Single immunizations of self-amplifying or non-replicating mRNA-LNP vaccines control HPV-associated tumors in mice

Menée à l'aide de lignées cellulaires et de modèles murins de tumeurs associées au papillomavirus humain de type 16, cette étude compare l'efficacité antitumorale de trois vaccins basés sur un ARN messager codant pour une protéine de fusion combinant l'oncoprotéine HPV-16-E7 et la glycoprotéine D de type 1 du virus Herpes simplex

Résumé en anglais

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. Self-amplifying and non-replicating mRNA vaccines are immunogenic and control tumor burden in mice bearing HPV-associated tumors. mRNA vaccines can be delivered through multiple platforms. Here, Ramos da Silva and colleagues compared three different mRNA platforms as a therapeutic vaccine for human papillomavirus–associated cancers. The three vaccines tested were an unmodified non-replicating mRNA vaccine, a nucleoside-modified non-replicating mRNA vaccine, and a self-amplifying mRNA vaccine. All three vaccines encoded the same antigen, a fusion protein of the HPV-16 E7 oncoprotein and the herpes simplex virus type 1 glycoprotein D, so differences between the vaccines’ efficacy were due to the platform. The authors found that a single dose of self-amplifying or unmodified non-replicating mRNA vaccines, both encapsulated in lipid nanoparticles, led to robust control of tumor burden in two orthotopic murine models. Further, all three vaccines outperformed a protein vaccine and an electroporated DNA vaccine containing or encoding the same antigen. These results highlight the translational potential of mRNA cancer vaccines.