Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD USA.
Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
Cell Biosci. 2016 Feb 25;6:16. doi: 10.1186/s13578-016-0080-z. eCollection 2016.
Human papillomavirus (HPV) has been identified as the primary etiologic factor of cervical cancer as well as subsets of anogenital and oropharyngeal cancers. The two HPV viral oncoproteins, E6 and E7, are uniquely and consistently expressed in all HPV infected cells and are therefore promising targets for therapeutic vaccination. Both recombinant naked DNA and protein-based HPV vaccines have been demonstrated to elicit HPV-specific CD8+ T cell responses that provide therapeutic effects against HPV-associated tumor models. Here we examine the immunogenicity in a preclinical model of priming with HPV DNA vaccine followed by boosting with filterable aggregates of HPV 16 L2E6E7 fusion protein (TA-CIN).
We observed that priming twice with an HPV DNA vaccine followed by a single TA-CIN booster immunization generated the strongest antigen-specific CD8+ T cell response compared to other prime-boost combinations tested in C57BL/6 mice, whether naïve or bearing the HPV16 E6/E7 transformed syngeneic tumor model, TC-1. We showed that the magnitude of antigen-specific CD8+ T cell response generated by the DNA vaccine prime, TA-CIN protein vaccine boost combinatorial strategy is dependent on the dose of TA-CIN protein vaccine. In addition, we found that a single booster immunization comprising intradermal or intramuscular administration of TA-CIN after priming twice with an HPV DNA vaccine generated a comparable boost to E7-specific CD8+ T cell responses. We also demonstrated that the immune responses elicited by the DNA vaccine prime, TA-CIN protein vaccine boost strategy translate into potent prophylactic and therapeutic antitumor effects. Finally, as seen for repeat TA-CIN protein vaccination, we showed that the heterologous DNA prime and protein boost vaccination strategy is well tolerated by mice.
Our results provide rationale for future clinical testing of HPV DNA vaccine prime, TA-CIN protein vaccine boost immunization regimen for the control of HPV-associated diseases.
人乳头瘤病毒（HPV）已被确定为宫颈癌以及肛门生殖器和口咽癌亚类的主要病因。HPV 的两种病毒致癌蛋白 E6 和 E7，在所有 HPV 感染细胞中独特且一致地表达，因此是治疗性疫苗接种的有前途的靶标。已经证明，重组裸露 DNA 和基于蛋白质的 HPV 疫苗能够引发 HPV 特异性 CD8+T 细胞反应，从而对 HPV 相关肿瘤模型提供治疗效果。在这里，我们在 HPV DNA 疫苗进行初步免疫接种，然后用 HPV 16 L2E6E7 融合蛋白（TA-CIN）的可过滤聚集体进行加强免疫的临床前模型中检查其免疫原性。
我们观察到，与在 C57BL/6 小鼠中测试的其他初免-加强组合相比，两次用 HPV DNA 疫苗进行初免，然后用单次 TA-CIN 加强免疫，可产生最强的抗原特异性 CD8+T 细胞反应，无论是在未感染的情况下还是携带 HPV16 E6/E7 转化的同基因肿瘤模型 TC-1 的情况下。我们表明，DNA 疫苗初免、TA-CIN 蛋白疫苗加强组合策略产生的抗原特异性 CD8+T 细胞反应的大小取决于 TA-CIN 蛋白疫苗的剂量。此外，我们发现，在用 HPV DNA 疫苗进行两次初免后，单次皮内或肌肉内给予 TA-CIN 加强免疫，可产生与 E7 特异性 CD8+T 细胞反应相当的加强。我们还证明，DNA 疫苗初免、TA-CIN 蛋白疫苗加强策略引发的免疫反应转化为有效的预防性和治疗性抗肿瘤作用。最后，与重复 TA-CIN 蛋白接种一样，我们表明，异源 DNA 初免和蛋白加强接种策略被小鼠很好地耐受。
我们的结果为 HPV DNA 疫苗初免、TA-CIN 蛋白疫苗加强免疫方案用于控制 HPV 相关疾病的未来临床测试提供了依据。
