Single immunizations of self-amplifying or non-replicating mRNA-LNP vaccines control HPV-associated tumors in mice
Single immunizations of self-amplifying or non-replicating mRNA-LNP vaccines control HPV-associated tumors in mice
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DOI：
10.1126/scitranslmed.abn3464
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发表时间：
2023-03-08
影响因子：
17.1
通讯作者：
Ferreira, Luis Carlos de Souza
中科院分区：
文献类型：
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作者：
da Silva, Jamile Ramos;Rodrigues, Karine Bitencourt;Ferreira, Luis Carlos de Souza
由于mRNA疫苗已被证明在对抗2019冠状病毒病（COVID-19）大流行方面非常成功，这种新模式引起了人们对开发针对其他传染病和癌症的强效疫苗的广泛兴趣。由持续的人乳头瘤病毒（HPV）感染引起的宫颈癌是妇女癌症相关死亡的主要原因，迫切需要制定安全有效的治疗策略。在本研究中，我们比较了三种不同mRNA疫苗模式在小鼠HPV-16感染相关肿瘤中的表现。我们制备了脂质纳米颗粒（LNP）封装的自扩增mRNA以及未修饰和核苷修饰的非复制mRNA疫苗，该疫苗编码由HPV-16 E7癌蛋白和单纯疱疹病毒1型糖蛋白D （gDE7）融合而成的嵌合蛋白。我们证明，使用三种gDE7 mRNA疫苗中的任何一种进行单次低剂量免疫可诱导e7特异性CD8+ T细胞的激活，产生能够防止肿瘤复发的记忆T细胞反应，并在不同生长阶段根除皮下肿瘤。此外，gDE7 mRNA-LNP疫苗在单剂量给药后对两种不同的原位小鼠肿瘤模型产生了有效的肿瘤保护作用。最后，比较研究表明，三种gDE7 mRNA-LNP疫苗均优于gDE7 DNA和gDE7重组蛋白疫苗。总的来说，我们在广泛的比较实验中证明了三种不同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。
As mRNA vaccines have proved to be very successful in battling the coronavirus disease 2019 (COVID-19) pan-demic, 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 clini-cal trials.