title: Adjuvanting a DNA vaccine with a TLR9 ligand plus Flt3 ligand results in enhanced cellular immunity against the simian immunodeficiency virus.
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.
authors.affiliation: Vaccine Research Center and Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kwissa
authors.forename: Rama R
authors.initials: RR
authors.lastname: Amara
authors.forename: Harriet L
authors.initials: HL
authors.lastname: Robinson
authors.forename: Bernard
authors.initials: B
authors.lastname: Moss
authors.forename: Sefik
authors.initials: S
authors.lastname: Alkan
authors.forename: Abdul
authors.initials: A
authors.lastname: Jabbar
authors.forename: Francois
authors.initials: F
authors.lastname: Villinger
authors.forename: Bali
authors.initials: B
authors.lastname: Pulendran
mesh_terms: D000818:Animals; D003001:Cloning, Molecular; D004279:DNA, Viral / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D007111:Immunity, Cellular; D008253:Macaca mulatta; D008565:Membrane Proteins / Q000276:immunology*; D012367:RNA, Viral / Q000097:blood / Q000235:genetics; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000276:immunology*; D019444:Vaccines, DNA; D019562:Viral Load
chemical_list: D004279:DNA, Viral; D008565:Membrane Proteins; D012367:RNA, Viral; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D019444:Vaccines, DNA; C084881:flt3 ligand protein