Aluminum hydroxide and immunostimulatory glycolipid adjuvant combination for enhanced COVID-19 subunit vaccine immunogenicity

Abstract

Protein-based subunit vaccines like RBD-Fc are promising tools to fight COVID-19. RBD-Fc fuses the receptor-binding domain (RBD) of the SARS-CoV-2 virus spike protein with the Fc region of human IgG1, making it more immunogenic than RBD alone. Earlier work showed that combining RBD-Fc with iNKT cell agonists as adjuvants improved neutralizing antibodies but did not sufficiently enhance T cell responses, a limitation RBD-Fc vaccines share with common adjuvants. Here we demonstrate that aluminum hydroxide combined with α-C-GC, a C-glycoside iNKT cell agonist, significantly improved the RBD-Fc vaccine’s induction of RBD-specific T-cell responses. Additionally, aluminum hydroxide with α-GC-CPOEt, a phosphonate diester derivative, synergistically elicited more robust neutralizing antibodies. Remarkably, modifying αGC with phosphate (OPO3H2) or phosphonate (CPO3H2) to potentially enhance aluminum hydroxide interaction did not improve efficacy over unmodified αGC with aluminum hydroxide. These findings underscore the straightforward yet potent potential of this approach in advancing COVID-19 vaccine development and provide insights for iNKT cell-based immunotherapy.