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Science. 2019 Dec 6;366(6470). pii: eaax4380. doi: 10.1126/science.aax4380. Epub 2019 Oct 31.

A generalized HIV vaccine design strategy for priming of broadly neutralizing antibody responses.

Steichen JM#1,2,3, Lin YC#4, Havenar-Daughton C#3,5, Pecetta S#4, Ozorowski G#2,3,6, Willis JR#1,2,3, Toy L3,5, Sok D1,2,3, Liguori A1,2,3, Kratochvil S4, Torres JL2,3,6, Kalyuzhniy O1,2,3, Melzi E4, Kulp DW1,2,3,7, Raemisch S1,2,3, Hu X1,2,3, Bernard SM2,3,6, Georgeson E1,2,3, Phelps N1,2,3, Adachi Y1,2,3, Kubitz M1,2,3, Landais E1,2,3, Umotoy J1,2,3, Robinson A1,2,3, Briney B1,2,3,8, Wilson IA2,3,6,9, Burton DR1,2,3, Ward AB2,3,6, Crotty S10,5,11, Batista FD12,13, Schief WR14,2,3,4.

Author information

1
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
2
IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
3
Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA 92037, USA.
4
The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA.
5
Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
6
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
7
Vaccine and Immune Therapy Center, The Wistar Institute, Philadelphia, PA 19104, USA.
8
Center for Viral Systems Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
9
Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
10
Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA 92037, USA. schief@scripps.edu fbatista1@mgh.harvard.edu shane@lji.org.
11
Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
12
The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA. schief@scripps.edu fbatista1@mgh.harvard.edu shane@lji.org.
13
Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
14
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA. schief@scripps.edu fbatista1@mgh.harvard.edu shane@lji.org.
#
Contributed equally

Abstract

Vaccine induction of broadly neutralizing antibodies (bnAbs) to HIV remains a major challenge. Germline-targeting immunogens hold promise for initiating the induction of certain bnAb classes; yet for most bnAbs, a strong dependence on antibody heavy chain complementarity-determining region 3 (HCDR3) is a major barrier. Exploiting ultradeep human antibody sequencing data, we identified a diverse set of potential antibody precursors for a bnAb with dominant HCDR3 contacts. We then developed HIV envelope trimer-based immunogens that primed responses from rare bnAb-precursor B cells in a mouse model and bound a range of potential bnAb-precursor human naïve B cells in ex vivo screens. Our repertoire-guided germline-targeting approach provides a framework for priming the induction of many HIV bnAbs and could be applied to most HCDR3-dominant antibodies from other pathogens.

PMID:
31672916
PMCID:
PMC7092357
[Available on 2020-06-06]
DOI:
10.1126/science.aax4380

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