Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys

Journal name:
Nature Medicine
Volume:
16,
Pages:
319–323
Year published:
DOI:
doi:10.1038/nm.2089
Received
Accepted
Published online

The worldwide diversity of HIV-1 presents an unprecedented challenge for vaccine development1, 2. Antigens derived from natural HIV-1 sequences have elicited only a limited breadth of cellular immune responses in nonhuman primate studies and clinical trials to date. Polyvalent 'mosaic' antigens, in contrast, are designed to optimize cellular immunologic coverage of global HIV-1 sequence diversity3. Here we show that mosaic HIV-1 Gag, Pol and Env antigens expressed by recombinant, replication-incompetent adenovirus serotype 26 vectors markedly augmented both the breadth and depth without compromising the magnitude of antigen-specific T lymphocyte responses as compared with consensus or natural sequence HIV-1 antigens in rhesus monkeys. Polyvalent mosaic antigens therefore represent a promising strategy to expand cellular immunologic vaccine coverage for genetically diverse pathogens such as HIV-1.

At a glance

Figures

  1. Breadth and magnitude of epitope-specific T lymphocyte responses to PTE peptides.
    Figure 1: Breadth and magnitude of epitope-specific T lymphocyte responses to PTE peptides.

    (a) Numbers of epitope-specific CD4+ (top) and CD8+ (bottom) T lymphocyte responses to individual PTE peptides are shown after a single immunization of rAd26 vectors expressing mosaic, M consensus, clade B + clade C or optimal natural clade C HIV-1 Gag, Pol and Env antigens. Individual monkeys are depicted on the x axis. The various shades of each color reflect responses to the different antigens (Gag, Pol and Env), as indicated. (b) Numbers of CD4+ (top) and CD8+ (bottom) T lymphocyte response regions. (c) Magnitude of all Gag-, Pol- and Env-specific CD8+ (top and middle) and CD4+ (bottom) T lymphocyte responses arranged from lowest to highest. Spot-forming cells (SFCs) per 1 × 106 PBMCs are shown for each epitope-specific response.

  2. Depth of epitope-specific T lymphocyte responses to PTE peptides.
    Figure 2: Depth of epitope-specific T lymphocyte responses to PTE peptides.

    (a) Example of mapped T lymphocyte responses in monkey 366, which received the optimal natural clade C antigens. (b) Example of mapped T lymphocyte responses in monkey 361, which received the bivalent mosaic antigens. In a and b, vaccine sequences are shown on the top and are designated OptC (optimal natural clade C), Mos1 (mosaic sequence 1) and Mos2 (mosaic sequence 2), and reactive PTE peptides are shown beneath the vaccine sequences denoted by the antigen (G, Gag; P, Pol; E, Env) and the PTE peptide number. Sequence polymorphisms between the two mosaic antigens are shown in blue. Differences between the vaccine sequences and the reactive PTE peptides are shown in red. Complete alignments of all positive peptides organized by response regions are shown in Supplementary Figure 3. (c) Depth of CD4+ (top) and CD8+ (bottom) T lymphocyte responses after immunization with rAd26 vectors expressing mosaic, M consensus, clade B + clade C or optimal natural clade C antigens. Individual monkeys are depicted on the x axis. One response variant or more than one response variants shown for each epitopic region.

  3. Breadth of epitope-specific T lymphocyte responses to five HIV-1 Gag sequences from clades A, B and C.
    Figure 3: Breadth of epitope-specific T lymphocyte responses to five HIV-1 Gag sequences from clades A, B and C.

    Breadth of cellular immune responses was assessed with subpools of overlapping peptides spanning the following strains of HIV-1 Gag: clade C DU422, clade C ZM651, consensus C, consensus A and consensus B. Numbers of positive subpools are shown after a single immunization of rAd26 vectors expressing mosaic, M consensus, clade B + clade C or optimal natural clade C HIV-1 Gag, Pol and Env antigens. Individual monkeys are depicted on the x axis.

  4. Cellular and humoral immune responses after the boost immunization.
    Figure 4: Cellular and humoral immune responses after the boost immunization.

    (a,b) Magnitude (a) and breadth (b) of T lymphocyte subpool responses at week 4 after prime (left data point) and at week 44 after boost (right data point) for each monkey. Monkeys were primed at week 0 with rAd26 vectors and boosted at week 40 with rAd5HVR48 vectors expressing mosaic, M consensus or optimal natural clade C HIV-1 Gag, Pol and Env antigens. Individual monkeys are depicted on the x axis. In a, red denotes epitope-specific CD8+ T lymphocyte responses, blue denotes epitope-specific CD4+ T lymphocyte responses, lines depict responses observed at both time points and dots depict responses observed at only one time point. (c) Env-specific ELISA end-point titers are shown at weeks 0, 4 and 44. (d) NAb titers to the tier 1 clade A (DJ263.8), clade B (SF162.LS) and clade C (MW965.26) viruses at week 44. NAb titers to murine leukemia virus as a negative control were <20 for all samples (data not shown).

