While Staphylococcus aureus (SA) commonly asymptomatically colonizes the skin and nose of healthy humans, severe disease can result from infection of the blood, bone, skin, and lungs, as well as sites of catheters and prosthetic devices. With currently approved therapy, about one-third of patients diagnosed with SA bacteremia succumb, accounting for more annual deaths than HIV, tuberculosis, and viral hepatitis combined. This R01 will develop an injectable vaccine depot comprising: (a) previously published cationic polymers to condense and charge neutralize anionic self-replicating mRNA (SR-mRNA) vaccines into nanometer-sized particles (i.e., “polyplexes”) that are then incorporated within (b) our recently reported injectable biodegradable gel of N-succinyl-chitosan (S-CS) and oxidized alginate (O-Alg). Ultimately, the temporary CS-Alg depots completely biodegrade into non-toxic by-products that are eliminated. This project will generate a self-immunizing biomaterials technology that is applied ONCE that is superior in immunization versus repeated systemic bolus injections.

This proposal will develop a Staphylococcus aureus (SA) vaccine delivery system comprising: (a) an injectable biodegradable (i.e., temporary) porous hydrogel “depot” that releases nanoparticles containing self-replicating mRNA (SR-mRNA) vaccine vectors expressing multi-valent SA adhesin genes. Novel cationic polymers condense and charge neutralize anionic SR-mRNA vaccines into nanoparticles (known as “polyplexes”) that are incorporated into the liquid hydrogel prior to injection and subsequent gelation.