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Abstract

The RV144 trial demonstrated 31% vaccine efficacy at preventing human immunodeficiency virus (HIV)-1 infection1. Antibodies against the HIV-1 envelope variable loops 1 and 2 (Env V1 and V2) correlated inversely with infection risk2. We proposed that vaccine-induced immune responses against V1/V2 would have a selective effect against, or sieve, HIV-1 breakthrough viruses. A total of 936 HIV-1 genome sequences from 44 vaccine and 66 placebo recipients were examined. We show that vaccine-induced immune responses were associated with two signatures in V2 at amino acid positions 169 and 181. Vaccine efficacy against viruses matching the vaccine at position 169 was 48% (confidence interval 18% to 66%; P = 0.0036), whereas vaccine efficacy against viruses mismatching the vaccine at position 181 was 78% (confidence interval 35% to 93%; P = 0.0028). Residue 169 is in a cationic glycosylated region recognized by broadly neutralizing and RV144-derived antibodies. The predicted distance between the two signature sites (21 ± 7 Å) and their match/mismatch dichotomy indicate that multiple factors may be involved in the protection observed in RV144. Genetic signatures of RV144 vaccination in V2 complement the finding of an association between high V1/V2-binding antibodies and reduced risk of HIV-1 acquisition, and provide evidence that vaccine-induced V2 responses plausibly had a role in the partial protection conferred by the RV144 regimen.

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Change history

  • 24 September 2012

    The web PDF was replaced to correct a corrupted Ångström symbol in three places

Accessions

Primary accessions

GenBank/EMBL/DDBJ

Data deposits

Sequences are available under GenBank accession numbers JX446645JX448316.

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Acknowledgements

We thank B. F. Haynes and F. A. Matsen for advice and comments, and I. A. Wilson and R. L. Stanfield for assistance. This study was supported in part by an Interagency Agreement Y1-AI-2642-12 between US Army Medical Research and Material Command (USAMRMC) and the National Institutes of Allergy and Infectious Diseases. This work was also supported by a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the US Department of Defense (DOD). Additional support was provided to P.B.G. through the NIH grant 2R37AI05465-10. The opinions herein are those of the authors and should not be construed as official or representing the views of the US Department of Defense or the Department of the Army.

Author information

Author notes

    • Morgane Rolland
    • , Paul T. Edlefsen
    • , Peter B. Gilbert
    • , James I. Mullins
    •  & Jerome H. Kim

    These authors contributed equally to this work.

Affiliations

  1. US Military HIV Research Program, Silver Spring, Maryland 20910, USA

    • Morgane Rolland
    • , Sodsai Tovanabutra
    • , Eric Sanders-Buell
    • , Meera Bose
    • , Shana Howell
    • , Adam Bates
    • , Michelle Lazzaro
    • , Annemarie O’Sullivan
    • , Esther Lei
    • , Andrea Bradfield
    • , Grace Ibitamuno
    • , Robert J. O’Connell
    • , Merlin L. Robb
    • , Nelson L. Michael
    •  & Jerome H. Kim
  2. Statistical Center for HIV/AIDS Research and Prevention, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA

    • Paul T. Edlefsen
    • , Tomer Hertz
    • , Allan C. deCamp
    • , Craig A. Magaret
    • , Hasan Ahmed
    • , Michal Juraska
    •  & Peter B. Gilbert
  3. Department of Microbiology, University of Washington, Seattle, Washington 98195, USA

    • Brendan B. Larsen
    • , Lennie Chen
    • , Philip Konopa
    • , Snehal Nariya
    • , Julia N. Stoddard
    • , Kim Wong
    • , Hong Zhao
    • , Wenjie Deng
    • , Brandon S. Maust
    •  & James I. Mullins
  4. Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA

    • Chris Carrico
    • , Sergey Menis
    •  & William R. Schief
  5. IAVI Neutralizing Antibody Center and Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California 92037, USA

    • Chris Carrico
    • , Sergey Menis
    •  & William R. Schief
  6. Royal Thai Army Component, AFRIMS, Bangkok 10400, Thailand

    • Vatcharain Assawadarachai
    • , Mark S. deSouza
    •  & Sorachai Nitayaphan
  7. Thai Ministry of Public Health, Nonthaburi 11000, Thailand

    • Supachai Rerks-Ngarm
  8. Vaccine Research Center, NIAID, NIH, Bethesda, Maryland 20892, USA

    • Jason S. McLellan
    • , Ivelin Georgiev
    •  & Peter D. Kwong
  9. Microsoft Research, Redmond, Washington 98052, USA

    • Jonathan M. Carlson

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Contributions

M.R. conducted the sequence analysis with contributions from B.B.L., W.D. and B.S.M.; P.T.E. and P.B.G. conducted the site-scanning sieve analyses. M.R., S.T., E.S.-B. and J.I.M. designed the sequencing experiments. B.B.L., L.C., P.K., S.N., J.N.S., K.W., H.Z., M.B., S.H., A. Bates, M.L., A.O’S., E.L., A. Bradfield, G.I. and V.A. performed viral sequencing. T.H., A.C.deC., C.A.M., H.A. and M.J. contributed statistical analyses. C.C., S.M. and W.R.S. developed the EPIMAP approach. J.S.M., I.G. and P.D.K. identified antibody contact residues and performed V2 structural analyses. J.M.C. performed phylogenetic dependency network analyses. R.J.O’C., M.S.deS., S.N., S.R.-N., M.L.R., N.L.M. and J.H.K. conducted the RV144 trial. M.R., P.T.E., P.B.G., J.I.M. and J.H.K. designed the studies, analysed data, prepared the manuscript (with contributions from J.M.C., P.D.K. and W.R.S.) and supervised the project.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Morgane Rolland.

Supplementary information

PDF files

  1. 1.

    Supplementary Information 1

    This file contains Supplementary Figures 1–5, Supplementary Methods, Supplementary Tables 1–11 and Supplementary Note 1.

  2. 2.

    Supplementary Information 2

    This Supplementary Information file contains the Code for differential VE and for the site-scanning methods.

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DOI

https://doi.org/10.1038/nature11519

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