MVA-based vaccine candidates expressing SARS-CoV-2 prefusion-stabilized spike proteins of the Wuhan, Beta or Omicron BA.1 variants protect transgenic K18-hACE2 mice against Omicron infection and elicit robust and broad specific humoral and cellular immune responses

Front Immunol. 2024 Aug 29:15:1420304. doi: 10.3389/fimmu.2024.1420304. eCollection 2024.

Abstract

Despite the decrease in mortality and morbidity due to SARS-CoV-2 infection, the incidence of infections due to Omicron subvariants of SARS-CoV-2 remains high. The mutations acquired by these subvariants, mainly concentrated in the receptor-binding domain (RBD), have caused a shift in infectivity and transmissibility, leading to a loss of effectiveness of the first authorized COVID-19 vaccines, among other reasons, by neutralizing antibody evasion. Hence, the generation of new vaccine candidates adapted to Omicron subvariants is of special interest in an effort to overcome this immune evasion. Here, an optimized COVID-19 vaccine candidate, termed MVA-S(3P_BA.1), was developed using a modified vaccinia virus Ankara (MVA) vector expressing a full-length prefusion-stabilized SARS-CoV-2 spike (S) protein from the Omicron BA.1 variant. The immunogenicity and efficacy induced by MVA-S(3P_BA.1) were evaluated in mice in a head-to-head comparison with the previously generated vaccine candidates MVA-S(3P) and MVA-S(3Pbeta), which express prefusion-stabilized S proteins from Wuhan strain and Beta variant, respectively, and with a bivalent vaccine candidate composed of a combination of MVA-S(3P) and MVA-S(3P_BA.1). The results showed that all four vaccine candidates elicited, after a single intramuscular dose, protection of transgenic K18-hACE2 mice challenged with SARS-CoV-2 Omicron BA.1, reducing viral loads, histopathological lesions, and levels of proinflammatory cytokines in the lungs. They also elicited anti-S IgG and neutralizing antibodies against various Omicron subvariants, with MVA-S(3P_BA.1) and the bivalent vaccine candidate inducing higher titers. Additionally, an intranasal immunization in C57BL/6 mice with all four vaccine candidates induced systemic and mucosal S-specific CD4+ and CD8+ T-cell and humoral immune responses, and the bivalent vaccine candidate induced broader immune responses, eliciting antibodies against the ancestral Wuhan strain and different Omicron subvariants. These results highlight the use of MVA as a potent and adaptable vaccine vector against new emerging SARS-CoV-2 variants, as well as the promising feature of combining multivalent MVA vaccine candidates.

Keywords: COVID-19; MVA-based vaccine; S protein; SARS-CoV-2; efficacy; immunogenicity; mice; variants of concern.

MeSH terms

  • Angiotensin-Converting Enzyme 2 / genetics
  • Angiotensin-Converting Enzyme 2 / immunology
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Animals
  • Antibodies, Neutralizing / blood
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral* / blood
  • Antibodies, Viral* / immunology
  • COVID-19 Vaccines* / immunology
  • COVID-19* / immunology
  • COVID-19* / prevention & control
  • Female
  • Humans
  • Immunity, Cellular*
  • Immunity, Humoral*
  • Immunogenicity, Vaccine
  • Mice
  • Mice, Transgenic*
  • SARS-CoV-2* / immunology
  • Spike Glycoprotein, Coronavirus* / genetics
  • Spike Glycoprotein, Coronavirus* / immunology
  • Vaccines, DNA / immunology
  • Vaccinia virus / genetics
  • Vaccinia virus / immunology

Substances

  • Spike Glycoprotein, Coronavirus
  • COVID-19 Vaccines
  • spike protein, SARS-CoV-2
  • Antibodies, Viral
  • Angiotensin-Converting Enzyme 2
  • Antibodies, Neutralizing
  • ACE2 protein, human
  • Vaccines, DNA

Supplementary concepts

  • SARS-CoV-2 variants

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was supported by Fondo COVID-19 grant COV20/00151 (Spanish Health Ministry, Instituto de Salud Carlos III (ISCIII)), Fondo Supera COVID-19 grant (Crue Universidades-Banco Santander), CSIC grant 202120E079, grant CNS2022-135511 funded by the Spanish Ministry of Science, Innovation and Universities (MCIU)/Spanish Research Agency (AEI)/10.13039/501100011033 and by the European Union NextGenerationEU/PRTR to promote the consolidation of research, and funds from Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC) co-financed with FEDER funds (to JG-A); CSIC grant 2020E84, la Caixa Banking Foundation grant CF01-00008, Ferrovial, and MAPFRE donations (to ME); and Spanish MCIU/AEI/10.13039/501100011033 grant PID2020-114481RB-I00 (to JG-A and ME). This research work was also funded by the European Commission-NextGenerationEU, through CSIC’s Global Health Platform (PTI Salud Global) (to JG-A and ME). JG-A also received grants from the European Commission HORIZON-HLTH-2023-DISEASE-03-18 (Project MARVAX: 101137183 and Project FLAVIVACCINE: 101137006). JG-A and ME also acknowledges financial support from the Spanish AEI/10.13039/501100011033, through the “Severo Ochoa” Programme for Centres of Excellence in R&D (SEV-2013-0347, SEV-2017-0712). JC acknowledges MCIU and CSIC support (project number 202020E079). RD received grants from ISCIII (FIS PI2100989), the European Commission Horizon 2020 Framework Programme (Project VIRUSCAN FETPROACT-2016: 731868 and Project EPIC-CROWN-2: 101046084), and Fundación Caixa-Health Research HR18-00469 (Project StopEbola). The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.