mRNA-based vaccines targeting HPV-induced tumors

• Grant number: 19/01523-3
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: May 20, 2019
• End date: February 19, 2020
• Field of knowledge: Biological Sciences - Microbiology - Applied Microbiology
• Principal Investigator: Luis Carlos de Souza Ferreira
• Grantee: Jamile Ramos da Silva
• Supervisor: Norbert Pardi
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of Pennsylvania, United States
• Associated to the scholarship: 16/11594-7 - Self-amplifying RNA as immunotherapeutic strategy for the control of tumors induced by HPV-16, BP.DR

Abstract

Cervical cancer is the third leading cause of cancer death in women and is associated with persistent infection with Human Papilloma Virus (HPV) in more than 99% of the cases. Given the epidemiological relevance of tumors induced by HPV, development of effective therapeutic vaccines is a high priority. Therefore, we have developed a DNA-based therapeutic vaccine encoding the HPV-16 E7 protein of the Herpes Simplex Virus type 1 (HSV-1) glycoprotein D (gD), named gDE7. In order to optimize this vaccine for clinical applications, the current Ph.D. project aims to develop highly effective RNA vaccines encoding gDE7 and use them to treat tumors induced by HPV-16. Our previous results showed that vaccination with in vitro-synthesized unmodified and unpurified mRNA was not efficient in expressing the antigen of interest due to induction of a strong inflammatory response and translational blockade by the unmodified and unpurified mRNA. To address this issue, we hypothesized that the use of nucleoside-modified mRNA and additional purification steps to remove double-stranded RNA contaminants may help to overcome these issues. Thus, we propose an internship at the University of Pennsylvania supervised by Norbert Pardi, to further improve our gDE7 vaccine against HPV-associated tumours. We will use 2 major vaccine types: nucleoside-modified non-replicative mRNA and self-amplifying mRNA. We expect to consolidate a new collaboration and to move further on aiming the development of RNA-based vaccines, especially against cancer.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

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; et al. Single immunizations of self-amplifying or non-replicating mRNA-LNP vaccines control HPV-associated tumors in mice. Science Translational Medicine, v. 15, n. 686, p. 18-pg., 2023-03-08. (16/20045-7, 16/00708-1, 15/16505-0, 16/11594-7, 13/15360-2, 17/21358-1, 19/01523-3, 18/26515-0, 21/03326-0, 18/07629-5, 16/14344-1)

FREYN, ALEC W.; DA SILVA, JAMILE RAMOS; ROSADO, VICTORIA C.; BLISS, CARLY M.; PINE, MATTHEW; MUI, BARBARA L.; TAM, YING K.; MADDEN, THOMAS D.; DE SOUZA FERREIRA, LUIS CARLOS; WEISSMAN, DREW; et al. A Multi-Targeting, Nucleoside-Modified mRNA Influenza Virus Vaccine Provides Broad Protection in Mice. MOLECULAR THERAPY, v. 28, n. 7, p. 1569-1584, JUL 8 2020. (19/01523-3)