Da Silva Diane M, Martinez Emma A, Bogaert Lies, Kast W Martin
Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA 90033, USA.
Cancers (Basel). 2022 Sep 5;14(17):4339. doi: 10.3390/cancers14174339.
Therapeutic vaccine studies should be designed to elicit durable, high magnitude, and efficacious T cell responses, all of which can be impacted by the choice of the vaccination schedule. Here, we compare different prime-boost intervals (PBI) in a human papillomavirus (HPV) model using a HPV16E7E6 Venezuelan equine encephalitis virus replicon particle (VRP) vaccination to address the optimal boosting schedule, quality of immune response, and overall in vivo efficacy. Six different vaccine regimens were tested with each group receiving booster vaccinations at different time intervals. Analysis of T-cell responses demonstrated a significant HPV16 E7 specific CD8 T cell response with at minimum a one-week PBI between antigen re-exposure. Significant E7-specific in vivo cytotoxicity was also observed with longer PBIs. Additionally, longer PBIs led to an enhanced memory recall response to tumor challenge, which correlated with differential expansion of T cell memory subsets. Our findings imply that when using alphavirus vector platforms as a vaccination strategy, a one-week PBI is sufficient to induce high magnitude effector T cells with potent anti-tumor activity. However, longer PBIs lead to enhanced long-term protective anti-tumor immunity. These findings have implications for therapeutic vaccine clinical trials in which shorter intervals of prime-boost regimens may lead to suboptimal durable immune responses.
治疗性疫苗研究的设计应旨在引发持久、高强度且有效的T细胞反应，而所有这些都可能受到疫苗接种方案选择的影响。在此，我们在人乳头瘤病毒（HPV）模型中，使用HPV16E7E6委内瑞拉马脑炎病毒复制子颗粒（VRP）疫苗接种来比较不同的初免-加强间隔（PBI），以确定最佳的加强接种方案、免疫反应质量和整体体内疗效。测试了六种不同的疫苗方案，每组在不同时间间隔接受加强接种。T细胞反应分析表明，在抗原再次暴露之间至少有一周的PBI时，会出现显著的HPV16 E7特异性CD8 T细胞反应。在较长的PBI时，还观察到显著的E7特异性体内细胞毒性。此外，较长的PBI会导致对肿瘤攻击的记忆回忆反应增强，这与T细胞记忆亚群的差异扩增相关。我们的研究结果表明，当使用甲病毒载体平台作为疫苗接种策略时，一周的PBI足以诱导具有强大抗肿瘤活性的高强度效应T细胞。然而，较长的PBI会导致增强的长期保护性抗肿瘤免疫力。这些发现对治疗性疫苗临床试验具有启示意义，在这些试验中，较短间隔的初免-加强方案可能会导致次优的持久免疫反应。
