Development of a multi-antigenic SARS-CoV-2 vaccine candidate using a synthetic poxvirus platform

Flavia Chiuppesi,Tae Hyuk Kang,Roman Levytskyy,Marcela D’Alincourt Salazar,Thomas F Rogers,Vu H Nguyen,Jenny Nguyen,Mindy Kha,Teodora Kaltcheva,Don J Diamond,Yuriy Shostak,Angelina Iniguez,Joy Martinez,Nancy D Ebelt,Qiao Zhou,Heidi Contreras,Xiwei Wu,Edwin R Manuel,Yoonsuh Park,Felix Wussow

doi:10.1038/s41467-020-19819-1

Abstract

Modified Vaccinia Ankara (MVA) is a highly attenuated poxvirus vector that is widely used to develop vaccines for infectious diseases and cancer. We demonstrate the construction of a vaccine platform based on a unique three-plasmid system to efficiently generate recombinant MVA vectors from chemically synthesized DNA. In response to the ongoing global pandemic caused by SARS coronavirus-2 (SARS-CoV-2), we use this vaccine platform to rapidly produce fully synthetic MVA (sMVA) vectors co-expressing SARS-CoV-2 spike and nucleocapsid antigens, two immunodominant antigens implicated in protective immunity. We show that mice immunized with these sMVA vectors develop robust SARS-CoV-2 antigen-specific humoral and cellular immune responses, including potent neutralizing antibodies. These results demonstrate the potential of a vaccine platform based on synthetic DNA to efficiently generate recombinant MVA vectors and to rapidly develop a multi-antigenic poxvirus-based SARS-CoV-2 vaccine candidate.

Highlights

Modified Vaccinia Ankara (MVA) is a highly attenuated poxvirus vector that is widely used to develop vaccines for infectious diseases and cancer
To develop the three-plasmid system of the synthetic MVA (sMVA) vaccine platform, we designed three unique synthetic sub-genomic MVA fragments based on the MVA genome sequence published by Antoine et al.[4], which is ~178 kbp in length and contains ~9.6 kbp inverted terminal repeats (ITRs) (Fig. 1a)
A duplex copy of the 165-nucleotide-long MVA terminal hairpin loop (HL) flanked by concatemeric resolution (CR) sequences was added to both ends of each of the three sMVA fragments (Fig. 1c)

Summary

Introduction

Modified Vaccinia Ankara (MVA) is a highly attenuated poxvirus vector that is widely used to develop vaccines for infectious diseases and cancer. In response to the ongoing global pandemic caused by SARS coronavirus-2 (SARS-CoV-2), we use this vaccine platform to rapidly produce fully synthetic MVA (sMVA) vectors co-expressing SARS-CoV-2 spike and nucleocapsid antigens, two immunodominant antigens implicated in protective immunity. We show that mice immunized with these sMVA vectors develop robust SARS-CoV-2 antigen-specific humoral and cellular immune responses, including potent neutralizing antibodies These results demonstrate the potential of a vaccine platform based on synthetic DNA to efficiently generate recombinant MVA vectors and to rapidly develop a multi-antigenic poxvirus-based SARS-CoV-2 vaccine candidate. These results emphasize the value of a vaccine platform based on synthetic DNA to efficiently produce recombinant poxvirus vectors and warrant further pre-clinical and clinical testing of a multi-antigenic sMVA vaccine candidate to control the ongoing SARS-CoV-2 pandemic and its devastating consequences

Methods

Results

Conclusion