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.

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 K ^b -restricted immunodominant CD8 ⁺ T cell epitope TSYKFESV (TSYKFESV mRNA-LNPs) or the ECTV EVM158 protein, which contains TSYKFESV (EVM-158 mRNA-LNPs). Following prime and boost with 10 μg of either vaccine, K ^b -TSYKFESV-specific CD8 ⁺ T cells fully protected male and female mice from ECTV at 29 (both mRNA-LNPs) or 90 days (EVM158 mRNA-LNPs) post boost (dpb) independently of CD4 ⁺ T cells. However, at 29 dpb with 1 μg mRNA-LNPs, males had lower frequencies of K ^b -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 K ^b -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.
Competing Interests: L.J.S is a member of the Scientific Board of RNA Advanced Technologies. N.P. is named on patents describing the use of nucleoside-modified mRNA in lipid nanoparticles as a vaccine platform. He has disclosed those interests fully to the University of Pennsylvania, and he has an approved plan for managing any potential conflicts arising from licensing those patents. N.P. served on the mRNA strategic advisory board of Sanofi Pasteur in 2022. N.P. is a member of the Scientific Advisory Board of AldexChem. Y.K.T. is an employee of Acuitas Therapeutics.
(© 2024 The Authors.)