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Adjuvant-dependent innate and adaptive immune signatures of risk of SIVmac251 acquisition

Nature Medicine volume 22, pages 762–770 (2016)Cite this article

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A Corrigendum to this article was published on 06 October 2016

This article has been updated

Abstract

A recombinant vaccine containing Aventis Pasteur's canarypox vector (ALVAC)–HIV and gp120 alum decreased the risk of HIV acquisition in the RV144 vaccine trial. The substitution of alum with the more immunogenic MF59 adjuvant is under consideration for the next efficacy human trial. We found here that an ALVAC–simian immunodeficiency virus (SIV) and gp120 alum (ALVAC–SIV + gp120) equivalent vaccine, but not an ALVAC–SIV + gp120 MF59 vaccine, was efficacious in delaying the onset of SIVmac251 in rhesus macaques, despite the higher immunogenicity of the latter adjuvant. Vaccine efficacy was associated with alum-induced, but not with MF59-induced, envelope (Env)-dependent mucosal innate lymphoid cells (ILCs) that produce interleukin (IL)-17, as well as with mucosal IgG to the gp120 variable region 2 (V2) and the expression of 12 genes, ten of which are part of the RAS pathway. The association between RAS activation and vaccine efficacy was also observed in an independent efficacious SIV-vaccine approach. Whether RAS activation, mucosal ILCs and antibodies to V2 are also important hallmarks of HIV-vaccine efficacy in humans will require further studies.

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Figure 1: Study design and vaccine efficacy.
Figure 2: Env-specific IgG responses in mucosa.
Figure 3: Serum and rectal IgG to cyclic V2, PB homing markers and SIVmac251 acquisition.
Figure 4: Vaccine-induced changes in the frequency and function of mucosal ILC subsets.
Figure 5: Transcription and immune profiles associated with the risk of SIVmac251 acquisition.
Figure 6: RAS-related genes associated with protection conferred by the SIV gp96 + gp120 alum vaccine.

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Change history

  • 16 June 2016

    In the version of this article initially published online, an affiliation for Luca Schifanella was omitted and there was an error in the description of the phenotypic analyses of plasmablasts in the Online Methods. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We would like to thank T. Nolan and D. Abram for their editorial assistance, N. Miller and A. Shultz for their help in the study design, and J. Warren for support with systems biology and several antibody assays under Simian Vaccine Evaluation Unit (SVEU) contract number HHSN266200600005C, awarded to Advanced BioScience Laboratories, Inc. (ABL). This work was supported by the intramural US National Cancer Institute (NCI) program and the extramural US National Institute of Allergy and Infectious Diseases (NIAID) program, together with the US Army Medical Research and Material Command (USAMRMC) (W81XWH-07-2-0067), the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the US Department of Defense, the Collaboration for AIDS Vaccine Discovery (CAVD) grants OPP1032325 and OPP1032817 from the Bill and Melinda Gates Foundation, and in part, with federal funds from the NCI, US National Institutes of Health (NIH), under contract no. HHSN261200800001E (to the whole team). We would like to acknowledge the following institutions for the grants supporting the authors: NIH primate grant HHSN27201100016C (D.M.); Center for AIDS Research grant AI064518 (G.F.); Bill and Melinda Gates' Foundation grant OPP111572 (M.E.A., C.B.K., E.F.B., K.G.D.); NIH/NIAID grant 5R01AI102691 (M.E.A, E.F.B.); Intramural Research Program of the Vaccine Research Center, NIAID, NIH, and CAVD from the Bill and Melinda Gates Foundation grants OPP1032325 (R.A.K.), R01 AI118581 and R01 AI102715 (D.F.). The views expressed are those of the authors and should not be construed to represent the positions of the US Army, the Department of Defense or the Department of Health and Human Services. Mention of trade names, commercial products, or organizations do not imply endorsement by the US Government. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: CEM.NKR CCR5+ by P. Creswell. The anti-α4β7 in APC was kindly provided by A. A. Ansari (cat. #11718, 1:50 dilution) through the NIH AIDS Reagent Program, Division of AIDS, NIAID.

Author information

Author notes

  1. Jerome H Kim & Susan W Barnett

    Present address: Present addresses: GSK Vaccines, Cambridge, Massachusetts, USA (S.W.B.) and the International Vaccine Institute, Seoul, Republic of Korea (J.H.K.).,

  2. Monica Vaccari, Shari N Gordon, Slim Fourati, Luca Schifanella, Namal P M Liyanage, Rafick-Pierre Sekaly and Genoveffa Franchini: These authors contributed equally to this work.

