Lipid-nanoparticle-encapsulated mRNA vaccines induce protective memory CD8 T cells against a lethal viral infection

Mol Ther. 2021 Sep 1;29(9):2769-2781. doi: 10.1016/j.ymthe.2021.05.011. Epub 2021 May 14.

Abstract

It is well established that memory CD8 T cells protect susceptible strains of mice from mousepox, a lethal viral disease caused by ectromelia virus (ECTV), the murine counterpart to human variola virus. While mRNA vaccines induce protective antibody (Ab) responses, it is unknown whether they also induce protective memory CD8 T cells. We now show that immunization with different doses of unmodified or N(1)-methylpseudouridine-modified mRNA (modified mRNA) in lipid nanoparticles (LNP) encoding the ECTV gene EVM158 induced similarly strong CD8 T cell responses to the epitope TSYKFESV, albeit unmodified mRNA-LNP had adverse effects at the inoculation site. A single immunization with 10 μg modified mRNA-LNP protected most susceptible mice from mousepox, and booster vaccination increased the memory CD8 T cell pool, providing full protection. Moreover, modified mRNA-LNP encoding TSYKFESV appended to green fluorescent protein (GFP) protected against wild-type ECTV infection while lymphocytic choriomeningitis virus glycoprotein (GP) modified mRNA-LNP protected against ECTV expressing GP epitopes. Thus, modified mRNA-LNP can be used to create protective CD8 T cell-based vaccines against viral infections.

Keywords: CD8 T cells; lipid nanoparticle; mRNA vaccine; modified mRNA; poxvirus; virus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / metabolism*
  • Drug Compounding
  • Ectromelia virus / immunology*
  • Ectromelia, Infectious / immunology
  • Ectromelia, Infectious / prevention & control*
  • Immunization, Secondary
  • Immunologic Memory
  • Liposomes
  • Male
  • Mice
  • Nanoparticles
  • Peptides / chemistry
  • Peptides / genetics
  • Peptides / immunology
  • Pseudouridine / analogs & derivatives
  • Pseudouridine / chemistry
  • Viral Proteins / chemistry
  • Viral Proteins / genetics*
  • Viral Proteins / immunology
  • Viral Vaccines / administration & dosage
  • Viral Vaccines / chemistry
  • Viral Vaccines / pharmacology
  • mRNA Vaccines / administration & dosage*
  • mRNA Vaccines / chemistry
  • mRNA Vaccines / pharmacology

Substances

  • Lipid Nanoparticles
  • Liposomes
  • Peptides
  • Viral Proteins
  • Viral Vaccines
  • mRNA Vaccines
  • 1-methylpseudouridine
  • Pseudouridine