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

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.