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

Havenar-Daughton, Colin; Sarkar, Anita; Kulp, Daniel W.; Toy, Laura; Hu, Xiaozhen; Deresa, Isaiah; Kalyuzhniy, Oleksandr; Kaushik, Kirti; Upadhyay, Amit A.; Menis, Sergey; Landais, Elise; Cao, Liwei; Diedrich, Jolene K.; Kumar, Sonu; Schiffner, Torben; Reiss, Samantha M.; Seumois, Grégory; Yates, John R.; Paulson, James C.; Bosinger, Steven E.; Wilson, Ian A.; Schief, William R.; Crotty, Shane

doi:10.1126/scitranslmed.aat0381

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

Journal Article · Wed Jul 04 00:00:00 EDT 2018 · Science Translational Medicine

DOI:https://doi.org/10.1126/scitranslmed.aat0381· OSTI ID:1499777

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La Jolla Inst. for Allergy and Immunology, CA (United States); The Scripps Research Inst., La Jolla, CA (United States)
The Scripps Research Inst., La Jolla, CA (United States)
The Scripps Research Inst., La Jolla, CA (United States); The Wistar Inst., Philadelphia, PA (United States)
La Jolla Inst. for Allergy and Immunology, CA (United States)
Emory Univ., Atlanta, GA (United States)
The Scripps Research Inst., La Jolla, CA (United States); Ragon Inst., Cambridge, MA (United States)
La Jolla Inst. for Allergy and Immunology, CA (United States); The Scripps Research Inst., La Jolla, CA (United States); Univ. of San Diego, La Jolla, CA (United States)

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). In this work, 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC); National Institute of Allergy and Infectious Diseases (NIAID); International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Consortium (NAC) and Center; Collaboration for AIDS Vaccine Discovery; Bill & Melinda Gates Foundation; Ministry of Foreign Affairs of Denmark; Irish Aid; Ministry of Finance of Japan; The World Bank; Ministry of Foreign Affairs of the Netherlands; Norwegian Agency for Development Cooperation (NORAD); UK Department for International Development (DFID); US Agency for International Development (USAID)

Grant/Contract Number:: UM1 AI100663; NIAID R01 Al113867; NIAID U24 Al120134

OSTI ID:: 1499777

Journal Information:: Science Translational Medicine, Vol. 10, Issue 448; ISSN 1946-6234

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 80 works

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