Ramos da Silva et al. used self-amplifying mRNA, unmodified non-replicating (nr) mRNA, or nucleoside-modified nr mRNA to generate mRNA-lipid nanoparticle (LNP) vaccines encoding an HPV-16 E7 oncoprotein/HSV type 1 glycoprotein D fusion (gDE7). In a murine HPV-associated s.c. tumor model, a single low i.m. dose of all three gDE7 mRNA-LNP vaccines induced E7-specific CD8+ T and memory T cell responses that cleared even advanced-stage tumors and prevented tumor recurrence better than gDE7-based plasmid DNA and recombinant protein vaccines (w/o adjuvant). A single gDE7 mRNA-LNP dose induced robust protection against HPV-associated intravaginal and sublingual tumors in mice.
Contributed by Paula Hochman
ABSTRACT: 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.
Author Info: (1) Vaccine Development Laboratory, Department of Microbiology, Institute of Biomedical Sciences, University of So Paulo, So Paulo, SP 05508-000, Brazil. Department of Medicine,
Author Info: (1) Vaccine Development Laboratory, Department of Microbiology, Institute of Biomedical Sciences, University of So Paulo, So Paulo, SP 05508-000, Brazil. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Vaccine Development Laboratory, Department of Microbiology, Institute of Biomedical Sciences, University of So Paulo, So Paulo, SP 05508-000, Brazil. (3) Vaccine Development Laboratory, Department of Microbiology, Institute of Biomedical Sciences, University of So Paulo, So Paulo, SP 05508-000, Brazil. (4) Vaccine Development Laboratory, Department of Microbiology, Institute of Biomedical Sciences, University of So Paulo, So Paulo, SP 05508-000, Brazil. (5) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (6) Vaccine Development Laboratory, Department of Microbiology, Institute of Biomedical Sciences, University of So Paulo, So Paulo, SP 05508-000, Brazil. (7) Vaccine Development Laboratory, Department of Microbiology, Institute of Biomedical Sciences, University of So Paulo, So Paulo, SP 05508-000, Brazil. Laboratory of Tumor Immunology, Department of Immunology, Biomedical Sciences Institute, University of So Paulo, So Paulo, SP 05508-000, Brazil. ImunoTera Solues Teraputicas Ltda., So Paulo, SP 05508-000, Brazil. (8) Vaccine Development Laboratory, Department of Microbiology, Institute of Biomedical Sciences, University of So Paulo, So Paulo, SP 05508-000, Brazil. (9) Vaccine Development Laboratory, Department of Microbiology, Institute of Biomedical Sciences, University of So Paulo, So Paulo, SP 05508-000, Brazil. ImunoTera Solues Teraputicas Ltda., So Paulo, SP 05508-000, Brazil. (10) Vaccine Development Laboratory, Department of Microbiology, Institute of Biomedical Sciences, University of So Paulo, So Paulo, SP 05508-000, Brazil. (11) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (12) Department of Parasitology, Institute for Biomedical Sciences, University of So Paulo, SP 05508-000, Brazil. (13) BioNTech SE, Mainz, 55131, Germany. (14) Acuitas Therapeutics, Vancouver, BC V6T1Z3, Canada. (15) Acuitas Therapeutics, Vancouver, BC V6T1Z3, Canada. (16) Vaccine Development Laboratory, Department of Microbiology, Institute of Biomedical Sciences, University of So Paulo, So Paulo, SP 05508-000, Brazil. (17) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (18) Vaccine Development Laboratory, Department of Microbiology, Institute of Biomedical Sciences, University of So Paulo, So Paulo, SP 05508-000, Brazil. Scientific Platform Pasteur USP, University of So Paulo, So Paulo, SP, 05508-020, Brazil.
