Tse et al. used mouse models to test the adjuvanticity of mRNA encoding immune-activating genes. Responses to mRNA tumor vaccines (expressing either E7 oncoprotein or MC38 tumor antigen) were measured alone and as coformulations with mRNA encoding a variety of constitutively active interferon pathway genes. Coformulation enhanced vaccine efficacy, as measured by CD8+ T cell response, tumor inhibition, and survival. The most efficacious vaccine contained mRNA encoding STING with the V155M mutation; further benefit was observed with ICB. Substitution of a chemical agonist of STING for STINGV155M mRNA also enhanced efficacy in the TC-1 lung metastasis model.
Contributed by Margot O’Toole
ABSTRACT: mRNA vaccines induce potent immune responses in preclinical models and clinical studies. Adjuvants are used to stimulate specific components of the immune system to increase immunogenicity of vaccines. We utilized a constitutively active mutation (V155M) of the stimulator of interferon (IFN) genes (STING), which had been described in a patient with STING-associated vasculopathy with onset in infancy (SAVI), to act as a genetic adjuvant for use with our lipid nanoparticle (LNP)-encapsulated mRNA vaccines. mRNA-encoded constitutively active STING(V155M) was most effective at maximizing CD8(+) T-cell responses at an antigen:adjuvant mass ratio of 5:1. STING(V155M) appears to enhance development of antigen-specific T cells by activating type I IFN responses via the NF_B and IFN-stimulated response elements (ISRE) pathways. mRNA-encoded STING(V155M) increased the efficacy of mRNA vaccines encoding the E6 and E7 oncoproteins of human papillomavirus (HPV), leading to reduced HPV+ TC-1 tumor growth and prolonged survival in vaccinated mice. This proof-of-concept study demonstrated the utility of an mRNA-encoded genetic adjuvant.
