Vaccinia Virus Strain MVA Expressing a Prefusion-Stabilized SARS-CoV-2 Spike Glycoprotein Induces Robust Protection and Prevents Brain Infection in Mouse and Hamster Models

Abstract

The COVID-19 pandemic has underscored the importance of swift responses and the necessity of dependable technologies for vaccine development. Our team previously developed a fast cloning system for the modified vaccinia virus Ankara (MVA) vaccine platform. In this study, we reported on the construction and preclinical testing of a recombinant MVA vaccine obtained using this system. We obtained recombinant MVA expressing the unmodified full-length SARS-CoV-2 spike (S) protein containing the D614G amino-acid substitution (MVA-Sdg) and a version expressing a modified S protein containing amino-acid substitutions designed to stabilize the protein a in a pre-fusion conformation (MVA-Spf). S protein expressed by MVA-Sdg was found to be expressed and was correctly processed and transported to the cell surface, where it efficiently produced cell–cell fusion. Version Spf, however, was not proteolytically processed, and despite being transported to the plasma membrane, it failed to induce cell–cell fusion. We assessed both vaccine candidates in prime-boost regimens in the susceptible transgenic K18-human angiotensin-converting enzyme 2 (K18-hACE2) in mice and in golden Syrian hamsters. Robust immunity and protection from disease was induced with either vaccine in both animal models. Remarkably, the MVA-Spf vaccine candidate produced higher levels of antibodies, a stronger T cell response, and a higher degree of protection from challenge. In addition, the level of SARS-CoV-2 in the brain of MVA-Spf inoculated mice was decreased to undetectable levels. Those results add to our current experience and range of vaccine vectors and technologies for developing a safe and effective COVID-19 vaccine.

Protective MVA-ST Vaccination Robustly Activates T Cells and Antibodies in an Aged-Hamster Model for COVID-19

“…To this end, we used 66-week-old hamsters, which correlates to about 65 years in human age [ 28 ]. In agreement with data from previous studies evaluating the effects of MVA-based COVID-19 vaccines in different preclinical models using different vaccination schedules [ 18 , 19 , 20 , 29 ], we confirmed the activation of SARS-CoV-2-specific immune response and protection in the aged MVA-ST-vaccinated hamsters compared to the control aged hamsters, which had been vaccinated with an empty MVA vector. Our results demonstrated the robust activation of SARS-CoV-2-specific antibodies and T cells and significantly reduced viral loads in the upper and lower respiratory tract in the MVA-ST-vaccinated aged hamsters.…”

“…In this context, all MVA-based COVID-19 candidate vaccines used the SARS-CoV-2 spike protein in a prefusion-stabilized conformation (ST-protein) as a vaccine antigen. These different MVA-COVID-19 vaccines confirmed their protective efficacy in different preclinical models [ 18 , 19 , 20 , 21 ].…”

Rendezvous with Vaccinia Virus in the Post-smallpox Era: R&D Advances

“…Most focus on viral diseases of clinical relevance. A wide array of vaccine research centers around HIV-1 [ 109 , 116 , 121 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 ]. Plentiful studies target arboviruses that are on the rise: dengue virus [ 161 ], Zika virus [ 50 , 162 , 163 , 164 , 165 ], West Nile virus [ 166 ], yellow fever virus [ 167 ], tick-borne encephalitis virus [ 168 , 169 ], chikungunya virus [ 163 , 170 ], and Crimean-Congo hemorrhagic fever virus [ 171 ].…”

“…Plentiful studies target arboviruses that are on the rise: dengue virus [ 161 ], Zika virus [ 50 , 162 , 163 , 164 , 165 ], West Nile virus [ 166 ], yellow fever virus [ 167 ], tick-borne encephalitis virus [ 168 , 169 ], chikungunya virus [ 163 , 170 ], and Crimean-Congo hemorrhagic fever virus [ 171 ]. Multiple diseases of high prevalence or fatality rate, especially those with epidemic or pandemic potential garner particular attention, including the following examples: ebolavirus [ 172 , 173 , 174 , 175 ], Nipah virus [ 176 ], influenza virus [ 177 , 178 , 179 , 180 ], respiratory syncytial virus [ 181 , 182 ], Middle East respiratory syndrome coronavirus [ 183 , 184 ], and needless to say, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [ 158 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 ]. Several VACV-vectored vaccines have entered clinical trials: HIV-1 [ 196 ], tuberculosis [ 197 , 198 ], respiratory syncytial virus [ 199 ], influenza A virus [ 200 ], and SARS-CoV-2 [ 201 ].…”

Immunogenicity and Efficacy of TNX-1800, A Live Virus Recombinant Poxvirus Vaccine Candidate, against SARS-CoV-2 Challenge in Nonhuman Primates

“…The vaccinia virus-based smallpox vaccine elicits robust, durable, and lifelong immunity following single-dose vaccination [17]. In addition, the recombinant modified vaccinia virus Ankara (MVA) vaccine expressing a prefusion-stabilized SARS-CoV-2 spike glycoprotein induces robust immunity and protection in mouse, Syrian hamster, and non-human primate models [18,19].…”