Abstract
The COVID-19 pandemic caused by SARS-CoV-2 has made the development of safe and effective vaccines a critical priority. To date, four vaccines have been approved by European and American authorities for preventing COVID-19, but the development of additional vaccine platforms with improved supply and logistics profiles remains a pressing need. Here we report the preclinical evaluation of a novel COVID-19 vaccine candidate based on the electroporation of engineered, synthetic cDNA encoding a viral antigen in the skeletal muscle. We constructed a set of prototype DNA vaccines expressing various forms of the SARS-CoV-2 spike (S) protein and assessed their immunogenicity in animal models. Among them, COVID-eVax—a DNA plasmid encoding a secreted monomeric form of SARS-CoV-2 S protein receptor-binding domain (RBD)—induced the most potent anti-SARS-CoV-2 neutralizing antibody responses (including against the current most common variants of concern) and a robust T cell response. Upon challenge with SARS-CoV-2, immunized K18-hACE2 transgenic mice showed reduced weight loss, improved pulmonary function, and lower viral replication in the lungs and brain. COVID-eVax conferred significant protection to ferrets upon SARS-CoV-2 challenge. In summary, this study identifies COVID-eVax as an ideal COVID-19 vaccine candidate suitable for clinical development. Accordingly, a combined phase I-II trial has recently started.
| Original language | English |
|---|---|
| Pages (from-to) | 311-316 |
| Number of pages | 16 |
| Journal | Molecular Therapy |
| Volume | 30 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 2022 |
Keywords
- animal models
- antiviral immunity
- DNA vaccine
- protection
- SARS-CoV-2
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
- Pharmacology
- Drug Discovery
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COVID-eVax, an electroporated DNA vaccine candidate encoding the SARS-CoV-2 RBD, elicits protective responses in animal models. / Conforti, Antonella; Marra, Emanuele; Palombo, Fabio et al.
In: Molecular Therapy, Vol. 30, No. 1, 01.2022, p. 311-316.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - COVID-eVax, an electroporated DNA vaccine candidate encoding the SARS-CoV-2 RBD, elicits protective responses in animal models
AU - Conforti, Antonella
AU - Marra, Emanuele
AU - Palombo, Fabio
AU - Roscilli, Giuseppe
AU - Ravà, Micol
AU - Fumagalli, Valeria
AU - Muzi, Alessia
AU - Maffei, Mariano
AU - Luberto, Laura
AU - Lione, Lucia
AU - Salvatori, Erika
AU - Compagnone, Mirco
AU - Pinto, Eleonora
AU - Pavoni, Emiliano
AU - Bucci, Federica
AU - Vitagliano, Grazia
AU - Stoppoloni, Daniela
AU - Pacello, Maria Lucrezia
AU - Cappelletti, Manuela
AU - Ferrara, Fabiana Fosca
AU - D'Acunto, Emanuela
AU - Chiarini, Valerio
AU - Arriga, Roberto
AU - Nyska, Abraham
AU - Di Lucia, Pietro
AU - Marotta, Davide
AU - Bono, Elisa
AU - Giustini, Leonardo
AU - Sala, Eleonora
AU - Perucchini, Chiara
AU - Paterson, Jemma
AU - Ryan, Kathryn Ann
AU - Challis, Amy Rose
AU - Matusali, Giulia
AU - Colavita, Francesca
AU - Caselli, Gianfranco
AU - Criscuolo, Elena
AU - Clementi, Nicola
AU - Mancini, Nicasio
AU - Groß, Rüdiger
AU - Seidel, Alina
AU - Wettstein, Lukas
AU - Münch, Jan
AU - Donnici, Lorena
AU - Conti, Matteo
AU - De Francesco, Raffaele
AU - Kuka, Mirela
AU - Ciliberto, Gennaro
AU - Castilletti, Concetta
AU - Capobianchi, Maria Rosaria
AU - Ippolito, Giuseppe
AU - Guidotti, Luca G.
