mRNA delivery of genetically encoded mosaic-8 pan-sarbecovirus RBD vaccines

Area of Science:

• Virology
• Immunology
• Vaccine Development

Background:

• Global health is threatened by zoonotic SARS-like betacoronaviruses (sarbecoviruses) with pandemic potential.
• A pan-sarbecovirus vaccine is crucial for mitigating future outbreaks.
• Previous research developed mosaic-8 nanoparticle vaccines eliciting cross-reactive antibodies.

Purpose of the Study:

• To convert protein-based mosaic-8 nanoparticle vaccines into mRNA vaccine formats for easier manufacturing.
• To evaluate the immunogenicity and protective potential of novel mRNA-based sarbecovirus vaccines.
• To compare the immune responses elicited by mRNA vaccines versus protein-based vaccines.

Main Methods:

• Generation of membrane-bound RBD quartets for mRNA vaccine constructs (dual quartet RBD-mRNA and dual quartet RBD-EABR-mRNA).
• Immunization of subjects with mRNA immunogens and assessment of binding antibody breadth, neutralization potency, and T cell responses.
• Application of systems serology and Systems Serology-Polyclonal Epitope Mapping (SySPEM) to analyze IgG subclass responses and epitope targeting.

Main Results:

• mRNA vaccines elicited equivalent or improved binding breadths, neutralization potencies, and T cell responses compared to protein-based vaccines.
• mRNA vaccines successfully targeted conserved receptor-binding domain (RBD) epitopes across sarbecoviruses.
• Systems serology revealed balanced IgG subclass responses with increased Fcγ receptor-binding IgGs, suggesting enhanced Fc effector functions.

Conclusions:

• Successful conversion of mosaic-8 RBD nanoparticle vaccines to mRNA formats (mRNA and EABR-mRNA) was achieved.
• The developed mRNA vaccines offer advantages in manufacturing and demonstrate potential for enhanced protection against sarbecovirus outbreaks.
• Distinct IgG-subclass-specific epitope targeting signatures were identified between mRNA and protein-based vaccine modalities.