物能够控制病毒表达，并且似乎比对照动物进展为疾病的速度更慢。保护作用似乎与任何测量的免疫参数均无关。联合使用NYVAC-细胞因子重组体进一步调节免疫反应似乎并未影响病毒攻击的结果。NYVAC-SIV重组疫苗本身在最能反映人类艾滋病的动物模型中似乎有效，这一事实支持了这样一种观点，即开发一种高度减毒的痘苗病毒疫苗候选物可能是一种有价值的方法，可以显著减少人类免疫缺陷病毒（HIV）通过黏膜途径的传播。
