School of Agriculture and Biology, Shanghai JiaoTong University, 800 Dongchuan Rd., Shanghai 200240, China.
Vaccine. 2012 Feb 8;30(7):1313-21. doi: 10.1016/j.vaccine.2011.12.085. Epub 2012 Jan 2.
Vesicular stomatitis virus (VSV) is a promising vector for vaccine and oncolysis, but it can also produce acute diseases in cattle, horses, and swine characterized by vesiculation and ulceration of the tongue, oral tissues, feet, and teats. In experimental animals (primates, rats, and mice), VSV has been shown to lead to neurotoxicities, such as hind limb paralysis. The virus matrix protein (M) and glycoprotein (G) are both major pathogenic determinants of wild-type VSV and have been the major targets for the production of attenuated strains. Existing strategies for attenuation included: (1) deletion or M51R substitution in the M protein (VSVΔM51 or VSVM51R, respectively); (2) truncation of the C-terminus of the G protein (GΔ28). Despite these mutations, recombinant VSV with mutated M protein is only moderately attenuated in animals, whereas there are no detailed reports to determine the pathogenicity of recombinant VSV with truncated G protein at high dose. Thus, a novel recombinant VSV (VSVΔM51-GΔ28) as well as other attenuated VSVs (VSVΔM51, VSV-GΔ28) were produced to determine their efficacy as vaccine vectors with low pathogenicity. In vitro studies indicated that truncated G protein (GΔ28) could play a more important role than deletion of M51 (ΔM51) for attenuation of recombinant VSV. VSVΔM51-GΔ28 was determined to be the most attenuated virus with low pathogenicity in mice, with VSV-GΔ28 also showing relatively reduced pathogenicity. Further, neutralizing antibodies stimulated by VSV-GΔ28 proved to be significantly higher than in mice treated with VSVΔM51-GΔ28. In conclusion, among different attenuated VSVs with mutated M and/or G proteins, recombinant VSV with only truncated G protein (VSV-GΔ28) demonstrated ideal balance between pathogenesis and stimulating a protective immune response. These properties make VSV-GΔ28 a promising vaccine vector and vaccine candidate for preventing vesicular stomatitis disease.
水疱性口炎病毒（VSV）是一种有前途的疫苗和溶瘤载体，但它也会在牛、马和猪中引起急性疾病，其特征是舌、口腔组织、脚和乳头出现水疱和溃疡。在实验动物（灵长类动物、大鼠和小鼠）中，VSV 已被证明会导致神经毒性，例如后肢瘫痪。病毒基质蛋白（M）和糖蛋白（G）都是野生型 VSV 的主要致病决定因素，也是减毒株产生的主要目标。现有的减毒策略包括：（1）M 蛋白中的缺失或 M51R 取代（分别为 VSVΔM51 或 VSVM51R）；（2）G 蛋白 C 末端的截断（GΔ28）。尽管存在这些突变，但具有突变 M 蛋白的重组 VSV 在动物中仅中度减毒，而对于高剂量截断 G 蛋白的重组 VSV 的致病性尚无详细报道。因此，产生了一种新型重组 VSV（VSVΔM51-GΔ28）以及其他减毒 VSV（VSVΔM51、VSV-GΔ28），以确定它们作为低致病性疫苗载体的功效。体外研究表明，截断的 G 蛋白（GΔ28）对于重组 VSV 的减毒作用可能比缺失 M51（ΔM51）更为重要。VSVΔM51-GΔ28 被确定为在小鼠中最具低致病性的病毒，VSV-GΔ28 也显示出相对降低的致病性。此外，由 VSV-GΔ28 刺激的中和抗体证明显著高于用 VSVΔM51-GΔ28 处理的小鼠。总之，在具有突变 M 和/或 G 蛋白的不同减毒 VSV 中，仅具有截断 G 蛋白（VSV-GΔ28）的重组 VSV 在发病机制和刺激保护性免疫反应之间表现出理想的平衡。这些特性使 VSV-GΔ28 成为预防水疱性口炎疾病的有前途的疫苗载体和候选疫苗。
