Enhancing COVID-19 Vaccine Efficacy: Dual Adjuvant Strategies with TLR7/8 Agonists and Glycolipids

J Med Chem. 2024 Dec 26;67(24):21916-21933. doi: 10.1021/acs.jmedchem.4c01801. Epub 2024 Dec 9.

Abstract

The controlled release of immunostimulatory agents represents a promising strategy to enhance vaccine efficacy while minimizing side effects. This study aimed to improve the efficacy of the RBD-Fc-based COVID-19 vaccine through combining of an iNKT cell agonist and a TLR7/8 agonist using covalent conjugation and temporal delivery. We hypothesized that these combinations would yield a more balanced Th1/Th2 immune response. For covalent conjugation, we employed an uncleavable linker and a self-immolative disulfide linker to conjugate α-galactosylceramide (αGC) to imidazoquinoline (IMDQ). The αGC-SS-IMDQ-Ac conjugate, designed with a prodrug strategy for controlled TLR7/8 agonist release, elicited a higher IFN-γ/IL-4 T cell response ratio than individual adjuvants or their admixture. In the temporal delivery approach, administering IMDQ followed by αGC after 2 h resulted in the highest IgG2a/IgG1 ratio, significantly surpassing other groups. A 6 h delay between glycolipid and IMDQ injections yielded balanced IgG responses, enhancing IgG, IgG1, and IgG2a levels synergistically.

MeSH terms

  • Adjuvants, Immunologic* / chemistry
  • Adjuvants, Immunologic* / pharmacology
  • Animals
  • COVID-19 / immunology
  • COVID-19 / prevention & control
  • COVID-19 / virology
  • COVID-19 Vaccines* / immunology
  • Female
  • Galactosylceramides* / chemistry
  • Galactosylceramides* / pharmacology
  • Glycolipids / chemistry
  • Glycolipids / pharmacology
  • Humans
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • Immunoglobulin G / immunology
  • Mice
  • Natural Killer T-Cells / drug effects
  • Natural Killer T-Cells / immunology
  • Quinolines / chemistry
  • Quinolines / pharmacology
  • SARS-CoV-2 / drug effects
  • SARS-CoV-2 / immunology
  • Toll-Like Receptor 7* / agonists
  • Toll-Like Receptor 8* / agonists

Substances

  • Toll-Like Receptor 8
  • Toll-Like Receptor 7
  • COVID-19 Vaccines
  • Adjuvants, Immunologic
  • Galactosylceramides
  • alpha-galactosylceramide
  • Glycolipids
  • Quinolines
  • Imidazoles
  • Immunoglobulin G