A cGAMP-containing hydrogel for prolonged SARS-CoV-2 RBD subunit vaccine exposure induces a broad and potent humoral response

The SARS-CoV-2 virus spike protein, specifically its receptor binding domain (RBD), has emerged as a promising target for generation of neutralizing antibodies. Although the RBD peptide subunit is easily manufactured and highly stable, RBD-based subunit vaccines have been hampered by its poor inherent immunogenicity. We hypothesize that this limitation can be overcome by sustained co-administration alongside a potent and optimized adjuvant. The innate immune second messenger, cGAMP, holds promise as it activates the potent anti-viral STING pathway, but has exhibited poor performance as a therapeutic due to its nonspecific pharmacodynamic profiles when administered systemically and its poor pharmacokinetics arising from rapid excretion and degradation by its hydrolase ENPP1. To overcome these limitations, we sought to mimic the natural scenario of viral infections by creating an artificial immunological niche that enables slow release of cGAMP and the RBD antigen. Specifically, we co-encapsulated cGAMP and RBD in an injectable polymer-nanoparticle (PNP) hydrogel system. This cGAMP-adjuvanted hydrogel vaccine elicited more potent, durable, and broad antibody responses and improved neutralization than both dose-matched bolus controls and a hydrogel-based vaccine lacking cGAMP. The cGAMP-adjuvanted hydrogel platform developed is suitable for delivery of other antigens and may provide enhanced immunity against a broad range of pathogens.