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Title: HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen

Induction of broadly neutralizing antibodies (bnAbs) is a major HIV vaccine goal. Germline-targeting immunogens aim to initiate bnAb induction by activating bnAb germline precursor B cells. Critical unmet challenges are to determine whether bnAb precursor naïve B cells bind germline-targeting immunogens and occur at sufficient frequency in humans for reliable vaccine responses. We employed deep mutational scanning and multi-target optimization to develop a germline-targeting immunogen (eOD-GT8) for diverse VRC01-class bnAbs. We then used the immunogen to isolate VRC01-class precursor naïve B cells from HIV-uninfected donors. Frequencies of true VRC01-class precursors, their structures, and their eOD-GT8 affinities support this immunogen as a candidate human vaccine prime. Lastly, these methods could be applied to germline targeting for other classes of HIV bnAbs and for Abs to other pathogens.
Authors:
 [1] ;  [1] ;  [2] ;  [1] ;  [1] ;  [1] ;  [3] ;  [4] ;  [1] ;  [2] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [5] ;  [6] ;  [1] ;  [7] more »;  [8] ;  [7] « less
  1. The Scripps Research Institute, La Jolla, CA (United States)
  2. The Scripps Research Institute, La Jolla, CA (United States); La Jolla Institute for Allergy and Immunology, La Jolla, CA (United States)
  3. The Scripps Research Institute, La Jolla, CA (United States); Ecole Polytechnique Federale de Lausanne, Lausanne (Switzerland)
  4. Hospital for Sick Children Research Institute, Toronto, ON (Canada)
  5. Fred Hutchinson Cancer Research Center, Seattle, WA (United States)
  6. The Scripps Research Institute, La Jolla, CA (United States); Hospital for Sick Children Research Institute, Toronto, ON (Canada); Univ. of Toronto, Toronto, ON (Canada)
  7. The Scripps Research Institute, La Jolla, CA (United States); Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA (United States)
  8. The Scripps Research Institute, La Jolla, CA (United States); La Jolla Institute for Allergy and Immunology, La Jolla, CA (United States); Univ. of California San Diego School of Medicine, La Jolla, CA (United States)
Publication Date:
Type:
Accepted Manuscript
Journal Name:
Science
Additional Journal Information:
Journal Volume: 351; Journal Issue: 6280; Journal ID: ISSN 0036-8075
Publisher:
AAAS
Research Org:
Scripps Research Inst., La Jolla, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES
OSTI Identifier:
1345050