Focused on improving long-term and cross-variant protective memory for mRNA vaccines, Aunins and Phan et al. first found that endogenous IL-12 was dispensable for generating CD8+ T cell responses to lipid nanoparticle (LNP)-encapsulated mRNA vaccines. However, as an adjuvant, co-administration of il12mRNA-LNPs with OVA mRNA-LNPs resulted in significantly expanded circulating effector and memory CD8+ T cells, including tissue-resident CD8+ T cells in crucial barrier sites. LNP-IL-12 enhanced CD8+ T cell responses to SARS-CoV-2 and influenza virus antigens, and improved protection against Listeria monocytogenes-OVA and B16-OVA melanoma.
Contributed by Katherine Turner
ABSTRACT: Optimizing vaccine design to induce CD8 T cell responses has been challenging, but lipid nanoparticle (LNP)-encapsulated mRNA vaccines effectively generate CD8 T cell memory. Interleukin-12 (IL-12) supports CD8 T cell expansion and acquisition of effector function, but the role of IL-12 in the generation of CD8 T responses to mRNA vaccination is unclear. Here, we determine that endogenous IL-12 is not required for CD8 T cell responses to mRNA-LNP vaccination. We assessed the adjuvant activity of an mRNA-LNP encapsulating a codon-optimized mRNA that encodes both subunits of IL-12 (LNP-IL-12). Coadministration of LNP-IL-12 with ovalbumin (OVA) mRNA-LNPs enhanced CD8 T cell expansion and effector function and expanded circulating, effector, and tissue-resident memory CD8 T cells. LNP-IL-12 increased CD8 T cell responses against SARS-CoV-2 and influenza virus antigens and improved protection against Listeria monocytogenes-OVA and B16F0-OVA melanoma. Thus, modification of mRNA-LNP formulations to include a cytokine mRNA provides a strategy to enhance CD8 T cell-mediated protection.
Author Info: (1) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (2) Department of Pathobiology, School of Veterinary Medicine, Uni
Author Info: (1) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (2) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (3) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Department of Medicine, Infectious Disease Division, University of Pennsylvania, Philadelphia, PA, USA. (4) Penn Institute for RNA Innovation, University of Pennsylvania, Philadelphia, PA, USA. (5) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (6) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (7) Acuitas Therapeutics, Vancouver, BC V6T 1Z3, Canada. (8) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (9) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (10) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (11) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (12) Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (13) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (14) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (15) Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (16) Department of Immunology, University of Colorado Anschutz School of Medicine, Denver, CO, USA. (17) Department of Medicine, Infectious Disease Division, University of Pennsylvania, Philadelphia, PA, USA. Penn Institute for RNA Innovation, University of Pennsylvania, Philadelphia, PA, USA. (18) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
