Hydrogel-based slow release of a receptor-binding domain subunit vaccine elicits neutralizing antibody responses against SARS-CoV-2 (preprint)

ABSTRACT

The development of an effective vaccine that can be rapidly manufactured and distributed worldwide is necessary to mitigate the devastating health and economic impacts of pandemics like COVID-19. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, which mediates host cell entry of the virus, is an appealing antigen for subunit vaccines because it is easy to manufacture and highly stable. Moreover, RBD is a target for neutralizing antibodies and robust cytotoxic T lymphocyte responses. Unfortunately, RBD is poorly immunogenic. While most subunit vaccines are commonly formulated with adjuvants to enhance their immunogenicity, most common adjuvant combinations have not been sufficient to improve RBD immunogenicity and none have afforded neutralizing responses in a single-dose RBD vaccine. Here we show that sustained delivery of an RBD subunit vaccine in an injectable hydrogel depot formulation increases total anti-RBD IgG titers compared to bolus administration of the same vaccines. Notably, a SARS-CoV-2 spike-pseudotyped lentivirus neutralization assay revealed neutralizing antibodies in all mice after a single hydrogel vaccine administration comprising clinically-approved adjuvants Alum and CpG. Together, these results suggest that extending the exposure to RBD subunit vaccines significantly enhances the immunogenicity of RBD and induces neutralizing humoral immunity following a single immunization.