COVID-19 Vaccine Candidates Based on Modified Vaccinia Virus Ankara Expressing the SARS-CoV-2 Spike Protein Induce Robust T- and B-Cell Immune Responses and Full Efficacy in Mice

Abstract

Vaccines against SARS-CoV-2, the causative agent of the COVID-19 pandemic, are urgently needed. We developed two COVID-19 vaccines based on modified vaccinia virus Ankara (MVA) vectors expressing the entire SARS-CoV-2 spike (S) protein (MVA-CoV2-S); their immunogenicity was evaluated in mice using DNA/MVA or MVA/MVA prime/boost immunizations. Both vaccines induced robust, broad and polyfunctional S-specific CD4+ (mainly Th1) and CD8+ T-cell responses, with a T effector memory phenotype. DNA/MVA immunizations elicited higher T-cell responses. All vaccine regimens triggered high titers of IgG antibodies specific for the S, as well as for the receptor-binding domain; the predominance of the IgG2c isotype was indicative of Th1 immunity. Notably, serum samples from vaccinated mice neutralized SARS-CoV-2 in cell cultures, and those from MVA/MVA immunizations showed a higher neutralizing capacity. Remarkably, one or two doses of MVA-CoV2-S protect humanized K18-hACE2 mice from a lethal dose of SARS-CoV-2. In addition, two doses of MVA-CoV2-S confer full inhibition of virus replication in the lungs. These results demonstrate the robust immunogenicity and full efficacy of MVA-based COVID-19 vaccines in animal models and support its translation to the clinic. IMPORTANCE The continuous dissemination of the novel emerging SARS-CoV-2 virus, with more than 78 million infected cases worldwide and higher than 1,700,000 deaths as of December 23, 2020, highlights the urgent need for the development of novel vaccines against COVID-19. With this aim, we have developed novel vaccine candidates based on the poxvirus modified vaccinia virus Ankara (MVA) strain expressing the full-length SARS-CoV-2 spike (S) protein, and we have evaluated their immunogenicity in mice using DNA/MVA or MVA/MVA prime/boost immunization protocols. The results showed the induction of a potent S-specific T-cell response and high titers of neutralizing antibodies. Remarkably, humanized K18-hACE2 mice immunized with one or two doses of the MVA-based vaccine were 100% protected from SARS-CoV-2 lethality. Moreover, two doses of the vaccine prevented virus replication in lungs. Our findings prove the robust immunogenicity and efficacy of MVA-based COVID-19 vaccines in animal models and support its translation to the clinic.

One or two injections of MVA-vectored vaccine shields hACE2 transgenic mice from SARS-CoV-2 upper and lower respiratory tract infection

“…After submission of our manuscript for review, two related studies were posted online in advance of publication (19) and as a preprint (63). In both studies, rMVA vectors that expressed Limitations of Study.…”

“…Vaccines based on mRNA and adenovirus vectors have demonstrated promising results in clinical trials and have received emergency regulatory approval (11)(12)(13)(14). Other candidate CoV-2 vaccines, including ones based on vesicular stomatitis virus (15), an alphavirusderived replicon RNA (16), an inactivated recombinant Newcastle Disease virus (17), and modified VACV Ankara (MVA) (18,19) are at early stages of evaluation.…”

Immunogenicity and efficacy of the COVID-19 candidate vector vaccine MVA-SARS-2-S in preclinical vaccination

“…Our prime-boost vaccinations with MVA--SARS-2-S did not impair the balanced T helper cell populations monitored in BALB/c mice by spectral flow cytometry. Of note, two additional studies also demonstrated the induction of predominantly TH1-type immune responses in mice immunized with MVA vector vaccines encoding SARS-CoV-2 S antigens (44,45). The importance of vaccine-induced T cell responses is illustrated by studies not only monitoring the adaptive immunity to SARS-CoV-2 in patients, but also demonstrating that strong SARS-CoV-2-specific CD4 + or CD8 + T cell responses are associated with low disease severity in individuals with COVID-19 (5).…”

Why do poxviruses still matter?

“…Recent efforts have focused on using Modified Vaccina virus Ankara to develop vaccines against SARS-CoV-2. These have shown promising effects in mice and macaques [84][85][86][87]. With further research, it is expected that poxvirus vector-based vaccines will be licensed for humans, which requires substantially increasing the investments and efforts to understand the fundamental aspects of poxvirus replication, as well as collaboration among poxvirologists, immunologists, clinicians, and veterinarians.…”