A cGAMP-Containing Hydrogel for Prolonged SARS-CoV-2 Receptor-Binding Domain Subunit Vaccine Exposure Induces a Broad and Potent Humoral Response

Abstract

The receptor-binding domain (RBD) of the SARS-CoV-2 virus spike protein has emerged as a promising target for the generation of neutralizing antibodies. Although the RBD subunit is more stable than its encoding mRNA, RBD is poorly immunogenic. It is hypothesized that this limitation can be overcome by sustained coadministration with a more potent and optimized adjuvant than standard adjuvants. One such candidate adjuvant, cGAMP, exhibits promising potency via activation of the antiviral STING pathway. Unfortunately, delivery of cGAMP as a therapeutic exhibits poor performance due to poor pharmacokinetics and pharmacodynamics from rapid excretion and degradation. To overcome these limitations, it is sought to create an artificial immunological niche enabling the slow release of cGAMP and RBD to mimic natural infections in which immune-activating molecules are colocalized with antigen. Specifically, through coencapsulation of cGAMP and RBD in an injectable polymer-nanoparticle (PNP) hydrogel, the cGAMP-adjuvanted hydrogel vaccine elicits more potent, durable, and broad antibody responses with improved neutralization as compared to dose-matched bolus controls and hydrogel-based vaccines lacking cGAMP. The cGAMP-adjuvanted hydrogel platform can be further explored for the delivery of other antigens to enhance immunity against a broad range of pathogens.