Vesicular stomatitis virus-based therapeutic vaccination targeted to the E1, E2, E6, and E7 proteins of cottontail rabbit papillomavirus
Vesicular stomatitis virus-based therapeutic vaccination targeted to the E1, E2, E6, and E7 proteins of cottontail rabbit papillomavirus
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DOI：
10.1128/jvi.02835-06
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发表时间：
2007-06-01
影响因子：
5.4
通讯作者：
Buonocore, Linda
中科院分区：
文献类型：
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作者：
Brandsma, Janet L.;Shylankevich, Mark;Buonocore, Linda
持续性人乳头瘤病毒（HPV）相关良性和恶性病变是全世界发病和死亡的主要原因。针对 HPV 早期蛋白的疫苗接种可以提供治疗已感染的个体的有效方法。重组水泡性口炎病毒（VSV）载体此前已被用于引发强烈的体液和细胞免疫反应并开发预防性疫苗。我们已经证明，VSV 载体还可用于在高危 HPV 感染的棉尾兔乳头瘤病毒 (CRPV)-兔模型中引发治疗性免疫。在本研究中，生产了三种表达 CRPV E1、E2 或 E7 蛋白的新 VSV 载体，并与之前生成的 VSV-E6 载体进行比较以了解治疗效果。为了确定同时接种两种 CRPV 蛋白是否可以增强疫苗功效，在 CRPV 感染 1 周后，将四种疫苗单独并以所有可能的配对方式注射给兔子。对照兔子仅接受重组野生型VSV载体或培养基。计算累积乳头状瘤体积以用于数据分析。分析表明，与对照组相比，针对 E1、E2、E6 或 E7 蛋白的基于 VSV 的疫苗接种显着减少了乳头状瘤体积。此外，基于 VSV 的 CRPV 疫苗接种治愈了 30 只兔子中的 5 只的所有乳头状瘤。在各种疫苗中，VSV-E7 是最有效的。仅 VSV-E7 疫苗是最有效的，因为与对照组相比，它总体上减少了 96.9% 的累积乳头状瘤体积，并最终消除了所有疫苗接种者的所有疾病。然而，没有发现疫苗配对是有益的，这表明共表达的 CRPV 蛋白之间存在抗原竞争。这些在 HPV 感染的生理相关动物模型中获得的临床前结果表明，VSV 载体值得认真考虑，以进一步开发为治疗性抗肿瘤疫苗。
Persistent human papillomavirus (HPV)-associated benign and malignant lesions are a major cause of morbidity and mortality worldwide. Vaccination against HPV early proteins could provide an effective means of treating individuals with established infections. Recombinant vesicular stomatitis virus (VSV) vectors have been used previously to elicit strong humoral and cellular immune responses and develop prophylactic vaccines. We have shown that VSV vectors also can be used to elicit therapeutic immunity in the cottontail rabbit papillomavirus (CRPV)-rabbit model of high-risk HPV infection. In the present study, three new VSV vectors expressing the CRPV E1, E2, or E7 protein were produced and compared to the previously generated VSV-E6 vector for therapeutic efficacy. To determine whether vaccine efficacy could be augmented by simultaneous vaccination against two CRPV proteins, the four vaccines were delivered individually and in all possible pairings to rabbits 1 week after CRPV infection. Control rabbits received the recombinant wild-type VSV vector or medium only. Cumulative papilloma volumes were computed for analysis of the data. The analyses showed that VSV-based vaccination against the E1, E2, E6, or E7 protein significantly reduced papilloma volumes relative to those of the controls. Furthermore, VSV-based CRPV vaccination cured all of the papillomas in 5 of 30 rabbits. Of the individual vaccines, VSV-E7 was the most effective. The VSV-E7 vaccine alone was the most effective, as it reduced cumulative papilloma volumes by 96.9% overall, relative to those of the controls, and ultimately eliminated all of the disease in all of the vaccinees. Vaccine pairing was not, however, found to be beneficial, suggesting antigenic competition between the coexpressed CRPV proteins. These preclinical results, obtained in a physiologically relevant animal model of HPV infection, demonstrate that VSV vectors deserve serious consideration for further development as therapeutic antitumor vaccines.