Priming HIV-1 broadly neutralizing antibody precursors in human Ig loci transgenic mice

Sok, Devin; Briney, Bryan; Jardine, Joseph G.; Kulp, Daniel W.; Menis, Sergey; Pauthner, Matthias; Wood, Andrew L.; Lee, E-Chiang; Le, Khoa; Jones, Meaghan; Ramos, Alejandra; Kalyuzhniy, Oleksandr; Adachi, Yumiko; Kubitz, Michael; MacPherson, Skye; Bradley, Allan; Friedrich, Glenn A.; Schief, William R.; Burton, Dennis R.

doi:10.1126/science.aah3945

Cited by 152 publications

(209 citation statements)

References 48 publications

(67 reference statements)

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“…Avi-tagged eOD-GT8 and eOD-GT8 KO2 monomers were biotinylated and purified (13). For simplicity, eOD-GT8 KO2 is referred to as eOD-GT8-KO in the main text and figures.…”

Section: Methodsmentioning

confidence: 99%

“…Initiating a clinical trial is an expensive and time-consuming process. Although human immunoglobulin (Ig) transgenic mice (such as Kymab mice) are one alternative, their BCR repertoire can be quite different from humans; for example, the frequency of VRC01-class naive B cells is 150- to 900-fold lower in these mice compared to humans (13). We have developed strategies to query the naive B cell repertoire directly in humans to identify antigen-specific and epitope-specific B cells.…”

Section: Introductionmentioning

confidence: 99%

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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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“…Avi-tagged eOD-GT8 and eOD-GT8 KO2 monomers were biotinylated and purified (13). For simplicity, eOD-GT8 KO2 is referred to as eOD-GT8-KO in the main text and figures.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

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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“…While eOD-GT8 was most effective in the VRC01 GL KI mouse model, its ability to engage 3BNC60 germline expressing mouse BCRs was substantially lower and even weaker still in more competitive polyclonal mouse B cell immune systems that express either germline VH1-2*02 (excluding the CDRH3) or the entire human heavy chain Ig locus KI mouse models [31,32]. For example, in the human Ig transgenic mouse model (KymAb), a single immunization with eOD-GT8 revealed selection of only 1% of epitope specific VRC01-like B cell precursors of the total eOD-GT8 binders [31]. The variable efficiency of eOD-GT8 to engage VRC01-like B cell precursors from different animal models could be attributed to various factors including, its diverse affinity for VRC01 GLs and differences in the frequencies of appropriate precursors compared to off-target B cells.…”

Section: Approaches To Design Immunogens Capable Of Inducing Hiv Bnabsmentioning

confidence: 99%

“…Nevertheless, precursor B cell adoptive transfers into wild-type animal models can provide models that more closely resemble those anticipated in humans and can provide estimates of the affinities of immunogens that may be required to trigger appropriate B cell lineages [49]. In addition, animal models with more complete human BCR repertoire diversity have been employed to assess the ability of germline-targeting immunogens to select appropriate precursors [31]. …”

Section: Development Of Animal Models For Vaccine Evaluationmentioning

confidence: 99%

“…It then becomes crucial to monitor progress at individual stages in the immunization strategy. Single B cell Ab isolation and next generation sequencing (NGS) of B cell expressed Ig transcripts made possible with the emergence of high-throughput sequencing platforms such as Illumina, have enabled the identification of the origin of B cell lineages and trace their development during affinity maturation in natural infection and in vaccination [3,6,31,33,42,51,52]. …”

Section: Technological Innovations To Interrogate Immune Responsesmentioning

confidence: 99%

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Strategies for a multi-stage neutralizing antibody-based HIV vaccine

Andrabi

Bhiman

Burton

2018

Current Opinion in Immunology

101

100

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A critical property of a prophylactic HIV vaccine is likely to be its ability to elicit broadly neutralizing antibodies (bnAbs). BnAbs typically have multiple unusual features and are generated in a fraction of HIV-infected individuals through complex pathways. Current vaccine design approaches seek to trigger quite rare B cell precursors and then steer affinity maturation toward bnAbs in a multi-stage multi-component immunization approach. These vaccine design strategies have been facilitated by molecular descriptions of bnAb interactions with stabilized HIV trimers, the use of an array of sophisticated approaches for immunogen design, the development of novel animal models for immunogen evaluation and advanced technologies to interrogate Ab responses. In this review, we will discuss leading HIV bnAb vaccine immunogens, immunization strategies and future improvements.

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HIV Vaccine Approaches

Kent

2017

Encyclopedia of Life Sciences

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An HIV (human immunodeficiency virus) vaccine is needed to combat the 1–2 million cases on new HIV infection each year. The goal of vaccination is to establish long‐term immunological readiness that allows rapid protection against infectious disease. All current successful vaccines achieve this by inducing neutralising antibodies, which are effective against acute, cytopathic infections that could otherwise prove fatal. By contrast, potential vaccines against highly variable pathogens that establish persistent infections, such as HIV, have had limited success. There have been multiple attempts to induce effective immunity to HIV in humans, with only one approach showing partial (31%) efficacy. Several clues on a better path forward have, however, emerged from HIV vaccine trials in humans, studies of humans who naturally control HIV infection and studies in animal models. There has been an improved understanding of anti‐HIV neutralising antibodies, which, if could be induced successfully, are likely to be highly effective. Antibodies that engage Fc receptors on innate immune cells (the so‐called ADCC (antibody‐dependent cellular cytotoxicity) antibodies) have emerged as a key component of successful vaccine strategies. New vaccine design and delivery strategies are now entering large‐scale human efficacy trials. These approaches offer real hope that a safe and effective HIV vaccine will eventually be developed to assist in the control of the HIV/AIDS (acquired immunodeficiency syndrome) pandemic. Key Concepts A HIV vaccine is urgently needed. There are many hurdles to induce effective HIV immunity. Only one HIV vaccine trial in humans has showed partial efficacy to date. Neutralising antibodies against HIV are highly effective in animal models but are difficult to induce by vaccination. Functional anti‐HIV antibodies that can engage innate immune cells to fight HIV are likely to be a key component of successful HIV vaccine strategies. T‐cell‐based immunity against HIV shows promise in certain settings. New HIV vaccines are entering human efficacy trials. There is considerable promise that an effective HIV vaccine will be developed in the future.

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Priming HIV-1 broadly neutralizing antibody precursors in human Ig loci transgenic mice

Cited by 152 publications

References 48 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

Strategies for a multi-stage neutralizing antibody-based HIV vaccine

HIV Vaccine Approaches

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