A Modified mRNA Vaccine Targeting Immunodominant NS Epitopes Protects Against Dengue Virus Infection in HLA Class I Transgenic Mice

Front Immunol. 2019 Jun 21;10:1424. doi: 10.3389/fimmu.2019.01424. eCollection 2019.

Abstract

Dengue virus (DENV) induces strong T and B cell responses upon infection. Hence, it is difficult to determine the contribution of cell-mediated immunity alone in the long lasting protection against DENV infection and disease. Numerous CD4+ and CD8+ T cell epitopes have been identified, mainly in the non-structural proteins of DENV. Taking into account the immunogenicity and peptide sequence conservation among the different DENV serotypes, a minimal DENV antigen, called DENV1-NS, has been designed. This antigen is enriched in conserved and highly antigenic epitopes located in the NS3, NS4B, and NS5 regions of DENV1. To evaluate the ability of the DENV1-NS poly-epitope to express the antigenic peptides in the context of different HLA class I molecules, we established its in vivo immunogenicity by measuring, after DNA immunization and electroporation, the activation of DENV-specific CD8 T cells in transgenic mice expressing the human HLA-A*0201, -A*2402, -B*0702, and -B*3502 class I alleles. We then engineered a lipid nanoparticle (LNP) encapsulated modified mRNA vaccine encoding DENV1-NS and tested immunogenicity and protection in these human HLA class I transgenic mice, after transient blockade of the interferon (IFN) type I receptor. Significant protection was observed, after two injections of the mRNA vaccine. Collectively, these data strongly support the development of T cell-based vaccines targeting immunodominant T cell epitopes that generate potent virus-specific T cell responses conferring immunity against DENV infection.

Keywords: DNA vaccine; NS epitopes; T cells; chimeric vaccine; dengue virus (DENV); human HLA transgenic mice; vaccine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Viral / immunology*
  • Dengue / immunology*
  • Dengue Vaccines / immunology*
  • Dengue Virus / immunology
  • Epitopes, T-Lymphocyte / immunology*
  • Histocompatibility Antigens Class I / genetics
  • Humans
  • Immunodominant Epitopes / immunology*
  • Mice
  • Mice, Transgenic
  • RNA, Messenger

Substances

  • Antigens, Viral
  • Dengue Vaccines
  • Epitopes, T-Lymphocyte
  • Histocompatibility Antigens Class I
  • Immunodominant Epitopes
  • RNA, Messenger