Authors and Affiliations

  1. Animal Models and Vaccine Section, National Cancer Institute, Bethesda, Maryland, USA

    Monica Vaccari, Shari N Gordon, Luca Schifanella, Namal P M Liyanage, Melvin N Doster, Nicolo Binello, Poonam Pegu, Matthew Blackburn, Francesca Caccuri, Massimiliano Bissa & Genoveffa Franchini

  2. Department of Pathology, Case Western Reserve, Cleveland, Ohio, USA

    Slim Fourati & Rafick-Pierre Sekaly

  3. Department of Biomedical and Clinical Sciences, 'L. Sacco' Hospital, University of Milan, Italy

    Luca Schifanella

  4. Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA

    Mark Cameron

  5. AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, USA

    Brandon F Keele

  6. Duke Human Vaccine Institute, Durham, North Carolina, USA

    Xiaoying Shen, Georgia D Tomaras & Guido Ferrari

  7. US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA

    Erik Billings, Mangala Rao, Silvia Ratto-Kim, Jerome H Kim & Nelson L Michael

  8. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Boston, Massachusetts, USA

    Amy W Chung & Galit Alter

  9. Department of Computer Science, Dartmouth College, Hanover, New Hampshire, USA

    Karen G Dowell & Chris Bailey-Kellogg

  10. Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire, USA

    Eric P Brown & Margaret E Ackerman

  11. Immune Biology of Retroviral Infection Section, National Cancer Institute, Bethesda, Maryland, USA

    Diego A Vargas-Inchaustegui & Marjorie Robert-Guroff

  12. Advanced Bioscience Laboratories, Rockville, Maryland, USA

    Stephen Whitney, Vaniambadi Kalyanaraman, Maria G Ferrari & DeVon Thompson

  13. Duke University Medical Center, Durham, North Carolina, USA

    David C Montefiori

  14. Vaccine Research Center, US National Institutes of Health, Bethesda, Maryland, USA

    Kathryn Foulds, David S Quinn, Mitzi Donaldson, Mario Roederer, Richard A Koup & Adrian McDermott

  15. Karolinska Institute, Stockholm, Sweden

    Frank Liang & Karin Loré

  16. California National Primate Research Center, University of California, Davis, California, USA

    Zhong-Min Ma & Christopher J Miller

  17. University of California, Irvine School of Medicine, Irvine, California, USA

    Tran B Phan & Donald N Forthal

  18. Sanofi Pasteur, Swiftwater, Pennsylvania, USA

    Sanjay Phogat & Jim Tartaglia

  19. Novartis Vaccines and Diagnostics, Inc., Cambridge, USA

    Susan W Barnett

  20. Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

    David Venzon

  21. The EMMES Corporation, Rockville, Maryland, USA

    Donald M Stablein

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  1. Monica Vaccari
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  2. Shari N Gordon
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  45. Nelson L Michael
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  53. Genoveffa Franchini
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G. Franchini, M.V. and S.N.G. designed and coordinated the study, analyzed the data, prepared the figures and wrote the manuscript. R.-P.S. and S.F. analyzed microarray data and correlates of protection, prepared figures and wrote the manuscript. L.S. performed PB analysis, and N.P.M.L. analyzed ILCs. M.C. performed microarray analysis and analyzed data; B.F.K. did the DNA sequencing and analyzed the transmitted founder variants; D.V. and D.M.S. provided statistical support for study design and data analysis. X.S., G.D.T., E.B., M. Rao, A.W.C., K.G.D., C.B.-K., E.P.B., M.E.A., G.A., D.C.M., T.B.P., G. Ferrari, D.N.F., D.A.V.-I. and M.R.-G. performed binding and functional antibody assays on sera and mucosal secretions. S.W. expressed, scaled up and purified the gp120 proteins. K.F., D.S.Q., M.D., M. Roederer, R.A.K., and A.M. performed T cell assays (ICS), Fluidigm. F.L. and K.L. performed neutrophil staining. Z.-M.M. and C.J.M. provided immunohistochemistry data in mucosa, and M.N.D, N.B, P.P., M. Bissa., F.C. and M. Blackburn helped with cell preparations from blood and tissues. V.K., M.G.F. and D.T. performed envelope-specific ELISA on sera and quantitative assays on viral RNA in plasma and viral DNA tissues. S.R.-K., J.H.K. and N.L.M. provided human samples. S.P., S.W.B. and J.T. provided MF59 and generated a new recombinant ALVAC–SIV.

Corresponding author

Correspondence to Genoveffa Franchini.

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Competing interests

G. Franchini and J.Tartaglia are authors on patent US 5766598 A: Recombinant attenuated ALVAC canarypoxvirus expression vectors containing heterologous DNA segments encoding lentiviral gene products (issued June 16, 1998), which is jointly held by Sanofi Pasteur and the US government. S.P. is an employee of Sanofi Pasteur; M.G.F. is an employee of Advanced Bioscience Laboratories; D.M.S. is an employee of The EMMES Corporation; and S.W.B. was an employee of Novartis Vaccines and Diagnostics, Inc. S.W.B. is now an employee of and owns stock in GSK Vaccines.

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Vaccari, M., Gordon, S., Fourati, S. et al. Adjuvant-dependent innate and adaptive immune signatures of risk of SIVmac251 acquisition. Nat Med 22, 762–770 (2016). https://doi.org/10.1038/nm.4105

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