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.
Author Info: (1) Moderna, Inc., 200 Technology Square, Cambridge, MA 02139. (2) Moderna, Inc., 200 Technology Square, Cambridge, MA 02139. (3) Moderna, Inc., 200 Technology Square, Cambridge, M
Author Info: (1) Moderna, Inc., 200 Technology Square, Cambridge, MA 02139. (2) Moderna, Inc., 200 Technology Square, Cambridge, MA 02139. (3) Moderna, Inc., 200 Technology Square, Cambridge, MA 02139. (4) Moderna, Inc., 200 Technology Square, Cambridge, MA 02139. (5) Moderna, Inc., 200 Technology Square, Cambridge, MA 02139. (6) Moderna, Inc., 200 Technology Square, Cambridge, MA 02139. (7) Moderna, Inc., 200 Technology Square, Cambridge, MA 02139. (8) Moderna, Inc., 200 Technology Square, Cambridge, MA 02139. (9) Moderna, Inc., 200 Technology Square, Cambridge, MA 02139. Electronic address: Eric.Huang@modernatx.com.
