MVA-based SARS-CoV-2 vaccine candidates encoding different spike protein conformations induce distinct early transcriptional responses which may impact subsequent adaptive immunity

Front Immunol. 2024 Dec 19:15:1500615. doi: 10.3389/fimmu.2024.1500615. eCollection 2024.

Abstract

Introduction: Vaccine platforms such as viral vectors and mRNA can accelerate vaccine development in response to newly emerging pathogens, as demonstrated during the COVID-19 pandemic. However, the differential effects of platform and antigen insert on vaccine immunogenicity remain incompletely understood. Innate immune responses induced by viral vector vaccines are suggested to have an adjuvant effect for subsequent adaptive immunity. Integrating data on both innate and adaptive immunity, systems vaccinology approaches can improve the understanding of vaccine-induced immune mechanisms.

Methods: Two vaccine candidates against SARS-CoV-2, both based on the viral vector Modified Vaccinia virus Ankara (MVA) and encoding the native (MVA-SARS-2-S) or prefusion-stabilized spike protein (MVA-SARS-2-ST), were evaluated in phase 1 clinical trials (ClinicalTrials.gov: NCT04569383, NCT04895449). Longitudinal dynamics of innate and early adaptive immune responses induced by vaccination in SARS-CoV-2-naïve individuals were analyzed based on transcriptome and flow cytometry data, in comparison to the licensed ChAd and mRNA vaccines.

Results: Compared to MVA-SARS-2-S, MVA-SARS-2-ST (encoding the prefusion-stabilized spike protein) induced a stronger transcriptional activation early after vaccination, as well as higher virus neutralizing antibodies. Positive correlations were observed between innate and adaptive immune responses induced by a second MVA-SARS-2-ST vaccination. MVA-, ChAd- and mRNA-based vaccines induced distinct immune signatures, with the overall strongest transcriptional activation as well as monocyte and circulating T follicular helper (cTFH) cell responses induced by ChAd.

Discussion: Our findings suggest a potential impact of the spike protein conformation not only on adaptive but also on innate immune responses. As indicated by positive correlations between several immune parameters induced by MVA-SARS-2-ST, the distinct transcriptional activation early after vaccination may be linked to the induction of classical monocytes and activation of cTFH1 cells, which may in turn result in the superior adaptive immunogenicity of MVA-SARS-2-ST, compared to MVA-SARS-2-S. Overall, our data demonstrate that both the vaccine platform and antigen insert can affect innate immune responses and subsequent vaccine immunogenicity in humans.

Keywords: COVID-19; SARS-CoV-2; T follicular helper cells; innate immunity; modified vaccinia virus Ankara; spike protein; systems vaccinology; transcriptome.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adaptive Immunity* / immunology
  • Adult
  • 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, Innate
  • Immunogenicity, Vaccine
  • Male
  • Middle Aged
  • SARS-CoV-2* / immunology
  • Spike Glycoprotein, Coronavirus* / genetics
  • Spike Glycoprotein, Coronavirus* / immunology
  • Vaccination
  • Vaccines, DNA / immunology
  • Vaccinia virus / genetics
  • Vaccinia virus / immunology
  • Young Adult

Substances

  • Spike Glycoprotein, Coronavirus
  • COVID-19 Vaccines
  • spike protein, SARS-CoV-2
  • Antibodies, Viral
  • Vaccines, DNA
  • Antibodies, Neutralizing

Associated data

  • ClinicalTrials.gov/NCT04569383
  • ClinicalTrials.gov/NCT04895449

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. MA reports grants (TTU 01.924, TTU 01.709, TTU 01.702, TTU 01.921) from the German Center for Infection Research (Deutsches Zentrum für Infektionsforschung, DZIF) and the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) – SFB 1648/1 2024 – 512741711. LW was supported by the Joachim Herz Foundation. IG was supported by the iDfellows program (493624519) funded by the DFG. M-LD was supported by an MD stipend from the DZIF Academy (TI07.003_Dieck). SM reports grants (Clinical Leave Stipend, TI 07.001_Mellinghoff) from the DZIF Academy. This work was supported by the DFG Research Infrastructure NGS_CC (project 407495230) as part of the Next Generation Sequencing Competence Network (project 423957469). NGS analyses were carried out at the Competence Center for Genomic Analysis (Kiel). We acknowledge financial support from the Open Access Publication Fund of the University Medical Center Hamburg-Eppendorf.