Adjuvanting a DNA vaccine with a TLR9 ligand plus Flt3 ligand results in enhanced cellular immunity against the simian immunodeficiency virus

J Exp Med. 2007 Oct 29;204(11):2733-46. doi: 10.1084/jem.20071211. Epub 2007 Oct 22.

Abstract

DNA vaccines offer promising strategies for immunization against infections. However, their clinical use requires improvements in immunogenicity. We explored the efficacy of Toll-like receptor (TLR) ligands (TLR-Ls) on augmenting the immunogenicity of a DNA prime-modified vaccinia virus Ankara (MVA) boost vaccine against SIV. Rhesus macaques were injected with Fms-like tyrosine kinase 3 (Flt3)-ligand (FL) to expand dendritic cells (DCs) and were primed with a DNA vaccine encoding immunodeficiency virus antigens mixed with ligands for TLR9 or TLR7/8. Subsequently, the animals were boosted with DNA and twice with recombinant MVA expressing the same antigens. TLR9-L (CpG DNA) mediated activation of DCs in vivo and enhanced the magnitude of antigen-specific CD8(+) interferon (IFN) gamma(+) T cells and polyfunctional CD8(+) T cells producing IFN-gamma, tumor necrosis factor alpha, and interleukin 2. Although this trial was designed primarily as an immunogenicity study, we challenged the animals with pathogenic SIVmac(251) and observed a reduction in peak viremia and cumulative viral loads in the TLR9-L plus FL-adjuvanted group relative to the unvaccinated group; however, the study design precluded comparisons between the adjuvanted groups and the group vaccinated with DNA/MVA alone. Viral loads were inversely correlated with the magnitude and quality of the immune response. Thus, the immunogenicity of DNA vaccines can be augmented with TLR9-L plus FL.

Publication types

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

MeSH terms

  • Animals
  • Cloning, Molecular
  • DNA, Viral / genetics
  • DNA, Viral / isolation & purification
  • Humans
  • Immunity, Cellular*
  • Macaca mulatta
  • Membrane Proteins / immunology*
  • RNA, Viral / blood
  • RNA, Viral / genetics
  • Simian Acquired Immunodeficiency Syndrome / immunology*
  • Simian Immunodeficiency Virus / genetics
  • Simian Immunodeficiency Virus / immunology*
  • Toll-Like Receptor 9 / immunology*
  • Vaccines, DNA*
  • Viral Load

Substances

  • DNA, Viral
  • Membrane Proteins
  • RNA, Viral
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • Vaccines, DNA
  • flt3 ligand protein