Abstract

No immunogen to date has reliably elicited broadly neutralizing antibodies to HIV in humans or animal models. Advances in the design of immunogens that antigenically mimic the HIV envelope glycoprotein (Env), such as the soluble cleaved trimer BG505 SOSIP1, have improved the elicitation of potent isolate-specific antibody responses in rabbits2 and macaques3, but so far failed to induce broadly neutralizing antibodies. One possible reason for this failure is that the relevant antibody repertoires are poorly suited to target the conserved epitope regions on Env, which are somewhat occluded relative to the exposed variable epitopes. Here, to test this hypothesis, we immunized four cows with BG505 SOSIP. The antibody repertoire of cows contains long third heavy chain complementary determining regions (HCDR3) with an ultralong subset that can reach more than 70 amino acids in length4,5,6,7,8,9. Remarkably, BG505 SOSIP immunization resulted in rapid elicitation of broad and potent serum antibody responses in all four cows. Longitudinal serum analysis for one cow showed the development of neutralization breadth (20%, n = 117 cross-clade isolates) in 42 days and 96% breadth (n = 117) at 381 days. A monoclonal antibody isolated from this cow harboured an ultralong HCDR3 of 60 amino acids and neutralized 72% of cross-clade isolates (n = 117) with a potent median IC50 of 0.028 μg ml−1. Breadth was elicited with a single trimer immunogen and did not require additional envelope diversity. Immunization of cows may provide an avenue to rapidly generate antibody prophylactics and therapeutics to address disease agents that have evolved to avoid human antibody responses.

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Primary accessions

NCBI Reference Sequence

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Acknowledgements

This work was supported by the International AIDS Vaccine Initiative Neutralizing Antibody Consortium through the Collaboration for AIDS Vaccine Discovery grant OPP1084519 (D.R.B., I.A.W., A.B.W.), NIH grants R21 AI120791 (V.V.S.), R01 GM105826 (V.V.S.), Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery Grant UM1AI100663 (D.R.B., I.A.W., A.B.W.), IOS 1257829 (M.F.C.), and USDA-NIFA grant number CSREES 2008-35204 (W.M.). D.R.B. acknowledges the support of the James and Jessie Minor Chair in Immunology. We thank B. Schief and S. Menis for providing MD39 for competition experiments. This work was funded in part by IAVI and made possible by the support of many donors, including: the Bill & Melinda Gates Foundation, the Ministry of Foreign Affairs of Denmark, Irish Aid, the Ministry of Finance of Japan in partnership with The World Bank, the Ministry of Foreign Affairs of the Netherlands, the Norwegian Agency for Development Cooperation (NORAD), the United Kingdom Department for International Development (DFID), and the United States Agency for International Development (USAID). The full list of IAVI donors is available at http://www.iavi.org. The contents of this manuscript do not necessarily reflect the views of USAID or the US Government.

Author information

Author notes

    • Devin Sok
    •  & Khoa M. Le

    These authors contributed equally to this work.

Affiliations

  1. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California 92037, USA

    • Devin Sok
    • , Khoa M. Le
    • , Karen L. Saye-Francisco
    • , Joseph G. Jardine
    • , Jennifer Ruiz
    • , Alejandra Ramos
    • , Chi-Hui Liang
    •  & Dennis R. Burton
  2. IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA

    • Devin Sok
    • , Khoa M. Le
    • , Karen L. Saye-Francisco
    • , Joseph G. Jardine
    • , Jennifer Ruiz
    • , Alejandra Ramos
    • , Chi-Hui Liang
    • , Ian A. Wilson
    • , Andrew B. Ward
    •  & Dennis R. Burton
  3. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA

    • Devin Sok
    • , Khoa M. Le
    • , Karen L. Saye-Francisco
    • , Joseph G. Jardine
    • , Jennifer Ruiz
    • , Alejandra Ramos
    • , Chi-Hui Liang
    • , Ian A. Wilson
    • , Andrew B. Ward
    •  & Dennis R. Burton
  4. International AIDS Vaccine Initiative, New York, New York 10004, USA

    • Devin Sok
    • , Khoa M. Le
    • , Jennifer Ruiz
    •  & Alejandra Ramos
  5. Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92037, USA

    • Melissa Vadnais
    •  & Vaughn V. Smider
  6. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA

    • Jonathan L. Torres
    • , Zachary T. Berndsen
    • , Leopold Kong
    • , Robyn Stanfield
    • , Ian A. Wilson
    •  & Andrew B. Ward
  7. Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas 77843, USA

    • Patricia L. Chen
    •  & Michael F. Criscitiello
  8. Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medical, Kansas State University, Manhattan, Kansas 66506, USA

    • Waithaka Mwangi
  9. Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02129, USA

    • Dennis R. Burton

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Contributions

D.S., K.M.L., J.R. and A.R. performed antigen B cell sorts. K.M.L., J.R. and A.R. performed PCR and antibody cloning, expression, and purification. K.L.S.-F., K.M.L. and J.R. performed neutralization and mutagenesis experiments. M.L.V. and D.S. designed and validated VH and VL gene-specific primers. D.S., K.M.L., M.L.V. and V.V.S. analysed V-region sequences. L.K. and I.A.W. provided protein for immunization experiments. J.L.T., Z.T.B., R.S., A.B.W. and I.A.W. performed structural analysis. J.G.J. performed pH experiments. C.-H.L. performed polyreactivity experiments. P.L.C., M.F.C. and W.M. performed cow immunization and serum ELISA experiments. P.L.C., M.F.C., W.M. and M.L.V. processed lymphocytes and produced mRNA and cDNA. D.S., V.V.S. and D.R.B. helped design and oversaw experiments. D.S., V.V.S. and D.R.B. wrote the manuscript.

Competing interests

D.S., D.R.B. and V.V.S. are inventors on a patent describing the NC-Cow antibodies: US provisional application filed on 14 July 2017.

Corresponding authors

Correspondence to Vaughn V. Smider or Dennis R. Burton.

Reviewer Information Nature thanks J. Mascola and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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