The roles of CD4+ T cell help, sex, and dose in the induction of protective CD8+ T cells against a lethal poxvirus by mRNA-LNP vaccines

Abstract

The role of CD4+ T-cells in the induction of protective CD8+ T-cells by mRNA Lipid Nanoparticle (LNP) vaccines is unknown. We used B6 or Tlr9-/- mice depleted or not of CD4+ T-cells and LNP vaccines loaded with mRNAs encoding the ectromelia virus (ECTV) MHC Class I H-2 Kb-restricted immunodominant CD8+ T-cell epitope TSYKFESV (TSYKFESV mRNA-LNP) or the ECTV EVM158 protein, which contains TSYKFESV (EVM-158 mRNA-LNP). Following prime and boost with 10 μg of either vaccine, Kb-TSYKFESV-specific CD8+ T-cells fully protected male and female mice from ECTV at 29- (both mRNA-LNPs) or 90-days (EVM158 mRNA-LNP) post boost (dpb) independently of CD4+ T-cells. However, at 29 dpb with 1 μg mRNA-LNPs, males had lower frequencies of Kb-TSYKFESV-specific CD8+ T-cells and were much less well protected than females from ECTV, also independently of CD4+ T-cells. At 90 dpb with 1 μg EVM158 mRNA-LNPs, the frequencies of Kb-TSYKFESV-specific CD8+ T-cells in males and females were similar, and both were similarly partially protected from ECTV, independently of CD4+ T-cells. Therefore, at optimal or suboptimal doses of mRNA-LNP vaccines, CD4+ T-cell help is unnecessary to induce protective anti-poxvirus CD8+ T-cells specific to a dominant epitope. At suboptimal doses, protection of males requires more time to develop.