Leachman Sancy A, Shylankevich Mark, Slade Martin D, Levine Dana, Sundaram Ranjini K, Xiao Wei, Bryan Marianne, Zelterman Daniel, Tiegelaar Robert E, Brandsma Janet L
Department of Dermatology, School of Medicine, Yale University, New Haven, Connecticut 06520, USA.
J Virol. 2002 Aug;76(15):7616-24. doi: 10.1128/jvi.76.15.7616-7624.2002.
Human papillomavirus (HPV) vaccines have the potential to prevent cervical cancer by preventing HPV infection or treating premalignant disease. We previously showed that DNA vaccination with the cottontail rabbit papillomavirus (CRPV) E6 gene induced partial protection against CRPV challenge and that the vaccine's effects were greatly enhanced by priming with granulocyte-macrophage colony-stimulating factor (GM-CSF). In the present study, two additional strategies for augmenting the clinical efficacy of CRPV E6 vaccination were evaluated. The first was to fuse a ubiquitin monomer to the CRPV E6 protein to enhance antigen processing and presentation through the major histocompatibility complex class I pathway. Rabbits vaccinated with the wild-type E6 gene plus GM-CSF or with the ubiquitin-fused E6 gene formed significantly fewer papillomas than the controls. The papillomas also required a longer time to appear and grew more slowly. Finally, a significant proportion of the papillomas subsequently regressed. The ubiquitin-fused E6 vaccine was significantly more effective than the wild-type E6 vaccine plus GM-CSF priming. The second strategy was to vaccinate with multiple CRPV early genes to increase the breadth of the CRPV-specific response. DNA vaccines encoding the wild-type CRPV E1-E2, E6, or E7 protein were tested alone and in all possible combinations. All vaccines and combinations suppressed papilloma formation, slowed papilloma growth, and stimulated subsequent papilloma regression. Finally, the two strategies were merged and a combination DNA vaccine containing ubiquitin-fused versions of the CRPV E1, E2, and E7 genes was tested. This last vaccine prevented papilloma formation at all challenge sites in all rabbits, demonstrating complete protection.
人乳头瘤病毒（HPV）疫苗有通过预防HPV感染或治疗癌前疾病来预防宫颈癌的潜力。我们之前表明，用棉尾兔乳头瘤病毒（CRPV）E6基因进行DNA疫苗接种可诱导对CRPV攻击的部分保护，并且通过用粒细胞-巨噬细胞集落刺激因子（GM-CSF）进行启动可大大增强疫苗的效果。在本研究中，评估了另外两种增强CRPV E6疫苗接种临床疗效的策略。第一种是将泛素单体与CRPV E6蛋白融合，以通过主要组织相容性复合体I类途径增强抗原加工和呈递。用野生型E6基因加GM-CSF或用泛素融合的E6基因接种的兔子形成的乳头瘤明显少于对照组。乳头瘤出现的时间也更长，生长更缓慢。最后，相当一部分乳头瘤随后消退。泛素融合的E6疫苗比野生型E6疫苗加GM-CSF启动显著更有效。第二种策略是用多个CRPV早期基因进行疫苗接种，以增加CRPV特异性反应的广度。单独测试并以所有可能的组合测试了编码野生型CRPV E1-E2、E6或E7蛋白的DNA疫苗。所有疫苗及其组合均抑制了乳头瘤的形成，减缓了乳头瘤的生长，并刺激了随后乳头瘤的消退。最后，将这两种策略合并，并测试了一种包含CRPV E1、E2和E7基因泛素融合版本的组合DNA疫苗。最后这种疫苗在所有兔子的所有攻击部位都预防了乳头瘤的形成，证明了完全保护作用。