AU - Rovati, Lucio
AU - Iannacone, Matteo
AU - Aurisicchio, Luigi
N1 - Funding Information: We thank the entire Rottapharm Biotech and IGEA Teams for useful scientific and regulatory discussions and for setting up the EPSGun technology in a short time. We also thank M. Mainetti, M. Freschi, and A. Fiocchi for technical support; M. Silva for secretarial assistance; and the members of the Iannacone laboratory for helpful discussions. Flow cytometry was carried out at FRACTAL, a flow cytometry resource and advanced cytometry technical applications laboratory established by the San Raffaele Scientific Institute. Confocal immunofluorescence histology was carried out at Alembic, an advanced microscopy laboratory established by the San Raffaele Scientific Institute and the Vita-Salute San Raffaele University. We would like to acknowledge the PhD program in Basic and Applied Immunology and Oncology at Vita-Salute San Raffaele University, as D.M. and E. Sala conducted this study as partial fulfillment of their PhD in Molecular Medicine within that program. M.I. is supported by European Research Council ( ERC ) Consolidator Grant 725038 , ERC Proof of Concept Grant 957502 , Italian Association for Cancer Research ( AIRC ) Grants 19891 and 22737 , Italian Ministry of Health Grants RF-2018-12365801 and COVID-2020-12371617 , Lombardy Foundation for Biomedical Research (FRRB) Grant 2015-0010 , the European Molecular Biology Organization Young Investigator Program , and Funded Research Agreements from Gilead Sciences , Takis Biotech , Toscana Life Sciences , and Asher Bio . L.G.G. is supported by AIRC Grant 22737 , Lombardy Open Innovation Grant 229452 , PRIN Grant 2017MPCWPY from the Italian Ministry of Education, University and Research , Funded Research Agreements from Gilead Sciences , Avalia Therapeutics , and CNCCS SCARL , and donations from FONDAZIONE SAME and FONDAZIONE PROSSIMO MIO for COVID-19-related research. M.K. is supported by Italian Ministry of Education, University and Research grant PRIN-2017ZXT5WR . J.M. is supported by funding from the Deutsche Forschungsgemeinschaft through Fokus-Förderung COVID-19 and the CRC1279, the European Union Horizon 2020 Framework Programme for Innovation and Research (Fight-nCoV), the Ministry for Science, Research and Arts of Baden-Württemberg , and the BMWi–Federal Ministry for Economic Affairs and Energy (COMBI-COV-2). R.G., A.S., and L.W. are part of the International Graduate School in Molecular Medicine Ulm. Takis Research activities are supported in part by the Italian Ministry of Economic Development through grants F/050298/02/X32 , F/090033/01-04/X36 , and F/190180/01/X44 . We are also grateful to Lazio Innova for the funding provided through grant A0376-2020-0700050 Prog. T0002E0001 “Emergenza Coronavirus ed oltre” to Vitares no profit organization, and Fondazione Melanoma for providing support to develop the assays used in clinical trials. PHE activities (Covivax project) are supported by the European Network of vaccine research and development ( TRANSVAC2 ). Funding Information: We thank the entire Rottapharm Biotech and IGEA Teams for useful scientific and regulatory discussions and for setting up the EPSGun technology in a short time. We also thank M. Mainetti, M. Freschi, and A. Fiocchi for technical support; M. Silva for secretarial assistance; and the members of the Iannacone laboratory for helpful discussions. Flow cytometry was carried out at FRACTAL, a flow cytometry resource and advanced cytometry technical applications laboratory established by the San Raffaele Scientific Institute. Confocal immunofluorescence histology was carried out at Alembic, an advanced microscopy laboratory established by the San Raffaele Scientific Institute and the Vita-Salute San Raffaele University. We would like to acknowledge the PhD program in Basic and Applied Immunology and Oncology at Vita-Salute San Raffaele University, as D.M. and E. Sala conducted this study as partial fulfillment of their PhD in Molecular Medicine within that program. M.I. is supported by European Research Council (ERC) Consolidator Grant 725038, ERC Proof of Concept Grant 957502, Italian Association for Cancer Research (AIRC) Grants 19891 and 22737, Italian Ministry of Health Grants RF-2018-12365801 and COVID-2020-12371617, Lombardy Foundation for Biomedical Research (FRRB) Grant 2015-0010, the European Molecular Biology Organization Young Investigator Program, and Funded Research Agreements from Gilead Sciences, Takis Biotech, Toscana Life Sciences, and Asher Bio. L.G.G. is supported by AIRC Grant 22737, Lombardy Open Innovation Grant 229452, PRIN Grant 2017MPCWPY from the Italian Ministry of Education, University and Research, Funded Research Agreements from Gilead Sciences, Avalia Therapeutics, and CNCCS SCARL, and donations from FONDAZIONE SAME and FONDAZIONE PROSSIMO MIO for COVID-19-related research. M.K. is supported by Italian Ministry of Education, University and Research grant PRIN-2017ZXT5WR. J.M. is supported by funding from the Deutsche Forschungsgemeinschaft through Fokus-F?rderung COVID-19 and the CRC1279, the European Union Horizon 2020 Framework Programme for Innovation and Research (Fight-nCoV), the Ministry for Science, Research and Arts of Baden-W?rttemberg, and the BMWi?Federal Ministry for Economic Affairs and Energy (COMBI-COV-2). R.G. A.S. and L.W. are part of the International Graduate School in Molecular Medicine Ulm. Takis Research activities are supported in part by the Italian Ministry of Economic Development through grants F/050298/02/X32, F/090033/01-04/X36, and F/190180/01/X44. We are also grateful to Lazio Innova for the funding provided through grant A0376-2020-0700050 Prog. T0002E0001 ?Emergenza Coronavirus ed oltre? to Vitares no profit organization, and Fondazione Melanoma for providing support to develop the assays used in clinical trials. PHE activities (Covivax project) are supported by the European Network of vaccine research and development (TRANSVAC2). A.C. E.M. F.P. G.R. M.R. V.F. A.M. M.M. L. Luberto, L. Lione, E. Salvatori, M. Compagnone, E. Pinto, E. Pavoni, F.B. G.V. D.S. M.L.P. M. Cappalletti, F.F.F. E.D. V.C, R.A. A.N. P.D.L. D.M. E.B. L.G. E. Sala, C.P. J.P. K.A.R. A.R.C. G.M. F.C. G. Caselli, E.C. N.C. N.M. R.G. A.S. L.W. L.D. and M. Conti performed experiments; A.C. M.R. V.F. E. Sala, G. Caselli, J.M. L.D. M. Compagnone, and R.D.F. analyzed and interpreted data; A.C. and M.R. prepared the figures and edited the manuscript; J.M. R.D.F. M.K. G. Ciliberto, C.C. M.R.C. G.I. L.G.G. and L.R. provided funding and conceptual advice and edited the manuscript; M.I. and L.A. coordinated the study, provided funding, and wrote the paper. A.C. and M.M. are Evvivax employees. E.M. F.P. G.R. A.M. L.L. L.L. E. Salvatori, M. Cappalletti, F.F.F. E.D. V.C. and L.A. are Takis employees. G. Caselli and L.R. are Rottapharm Biotech employees. Takis and Rottapharm Biotech are jointly developing COVID-eVax. M.I. participates in advisory boards/consultancies for or receives funding from Gilead Sciences, Roche, Third Rock Ventures, Amgen, Allovir, Asher Bio. L.G.G is a member of the board of directors at Genenta Science and Epsilon Bio and participates in advisory boards/consultancies for Gilead Sciences, Roche, and Arbutus Biopharma. Publisher Copyright: © 2021 The American Society of Gene and Cell Therapy
PY - 2022/1
Y1 - 2022/1
N2 - The COVID-19 pandemic caused by SARS-CoV-2 has made the development of safe and effective vaccines a critical priority. To date, four vaccines have been approved by European and American authorities for preventing COVID-19, but the development of additional vaccine platforms with improved supply and logistics profiles remains a pressing need. Here we report the preclinical evaluation of a novel COVID-19 vaccine candidate based on the electroporation of engineered, synthetic cDNA encoding a viral antigen in the skeletal muscle. We constructed a set of prototype DNA vaccines expressing various forms of the SARS-CoV-2 spike (S) protein and assessed their immunogenicity in animal models. Among them, COVID-eVax—a DNA plasmid encoding a secreted monomeric form of SARS-CoV-2 S protein receptor-binding domain (RBD)—induced the most potent anti-SARS-CoV-2 neutralizing antibody responses (including against the current most common variants of concern) and a robust T cell response. Upon challenge with SARS-CoV-2, immunized K18-hACE2 transgenic mice showed reduced weight loss, improved pulmonary function, and lower viral replication in the lungs and brain. COVID-eVax conferred significant protection to ferrets upon SARS-CoV-2 challenge. In summary, this study identifies COVID-eVax as an ideal COVID-19 vaccine candidate suitable for clinical development. Accordingly, a combined phase I-II trial has recently started.
AB - The COVID-19 pandemic caused by SARS-CoV-2 has made the development of safe and effective vaccines a critical priority. To date, four vaccines have been approved by European and American authorities for preventing COVID-19, but the development of additional vaccine platforms with improved supply and logistics profiles remains a pressing need. Here we report the preclinical evaluation of a novel COVID-19 vaccine candidate based on the electroporation of engineered, synthetic cDNA encoding a viral antigen in the skeletal muscle. We constructed a set of prototype DNA vaccines expressing various forms of the SARS-CoV-2 spike (S) protein and assessed their immunogenicity in animal models. Among them, COVID-eVax—a DNA plasmid encoding a secreted monomeric form of SARS-CoV-2 S protein receptor-binding domain (RBD)—induced the most potent anti-SARS-CoV-2 neutralizing antibody responses (including against the current most common variants of concern) and a robust T cell response. Upon challenge with SARS-CoV-2, immunized K18-hACE2 transgenic mice showed reduced weight loss, improved pulmonary function, and lower viral replication in the lungs and brain. COVID-eVax conferred significant protection to ferrets upon SARS-CoV-2 challenge. In summary, this study identifies COVID-eVax as an ideal COVID-19 vaccine candidate suitable for clinical development. Accordingly, a combined phase I-II trial has recently started.
KW - animal models
KW - antiviral immunity
KW - DNA vaccine
KW - protection
KW - SARS-CoV-2
UR - http://www.scopus.com/inward/record.url?scp=85116168040&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85116168040&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2021.09.011
DO - 10.1016/j.ymthe.2021.09.011
M3 - Article
AN - SCOPUS:85116168040
SN - 1525-0016
VL - 30
SP - 311
EP - 316
JO - Molecular Therapy
JF - Molecular Therapy
IS - 1
ER -