Abstract：
Human papilloma virus (HPV) infections are associated with almost all cervical cancers and to a lower extend also with anogenital or oropharyngeal cancers. HPV proteins expressed in HPV-associated tumors are attractive antigens for cancer vaccination strategies as self-tolerance, which is associated with most endogenous tumor-associated antigens, does not need to be overcome. In this study, we generated a live attenuated cancer vaccine based on the chimeric vesicular stomatitis virus VSV-GP, which has previously proven to be a potent vaccine vector and oncolytic virus. Genes at an earlier position in the genome more to the 3\' end are expressed stronger compared to genes located further downstream. By inserting an HPV16-derived antigen cassette consisting of E2, E6 and E7 into VSV-GP either at first (HPVp1) or fifth (HPVp5) position in VSV-GP\'s genome we aimed to analyze the effect of vaccine antigen position and consequently expression level on viral fitness, immunogenicity, and anti-tumoral efficacy in a syngeneic mouse tumor model. HPVp1 expressed higher amounts of HPV antigens compared to HPVp5 in vitro but had a slightly delayed replication kinetic which overall translated into increased HPV-specific T cell responses upon vaccination of mice. Immunization with both vectors protected mice in prophylactic and in therapeutic TC-1 tumor models with HPVp1 being more effective in the prophylactic setting. Taken together, VSV-GP is a promising candidate as therapeutic HPV vaccine and first position of the vaccine antigen in a VSV-derived vector seems to be superior to fifth position.
摘要：
人乳头瘤病毒（HPV）感染与几乎所有宫颈癌有关，并且在较低的程度上也与肛门生殖器或口咽癌有关。在HPV相关肿瘤中表达的HPV蛋白是癌症疫苗接种策略的有吸引力的抗原，与大多数内源性肿瘤相关抗原有关，不需要克服。在这项研究中,我们产生了一种基于嵌合水泡性口炎病毒VSV-GP的减毒活疫苗，先前已被证明是一种有效的疫苗载体和溶瘤病毒。与位于更下游的基因相比，位于基因组中更早位置的基因表达更强。通过在VSV-GP基因组的第一(HPVp1)或第五(HPVp5)位置插入由E2、E6和E7组成的HPV16衍生的抗原盒，我们旨在分析疫苗抗原位置和表达水平对病毒适应性的影响。免疫原性,在同基因小鼠肿瘤模型中的抗肿瘤功效。与HPVp5相比,HPVp1在体外表达更高量的HPV抗原,但具有稍微延迟的复制动力学,其在接种小鼠后总体上转化为增加的HPV特异性T细胞应答。用两种载体免疫在预防性和治疗性TC-1肿瘤模型中保护小鼠,其中HPVp1在预防性设置中更有效。一起来看,VSV-GP是作为治疗性HPV疫苗的有希望的候选物,并且VSV来源的载体中疫苗抗原的第一位置似乎优于第五位置。
