A lipid nanoparticle formulation that elicits a strong innate immune response for improved vaccine protection

Lipid nanoparticle (LNP)-formulated mRNA vaccines have revolutionized modern vaccinology through their ability to deliver mRNA vaccines with remarkable manufacturing flexibility. However, the modified (pseudouridylated) mRNA used in this platform is optimized for protein production and, consequently, the mRNA itself does not activate innate immune sensors strongly. This diminishes the protective immunity imparted by the vaccine.

LNPs are modular in that lipids may be functionalized to impart different capabilities upon them. Here, the inventors enhance the immunogenicity of the COVID19 LNP-mRNA vaccine by incorporating adjuvant-derived lipidoid into the encapsulating LNP. Delivery of immunostimulatory molecules at the site of antigen production causes a strong innate immune response and greater protective immunity compared to the conventional COVID19 LNP-mRNA vaccine.

The pseudouridylation of mRNA vaccines allows for optimized antigen production, but a muted innate immune response. However, a robust innate immune response is critical to generate protective immunity. Here, the functionalization of LNPs with adjuvant-derived lipidoid stimulates the innate immune response at the site of antigen production. This is accomplished via the ring opening reaction between amine-containing TLR7/8 agonist 1 and C12 epoxide. Adjuvanted LNPs display greater mRNA delivery efficiency compared to conventional LNPs and result in greater protective immunity in a pre-clinical mouse model via several correlates of immunity including dendritic cell activation, T cell responses, and humoral responses.

• Enhanced mRNA delivery and innate immunogenicity
• Adjuvant-derived lipidoid delivered precisely at the site of antigen production
• Easily implemented into the current manufacturing pipeline
• Improved protective immunity without alteration to the antigen (here, the Spike protein)