References

  1. Barouch, D.H. Challenges in the development of an HIV-1 vaccine. Nature 455, 613619 (2008).
  2. Korber, B.T., Letvin, N.L. & Haynes, B.F. T-cell vaccine strategies for human immunodeficiency virus, the virus with a thousand faces. J. Virol. 83, 83008314 (2009).
  3. Fischer, W. et al. Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants. Nat. Med. 13, 100106 (2007).
  4. Kiepiela, P. et al. CD8+ T-cell responses to different HIV proteins have discordant associations with viral load. Nat. Med. 13, 4653 (2007).
  5. Liu, J. et al. Immune control of an SIV challenge by a T-cell–based vaccine in rhesus monkeys. Nature 457, 8791 (2009).
  6. Abbink, P. et al. Comparative seroprevalence and immunogenicity of six rare serotype recombinant adenovirus vaccine vectors from subgroups B and D. J. Virol. 81, 46544663 (2007).
  7. Santra, S. et al. A centralized gene-based HIV-1 vaccine elicits broad cross-clade cellular immune responses in rhesus monkeys. Proc. Natl. Acad. Sci. USA 105, 1048910494 (2008).
  8. Li, F. et al. Peptide selection for human immunodeficiency virus type 1 CTL-based vaccine evaluation. Vaccine 24, 68936904 (2006).
  9. Pinheiro, J.C. & Bates, D.M. Mixed-Effects Models in S and S-plus (Springer, New York, 2000).
  10. Roberts, D.M. et al. Hexon-chimaeric adenovirus serotype 5 vectors circumvent pre-existing anti-vector immunity. Nature 441, 239243 (2006).
  11. Montefiori, D. Evaluating neutralizing antibodies against HIV, SIV and SHIV in luciferase reporter gene assays. Curr. Protoc. Immunol. 64, 12.1.112.1.17 (2004).
  12. Kong, W.P. et al. Expanded breadth of the T-cell response to mosaic human immunodeficiency virus type 1 envelope DNA vaccination. J. Virol. 83, 22012215 (2009).
  13. Buchbinder, S.P. et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the STEP Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 372, 18811893 (2008).
  14. McElrath, M.J. et al. HIV-1 vaccine–induced immunity in the test-of-concept STEP Study: a case-cohort analysis. Lancet 372, 18941905 (2008).
  15. Goonetilleke, N. et al. The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection. J. Exp. Med. 206, 12531272 (2009).
  16. Barouch, D.H. et al. Dynamic immune responses maintain cytotoxic T lymphocyte epitope mutations in transmitted simian immunodeficiency virus variants. Nat. Immunol. 6, 247252 (2005).
  17. Barry, A.P. et al. Depletion of CD8+ cells in sooty mangabey monkeys naturally infected with simian immunodeficiency virus reveals limited role for immune control of virus replication in a natural host species. J. Immunol. 178, 80028012 (2007).
  18. Sodora, D.L. et al. Toward an AIDS vaccine: lessons from natural simian immunodeficiency virus infections of African nonhuman primate hosts. Nat. Med. 15, 861865 (2009).
  19. Thurmond, J. et al. Web-based design and evaluation of T-cell vaccine candidates. Bioinformatics 24, 16391640 (2008).
  20. Priddy, F.H. et al. Safety and immunogenicity of a replication-incompetent adenovirus type 5 HIV-1 clade B gag/pol/nef vaccine in healthy adults. Clin. Infect. Dis. 46, 17691781 (2008).

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Author information

Affiliations

  1. Division of Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

    • Dan H Barouch,
    • Kara L O'Brien,
    • Nathaniel L Simmons,
    • Sharon L King,
    • Peter Abbink,
    • Lori F Maxfield,
    • Ying-Hua Sun,
    • Annalena La Porte,
    • Ambryice M Riggs,
    • Diana M Lynch,
    • Sarah L Clark,
    • Katherine Backus,
    • James R Perry &
    • Michael S Seaman
  2. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA.

    • Dan H Barouch
  3. New England Primate Research Center, Southborough, Massachusetts, USA.

    • Angela Carville &
    • Keith G Mansfield
  4. Los Alamos National Laboratory, Los Alamos, New Mexico, USA.

    • James J Szinger,
    • Will Fischer &
    • Bette Korber
  5. School of Mathematics, University of Manchester, Manchester, UK.

    • Mark Muldoon
  6. Santa Fe Institute, Santa Fe, New Mexico, USA.

    • Mark Muldoon &
    • Bette Korber

Contributions

W.F., B.K. and D.H.B. designed the antigens. S.L.K., P.A., L.F.M., Y.-H.S. and D.H.B. generated the vaccine vectors. K.L.O., N.L.S., A.L.P., A.M.R., D.M.L., S.L.C. and D.H.B. designed and conducted the cellular immunologic assays. A.L.P., K.B., J.R.P. and M.S.S. designed and conducted the humoral immunologic assays. A.C. and K.G.M. led the monkey work. M.M. and B.K. led the data analysis and J.J.S. wrote the response mapping software. D.H.B. and B.K. designed the study, and D.H.B. led the study. All authors contributed to the writing of the manuscript.

Competing financial interests

The authors declare no competing financial interests.

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