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Author Notes:

Correspondence to Colin Havenar-Daughton, chavenar@lji.org; or Shane Crotty, shane@lji.org

C.H.-D., W.R.S., S.C. designed the study.

L.T., K.K., I.D., A.S., X.H., O.K., L.C., J.K.D. and G.S. performed experiments.

C.H.-D., A.S., D.W.K., X.H., T.S., A.A.U., S.M., S.K., L.C., S.M.R., J.R.Y., J.C.P., S.E.B., and I.A.W. analyzed data sets.

D.W.K., E.L., X.H., S.M., A.S., I.A.W., and W.R.S. contributed edits.

C.H.-D., S.C. wrote the manuscript.

We thank the La Jolla Institute (LJI) Flow Cytometry Core for expert cell sorting assistance.

We thank the LJI Sequencing Core, as well as J. Ashton and his team at the Genomics Research Center, University of Rochester, for single cell RNA sequencing.

We thank J. Jardine, B. Dekosky, and G. Georgiou for early assistance with this project.

IAVI and the Scripps Research Institute have filed a patent relating to the eOD-GT8 immunogens in this manuscript, which included inventors D.W.K. and W.R.S.

W.R.S. is a cofounder and stockholder in CompuVax Inc., which has programs in non-HIV vaccine design that might benefit indirectly from this research.

Subject:

Research Funding:

This work was supported by NIH National Institute of Allergy and Infectious Disease (NIAID)UM1 AI100663 (Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery) (to S.C., W.R.S., I.A.W., and J.C.P.), NIAID R01 Al113867 (to J.C.P and W.R.S.), and NIAID U24 Al120134 (to S.E.B.); by the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Consortium and Center (NAC) (to W.R.S. and I.A.W.) and through The Collaboration for AIDS Vaccine Discovery (CAVD) funding for the IAVI NAC Center (W.R.S., I.A.W.).

IAVI’s work is made possible by generous support from 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 UK Department for International Development (DFID), and the U.S. Agency for International Development (USAID).

The full list of IAVI donors is available at http://www.iavi.org.

The NIH Office of the Director supported purchase of a BD FACSAria II (NIH S10RR027366) and an Illumina HiSeq 2500 (NIH S10OD016262).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • BROADLY NEUTRALIZING ANTIBODIES
  • IG KNOCKIN MICE
  • MASS-SPECTROMETRY
  • CD4-BINDING SITE
  • GERMINAL-CENTERS
  • STRUCTURAL BASIS
  • PAIRED HEAVY
  • DESIGN
  • REARRANGEMENTS
  • PRECURSORS

The human naive B cell repertoire contains distinct subclasses for a germline-targeting HIV-1 vaccine immunogen

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Journal Title:

Science Translational Medicine

Volume:

Volume 10, Number 448

Publisher:

, Pages eaat0381-eaat0381

Type of Work:

Article | Post-print: After Peer Review

Abstract:

No claim to original U.S. Government Works Traditional vaccine development to prevent some of the worst current pandemic diseases has been unsuccessful so far. Germline-targeting immunogens have potential to prime protective antibodies (Abs) via more targeted immune responses. Success of germline-targeting vaccines in humans will depend on the composition of the human naive B cell repertoire, including the frequencies and affinities of epitope-specific B cells. However, the human naive B cell repertoire remains largely undefined. Assessment of antigen-specific human naive B cells among hundreds of millions of B cells from multiple donors may be used as pre-phase 1 ex vivo human testing to potentially forecast B cell and Ab responses to new vaccine designs. VRC01 is an HIV broadly neutralizing Ab (bnAb) against the envelope CD4-binding site (CD4bs). We characterized naive human B cells recognizing eOD-GT8, a germline-targeting HIV-1 vaccine candidate immunogen designed to prime VRC01-class Abs. Several distinct subclasses of VRC01-class naive B cells were identified, sharing sequence characteristics with inferred precursors of known bnAbs VRC01, VRC23, PCIN63, and N6. Multiple naive B cell clones exactly matched mature VRC01-class bnAb L-CDR3 sequences. Non-VRC01-class B cells were also characterized, revealing recurrent public light chain sequences. Unexpectedly, we also identified naive B cells related to the IOMA-class CD4bs bnAb. These different subclasses within the human repertoire had strong initial affinities (KD) to the immunogen, up to 13 nM, and represent encouraging indications that multiple independent pathways may exist for vaccine-elicited VRC01-class bnAb development in most individuals. The frequencies of these distinct eOD-GT8 B cell specificities give insights into antigen-specific compositional features of the human naive B cell repertoire and provide actionable information for vaccine design and advancement.

Copyright information:

Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.

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