Vaccine Development Laboratory, Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil.
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Sci Transl Med. 2023 Mar 8;15(686):eabn3464. doi: 10.1126/scitranslmed.abn3464.
As mRNA vaccines have proved to be very successful in battling the coronavirus disease 2019 (COVID-19) pandemic, this new modality has attracted widespread interest for the development of potent vaccines against other infectious diseases and cancer. Cervical cancer caused by persistent human papillomavirus (HPV) infection is a major cause of cancer-related deaths in women, and the development of safe and effective therapeutic strategies is urgently needed. In the present study, we compared the performance of three different mRNA vaccine modalities to target tumors associated with HPV-16 infection in mice. We generated lipid nanoparticle (LNP)-encapsulated self-amplifying mRNA as well as unmodified and nucleoside-modified non-replicating mRNA vaccines encoding a chimeric protein derived from the fusion of the HPV-16 E7 oncoprotein and the herpes simplex virus type 1 glycoprotein D (gDE7). We demonstrated that single low-dose immunizations with any of the three gDE7 mRNA vaccines induced activation of E7-specific CD8 T cells, generated memory T cell responses capable of preventing tumor relapses, and eradicated subcutaneous tumors at different growth stages. In addition, the gDE7 mRNA-LNP vaccines induced potent tumor protection in two different orthotopic mouse tumor models after administration of a single vaccine dose. Last, comparative studies demonstrated that all three gDE7 mRNA-LNP vaccines proved to be superior to gDE7 DNA and gDE7 recombinant protein vaccines. Collectively, we demonstrated the immunogenicity and therapeutic efficacy of three different mRNA vaccines in extensive comparative experiments. Our data support further evaluation of these mRNA vaccines in clinical trials.
由于信使 RNA(messenger RNA, mRNA)疫苗已被证明在抗击 2019 年冠状病毒病(coronavirus disease 2019, COVID-19)大流行方面非常成功，这种新方法引起了人们广泛关注，希望能开发出针对其他传染病和癌症的有效疫苗。持续性人乳头瘤病毒(human papillomavirus, HPV)感染引起的宫颈癌是导致女性癌症相关死亡的主要原因，迫切需要开发安全有效的治疗策略。在本研究中，我们比较了三种不同的 mRNA 疫苗模式靶向 HPV-16 感染相关肿瘤的性能。我们生成了包被于脂质纳米颗粒(lipid nanoparticle, LNP)的自我扩增 mRNA 以及未经修饰和核苷修饰的非复制性 mRNA 疫苗，编码源自 HPV-16 E7 癌蛋白和单纯疱疹病毒 1 糖蛋白 D(glycoprotein D, gD)融合的嵌合蛋白。我们证明，三种 gDE7 mRNA 疫苗中的任何一种单次低剂量免疫均可诱导 HPV-16 E7 特异性 CD8 T 细胞的激活，产生能够预防肿瘤复发的记忆 T 细胞反应，并根除不同生长阶段的皮下肿瘤。此外，在单次疫苗接种后，gDE7 mRNA-LNP 疫苗在两种不同的原位小鼠肿瘤模型中也诱导了强烈的肿瘤保护作用。最后，比较研究表明，所有三种 gDE7 mRNA-LNP 疫苗均优于 gDE7 DNA 和 gDE7 重组蛋白疫苗。综上所述，我们在广泛的比较实验中证明了三种不同的 mRNA 疫苗的免疫原性和治疗效果。我们的数据支持在临床试验中进一步评估这些 mRNA 疫苗。
