A Single Dose of an MVA Vaccine Expressing a Prefusion-Stabilized SARS-CoV-2 Spike Protein Neutralizes Variants of Concern and Protects Mice From a Lethal SARS-CoV-2 Infection

Abstract

We generated an optimized COVID-19 vaccine candidate based on the modified vaccinia virus Ankara (MVA) vector expressing a full-length prefusion-stabilized SARS-CoV-2 spike (S) protein, termed MVA-CoV2-S(3P). The S(3P) protein was expressed at higher levels (2-fold) than the non-stabilized S in cells infected with the corresponding recombinant MVA viruses. One single dose of MVA-CoV2-S(3P) induced higher IgG and neutralizing antibody titers against parental SARS-CoV-2 and variants of concern than MVA-CoV2-S in wild-type C57BL/6 and in transgenic K18-hACE2 mice. In immunized C57BL/6 mice, two doses of MVA-CoV2-S or MVA-CoV2-S(3P) induced similar levels of SARS-CoV-2-specific B- and T-cell immune responses. Remarkably, a single administration of MVA-CoV2-S(3P) protected all K18-hACE2 mice from morbidity and mortality caused by SARS-CoV-2 infection, reducing SARS-CoV-2 viral loads, histopathological lesions, and levels of pro-inflammatory cytokines in the lungs. These results demonstrated that expression of a novel full-length prefusion-stabilized SARS-CoV-2 S protein by the MVA poxvirus vector enhanced immunogenicity and efficacy against SARS-CoV-2 in animal models, further supporting MVA-CoV2-S(3P) as an optimized vaccine candidate for clinical trials.

Poxvirus MVA Expressing SARS-CoV-2 S Protein Induces Robust Immunity and Protects Rhesus Macaques From SARS-CoV-2

“…Both the full-length non-stabilized S protein and a stabilized prefusion form of the S protein have been applied in current vaccines against COVID-19. There is currently no indication that either one of these strategies might result in lower vaccine efficacy in humans against either the Wuhan strain or the alpha or beta VOC, although in mice we have observed higher neutralization capacity against VOC of serum from animals vaccinated with a prefusion-stabilized S over non-stabilized S protein ( 19 ). Nonetheless, such differences could arise for other newly emerging VOC.…”

“…In this investigation, we evaluated the safety, immunogenicity, and efficacy in rhesus macaques of a COVID-19 vaccine candidate based on the poxvirus MVA vector expressing a human codon-optimized full-length SARS-CoV-2 S protein (MVA-S), which was previously reported to induce potent B- and T-cell immune responses and full efficacy in mice ( 16 , 17 , 19 ). Due to the close relatedness of NHPs to humans, inoculation of rhesus macaques with SARS-CoV-2 has been used for current vaccines as a preclinical animal model system, as it leads to a respiratory disease, with virus replication in lungs and in the upper and lower respiratory tracts ( 52 ).…”

“…In the present study, we evaluated the safety, immunogenicity, and efficacy in rhesus macaques of a novel MVA-based vaccine candidate expressing a human codon-optimized full-length SARS-CoV-2 S protein (MVA-S), which was previously reported to induce potent B- and T-cell responses and full efficacy in mice ( 16 , 17 , 19 ). The MVA-S vaccine was well tolerated, and strong binding IgG antibody responses, neutralizing antibodies against parental SARS-CoV-2 and VOC and S-specific IFNγ-producing cells, were induced.…”

MVA-CoV2-S Vaccine Candidate Neutralizes Distinct Variants of Concern and Protects Against SARS-CoV-2 Infection in Hamsters

“…Among the different vaccine approaches, one of the most promising is the use of viral vectors, such as poxviruses, which have shown potent immunogenicity and efficacy in preclinical and clinical trials against several infectious diseases ( 8 , 9 ). In fact, we have previously reported the high immunogenicity and efficacy profile in vaccinated mice of a COVID-19 vaccine candidate based on the highly attenuated modified vaccinia virus Ankara (MVA) vector expressing the full-length SARS-CoV-2 S protein, termed MVA-S ( 10 – 12 ). MVA-S induced robust SARS-CoV-2-specific T-cell and humoral immune responses in C57BL/6 mice, and one or two doses of MVA-S fully protected susceptible K18-hACE2 transgenic mice against lethal SARS-CoV-2 challenge ( 10 – 12 ).…”

“…In fact, we have previously reported the high immunogenicity and efficacy profile in vaccinated mice of a COVID-19 vaccine candidate based on the highly attenuated modified vaccinia virus Ankara (MVA) vector expressing the full-length SARS-CoV-2 S protein, termed MVA-S ( 10 – 12 ). MVA-S induced robust SARS-CoV-2-specific T-cell and humoral immune responses in C57BL/6 mice, and one or two doses of MVA-S fully protected susceptible K18-hACE2 transgenic mice against lethal SARS-CoV-2 challenge ( 10 – 12 ).…”