Qualitative differences in the innate and adaptive responses elicited by different HIV vaccine candidates have not been thoroughly investigated. We tested the ability of the Aventis Pasteur live recombinant canarypox vector (ALVAC)–SIV, DNA–SIV and Ad26–SIV vaccine prime modalities together with two ALVAC–SIV + gp120 protein boosts to reduce the risk of SIVmac251 acquisition in rhesus macaques. We found that the DNA and ALVAC prime regimens were effective, but the Ad26 prime was not. The activation of hypoxia and the inflammasome in CD14+CD16 monocytes, gut-homing CCR5-negative CD4+ T helper 2 (TH2) cells and antibodies to variable region 2 correlated with a decreased risk of SIVmac251 acquisition. By contrast, signal transducer and activator of transcription 3 activation in CD16+ monocytes was associated with an increased risk of virus acquisition. The Ad26 prime regimen induced the accumulation of CX3CR1+CD163+ macrophages in lymph nodes and of long-lasting CD4+ TH17 cells in the gut and lungs. Our data indicate that the selective engagement of monocyte subsets following a vaccine prime influences long-term immunity, uncovering an unexpected association of CD14+ innate monocytes with a reduced risk of SIVmac251 acquisition.

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We thank D. Ahern for editorial and graphical support and all of the staff at Advanced BioScience Laboratories for helping with the execution of the animal study. We thank J. Lucas, J. Peel and Y. Lin for specific binding and total antibody assays and G. Overman and N. Yates for assay and technical assistance. We thank D. Barouch (Harvard Medical School) for providing the Ad26–SIV recombinant vaccine. This work was mostly supported with federal funds from the intramural program of the National Cancer Institute, NIH, including contract no. HHSN261200800001E (G.F.). Contributions were made by the extramural NIAID program (HHSN27201100016C; D.M.), the Henry M. Jackson Foundation, the US Department of Defense and the Collaboration for Aids Vaccine Discovery (CAVD) grants OPP1032325 (R.A.K.) and OPP1147555 (R.A.K.) from the Bill and Melinda Gates Foundation. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.

Author information


  1. Animal Models and Retroviral Vaccines Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    • Monica Vaccari
    • , Shari N. Gordon
    • , Dallas R. Brown
    • , Massimilano Bissa
    • , Luca Schifanella
    • , Isabela Silva de Castro
    • , Melvin N. Doster
    • , Veronica Galli
    • , Maria Omsland
    • , Dai Fujikawa
    • , Giacomo Gorini
    • , Namal P. M. Liyanage
    •  & Genoveffa Franchini
  2. Department of Pathology, Case Western Reserve University, Cleveland, OH, USA

    • Slim Fourati
    •  & Rafick-Pierre Sekaly
  3. US Military HIV Research Program, Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA

    • Hung V. Trinh
    •  & Mangala Rao
  4. US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA

    • Hung V. Trinh
  5. Vaccine Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    • Katherine M. McKinnon
  6. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    • Kathryn E. Foulds
    • , Mario Roederer
    •  & Richard A. Koup
  7. AIDS and Cancer Virus Program, Leidos Biomedical Research Inc., Frederick National Laboratory, Frederick, MD, USA

    • Brandon F. Keele
  8. Duke Human Vaccine Institute, Duke University, Durham, NC, USA

    • Xiaoying Shen
    •  & Georgia D. Tomaras
  9. Division of Infectious Diseases, Department of Medicine, University of California, Irvine School of Medicine, Irvine, CA, USA

    • Marcus P. Wong
    • , Karissa J. Munoz
    • , Johannes S. Gach
    •  & Donald N. Forthal
  10. Division of Surgical Sciences, Duke University School of Medicine, Durham, NC, USA

    • David C. Montefiori
  11. Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    • David J. Venzon
  12. Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA

    • Barbara K. Felber
  13. Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA

    • Margherita Rosati
    •  & George N. Pavlakis


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G.F. designed and coordinated the study with M.V. and S.N.G., interpreted the data and wrote the manuscript. S.F. and R.P.S. analyzed the gene expression data, performed the correlates of risk analyses, prepared the figures and helped to write the manuscript. D.R.B. performed the flow cytometry for monocytes in the blood. M.V. performed the studies on TH cell types and analyzed the antibody data and prepared some of the figures together with S.N.G. M.B., L.S., I.S.d.C. M.N.D. performed the analysis of cytokines in the serum. V.G., M.O. and D.F. performed the PCR analysis and RNA extraction. G.G. and N.P.M.L. measured the serum IgG titers and NK cells in the mucosa. H.V.T. and M. Rao measured and analyzed responses to cyclic V2. K.M.M. helped with sorting of monocytes. K.E.F., M. Roederer and R.A.K. performed the intracellular cytokine analysis. B.F.K. measured the number of transmitted variants. X.S., G.D.T., M.P.W., K.J.M., J.S.G., D.N.F., D.C.M. and M. Rosati studied humoral responses in the serum. D.J.V. assisted with statistical analyses. B.K.F., M. Rosati and G.N.P. provided the SIV DNAs.

Competing interests

The US Government in conjunction with Sanofi Pasteur holds Patent 5766598: A Recombinant Attenuated ALVAC Canarypox virus Expression Vectors Containing Heterologous DNA Segments Encoding Lentiviral Gene, inventors E. Paoletti, J. Tartaglia and W. I. Cox, issued 16 June 1998, for the ALVAC vaccine. The US Government also holds Patent 7094408: Improved Immunogenicity Using a Combination of DNA and Vaccinia Virus Vector Vaccines, inventors G. Franchini, Z. Hel and G. Pavlakis, issued 22 August 2006. This patent is for the combination DNA and ALVAC poxvirus vaccines.

Corresponding author

Correspondence to Genoveffa Franchini.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–9 and Supplementary Tables 1 and 4–6

  2. Reporting Summary

  3. Supplementary Table 2

    Genes associated with protection from SIVmac251 acquisition

  4. Supplementary Table 3

    Immune markers associated with the risk of SIVmac251 acquisition

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