The Journal of Experimental Medicine
Torrey Pines Biolabs
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Published online
doi:10.1084/jem.20071211
The Journal of Experimental Medicine, Vol. 204, No. 11, 2733-2746
The Rockefeller University Press, 0022-1007 $30.00
© Kwissa et al.
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ARTICLE

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

Marcin Kwissa1, Rama R. Amara1,2, Harriet L. Robinson1,2, Bernard Moss4, Sefik Alkan5, Abdul Jabbar1, Francois Villinger3, and Bali Pulendran1,3

1 Vaccine Research Center and Yerkes National Primate Research Center, 2 Department of Microbiology & Immunology, and 3 Department of Pathology & Laboratory Medicine, Emory University, Atlanta, GA 30329
4 Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD 20892
5 3M Pharmaceuticals, St. Paul, MN 55144

CORRESPONDENCE Bali Pulendran: bpulend{at}rmy.emory.edu

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 SIVmac251 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.

Abbreviations used: AUC, area under the curve; CCR, CC chemokine receptor; FL, Fms-like tyrosine kinase 3 (Flt3)–ligand; ICC, intracellular cytokine; i.d., intradermal(ly); MVA, modified vaccinia virus Ankara; NHP, nonhuman primate; pDC, plasmacytoid DC; pDNA, plasmid DNA; TLR, Toll-like receptor, TLR-L, TLR ligand.


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