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

被引:67
作者
da Silva, Jamile Ramos [1 ,2 ]
Rodrigues, Karine Bitencourt [1 ]
Pelegrin, Guilherme Formoso [1 ]
Sales, Natiely Silva [1 ]
Muramatsu, Hiromi [2 ,3 ]
Silva, Mariangela de Oliveira [1 ]
Porchia, Bruna F. M. M. [1 ,4 ,5 ]
Moreno, Ana Carolina Ramos [1 ]
Aps, Luana Raposo M. M. [1 ,5 ]
Venceslau-Carvalho, Alexia Adrianne [1 ]
Tombacz, Istvan [2 ]
Fotoran, Wesley Luzetti [6 ]
Kariko, Katalin [7 ]
Lin, Paulo J. C. [8 ]
Tam, Ying K. [8 ]
Diniz, Mariana de Oliveira [1 ]
Pardi, Norbert [2 ,3 ]
Ferreira, Luis Carlos de Souza [1 ,9 ]
机构
[1] Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, Vaccine Dev Lab, BR-05508000 Sao Paulo, SP, Brazil
[2] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA
[3] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA
[4] Univ Sao Paulo, Biomed Sci Inst, Dept Immunol, Lab Tumor Immunol, BR-05508000 Sao Paulo, SP, Brazil
[5] ImunoTera Solucoes Terapeut Ltd, BR-05508000 Sao Paulo, SP, Brazil
[6] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, BR-05508000 Sao Paulo, SP, Brazil
[7] BioNTech SE, D-55131 Mainz, Germany
[8] Acuitas Therapeut, Vancouver, BC V6T 1Z3, Canada
[9] Univ Sao Paulo, Sci Platform Pasteur USP, BR-05508020 Sao Paulo, SP, Brazil
基金
巴西圣保罗研究基金会;
关键词
HERPESVIRUS ENTRY MEDIATOR; HUMAN-PAPILLOMAVIRUS; IMMUNE-RESPONSES; LIPID NANOPARTICLES; GLYCOPROTEIN-D; DENDRITIC CELLS; T-CELLS; CD8(+); CANCER; ACTIVATION;
D O I
10.1126/scitranslmed.abn3464
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
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页数:18
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