Abstract

The threat of future coronavirus pandemics requires developing cost-effective vaccine technologies that provide broad and long-lasting protection against diverse circulating and emerging strains. Here we report a multivalent liposomal hydrogel depot vaccine technology comprising the receptor binding domain (RBD) of up to four relevant SARS and MERS coronavirus strains non-covalently displayed on the surface of the liposomes within the hydrogel structure. The multivalent presentation and sustained exposure of RBD antigens improved the potency, neutralizing activity, durability, and consistency of antibody responses across homologous and heterologous coronavirus strains in a naive murine model. When administrated in animals previously exposed to the wild-type SARS-CoV-2 antigens, liposomal hydrogels elicited durable antibody responses against the homologous SARS and MERS strains for over 6 months and elicited neutralizing activity against the immune-evasive SARS-CoV-2 variant Omicron BA.4/BA.5. Overall, the tunable antigen-decorated liposomal hydrogel platform we report here generates robust and durable humoral responses across diverse coronaviruses, supporting global efforts to effectively respond to future viral outbreaks. Progress and PotentialRapidly mutating infectious diseases such as influenza, HIV, and COVID-19 pose serious threats to human health. Yet, most vaccines still do not mount durable protection against mutagenic viruses and fail to induce broad responses to protect against emergent strains. Materials approaches to vaccine design, such as employing sustained delivery approaches or decorating nanoparticle constructs with multiple antigens, have shown promise in improving the breadth and potency of vaccines. Yet, these approaches typically require cumbersome chemistries and have not been explored in pre-exposed populations over clinically relevant time scales. Here, we report the development of an injectable liposomal hydrogel depot technology capable of prolonged presentation of multiple coronavirus antigens non-covalently coordinated on the surface of the liposomes forming the hydrogel structure. These hydrogels improve the potency, durability and breadth of vaccine response and are easy to fabricate, enabling the rapid design of next generation vaccines that confer protection against rapidly evolving pandemics.