mRNA-encoded, constitutively active STINGV155M is a potent genetic adjuvant of antigen-specific CD8+ T cell response

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 nuclear factor kB (NF-kB) and IFN-stimulated response element (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.

Lipid nanoparticles for mRNA delivery

“…To further improve vaccine efficacy, APC uptake and T cell activation can be optimized; for example, mannose-modified lipid nanoparticle–mRNA formulations are preferentially taken up by dendritic cells 150 , 201 , 202 . The efficacy of cancer vaccines can also be boosted by co-delivery of antigen mRNA with adjuvants 32 , 63 , 94 , 203 – 206 , co-stimulatory molecules 148 , 150 , 207 , 208 and immune checkpoint inhibitors 200 – 202 , 209 – 211 .…”

Understanding Structure–Function Relationships of Nanoadjuvants for Enhanced Cancer Vaccine Efficacy

“…reported a structurally active mutation (V155M) of the interferon (IFN) gene stimulator (STING) as a genetic adjuvant for a lipid nanoparticle coated mRNA vaccine. [ 52 ] The result showed that it was effective in promoting CD8 + T cell responses (Figure 2a).…”

“…Reproduced with permission. [ 52 ] Copyright 2021, Cell Press. b) Simplified diagram of the response to CpG ODNs.…”

Overcoming STING Agonists Barriers: Peptide, Protein, and Biomembrane‐based Biocompatible Delivery Strategies

“…[54] Omomyc effectively enhanced the cell penetration of CP-STING ~TM + cGAMP, resulting in higher level of CXCL10 secretion in dendritic cells and STING-impaired tumor cells compared with STING ~TM + cGAMP. Apart from these studies, another work needs to be mentioned is that a mRNA-encoded STING V155M mutant was developed as a genetic adjuvant by Huang et al [55] STING V155M is constitutively active with no need of agonist stimulation, [45] Reproduced with permission from Ref. 5.…”