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

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da Silva, Jamile Ramos ; Rodrigues, Karine Bitencourt ; Pelegrin, Guilherme Formoso ; Sales, Natiely Silva ; Muramatsu, Hiromi ; Silva, Mariangela de Oliveira ; Porchia, Bruna F. M. M. ; Moreno, Ana Carolina Ramos ; Aps, Luana Raposo M. M. ; Venceslau-Carvalho, Alexia Adrianne ; Tombacz, Istvan ; Fotoran, Wesley Luzetti ; Kariko, Katalin ; Lin, Paulo J. C. ; Tam, Ying K. ; Diniz, Mariana de Oliveira ; Pardi, Norbert ; Ferreira, Luis Carlos de Souza

• Document type: Journal article
• Source: Science Translational Medicine; v. 15, n. 686, p. 18-pg., 2023-03-08.

Abstract

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. (AU)

• FAPESP's process: 16/20045-7 - Antigen discovery and development of serological diagnostic methods and vaccine approaches against the Zika Virus (ZIKV)
• Grantee: Luis Carlos de Souza Ferreira
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 16/00708-1 - Indoleamine 2,3 dioxygenase in the biology of papillomaviruses-induced tumors: neoadjuvant effects on the immunetherapy of tumors
• Grantee: Ana Carolina Ramos Moreno
• Support Opportunities: Scholarships in Brazil - Young Researchers
• FAPESP's process: 15/16505-0 - Indoleamine 2,3 dioxygenase in the biology of papillomaviruses-induced tumors: neoadjuvant effects on the immunetherapy of tumors
• Grantee: Ana Carolina Ramos Moreno
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 16/11594-7 - Self-amplifying RNA as immunotherapeutic strategy for the control of tumors induced by HPV-16
• Grantee: Jamile Ramos da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/15360-2 - New therapeutic frontiers against tumors caused by human papilloma virus (HPV): experimental evaluation of the chemotherapy in association to vaccine strategies
• Grantee: Luana Raposo de Melo Moraes Aps
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/21358-1 - Human papillomavirus (HPV)-associated neoplasia: a new therapeutic approach based on active immunotherapy through targeted stimulation of dendritic cells
• Grantee: Bruna Felício Milazzotto Maldonado Porchia Ribeiro
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/01523-3 - mRNA-based vaccines targeting HPV-induced tumors
• Grantee: Jamile Ramos da Silva
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 18/26515-0 - Antigen targeting to dendritic cells as a strategy to improve the efficiency of immunotherapies to HPV-16-associated tumors.
• Grantee: Luis Carlos de Souza Ferreira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/03326-0 - Active immunotherapy based on dendritic cells combined with chemotherapy in the treatment of advanced tumors associated with HPV-16
• Grantee: Karine Bitencourt Victorelli
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 18/07629-5 - Targeting antigens to dendritic cells as an immunotherapeutic strategy to control HPV-induced tumors
• Grantee: Mariângela de Oliveira Silva
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 16/14344-1 - Control tumors induced by HPV -based immunotherapy in combination monoclonal antibodies blocking immunosuppressive pathways a therapeutic vaccine capable of activating CD8 + cytotoxic T lymphocytes
• Grantee: Natiely Silva Sales
• Support Opportunities: Scholarships in Brazil - Doctorate