Tailored Immunogens Direct Affinity Maturation toward HIV Neutralizing Antibodies

Briney, Bryan; Sok, Devin; Jardine, Joseph G.; Kulp, Daniel W.; Skog, Patrick; Menis, Sergey; Jacak, Ronald; Kalyuzhniy, Oleksandr; Val, Natalia de; Sesterhenn, Fabian; Le, Khoa; Ramos, Alejandra; Jones, Meaghan; Saye-Francisco, Karen L.; Blane, Tanya R.; Spencer, Skye; Georgeson, Erik; Hu, Xiaozhen; Ozorowski, Gabriel; Adachi, Yumiko; Kubitz, Michael; Sarkar, Achyut; Wilson, Ian A.; Ward, Andrew B.; Nemazee, David; Burton, Dennis R.; Schief, William R.

doi:10.1016/j.cell.2016.08.005

Cited by 236 publications

(311 citation statements)

References 69 publications

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“…Encouragingly, many parallel results are found between the mouse immunization models and human repertoire analysis; VH1-2 + naive B cells expressing a 5 aa L-CDR3 bind to eOD-GT8 (6, 13, 16). In additional, both in vivo mouse experiments and direct screening of human B cells found eOD-GT8-specific VH1-2 + HCs paired with LCs using V genes of known VRC01-class bnAbs (13) and L-CDR3 sequences showing selection for the QQYxx motif used by VRC01-class bnAbs (6, 11, 13). Although VRC01-class responding cells were rare in Kymab mice, PCIN63-subclass, VRC23-subclass, and N6-subclass B cells were all found in the Kymab model (13), similar to the subclasses identified in the naive human B cell repertoire.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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One Sentence Summary: Inspection of the naive B cell repertoire specific for an HIV vaccine immunogen provides actionable information for human vaccine design and advancement. 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 I 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 Env 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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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“…103 Furthermore, administration of boosting immunogens (BG505 core-GT3 nanoparticle (NP) and BG505 SOSIP-GT3 trimer) drove the maturation of eOD-GT8 60-mer primed B cells toward VRC01-class bnAb and induced broad neutralization of near-native (N276A) viruses and weak neutralization of a fully native virus in VRC01 gH mice. 104 These data showed that B-cell lineage vaccine design has the potential to induce bnAb.…”

Section: Eliciting Broadly Neutralizing Antibodies Through Immunizationmentioning

confidence: 95%

Progress in HIV vaccine development

Hsu

O’Connell

2017

Human Vaccines & Immunotherapeutics

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“…However, apart from this example (77), it has been observed that, some early bnAb family members can only neutralize in the absence of specific glycan sites proximal to their epitopes. Such glycan shields are then tolerated by the related fully matured bnAbs (78,79). In summary, the large body of work on bnAb lineages to date has provided clues as to how breadth develops, and the significance of the glycan shield in restricting neutralization breadth.…”

Section: How Do Bnabs Develop During Infection?mentioning

confidence: 99%

Lessons learned from humoral responses of HIV patients

McCoy

2017

Current Opinion in HIV and AIDS

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Tailored Immunogens Direct Affinity Maturation toward HIV Neutralizing Antibodies

Cited by 236 publications

References 69 publications

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

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

Progress in HIV vaccine development

Lessons learned from humoral responses of HIV patients

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