Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires

Tian, Ming; Cheng, Cheng; Chen, Xuejun; Duan, Hongying; Cheng, Hwei-Ling; Dao, Mai N.; Sheng, Zizhang; Kimble, Michael T; Wang, Lingshu; Lin, Sherry; Schmidt, Stephen D.; Du, Zhou; Joyce, Michael; Chen, Yiwei; DeKosky, Brandon J.; Chen, Yimin; Normandin, Erica; Cantor, Elizabeth; Chen, Rita E.; Doria‐Rose, Nicole A.; Zhang, Yi; Shi, Wei; Kong, Wing-Pui; Choe, Misook; Henry, Amy R.; Laboune, Farida; Georgiev, Ivelin S.; Huang, Peng; Jain, Suvi; McGuire, Andrew T.; Georgeson, Eric; Menis, Sergey; Douek, Daniel C.; Schief, William R.; Stamatatos, Leonidas; Kwong, Peter D.; Shapiro, Lawrence; Haynes, Barton F.; Mascola, John R.; Alt, Frederick W.

doi:10.1016/j.cell.2016.07.029

Cited by 217 publications

(339 citation statements)

References 41 publications

Supporting

Mentioning

329

Contrasting

Order By: Relevance

“…In addition, these eOD-GT8 primed responses displayed accumulation of somatic hypermutation along the VRC01-class maturation pathway. However, the lack of tier 2 neutralizing activity by these responses relied on their inability to tolerate the N276 glycan [add refs 32 and 33]. Trimeric boosting immunogens with increasing glycan complexity have been proposed to overcome the N267 hurdle to neutralization.…”

Section: Approaches To Design Immunogens Capable Of Inducing Hiv Bnabsmentioning

confidence: 99%

“…Although, eOD-GT8 immunogen can effectively prime the VRC01-like B cell precursors in appropriate animal models, its ability to select these germline B cell precursors varied substantially across different model systems [29–32]. 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].…”

Section: Approaches To Design Immunogens Capable Of Inducing Hiv Bnabsmentioning

confidence: 99%

“…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].…”

Section: Approaches To Design Immunogens Capable Of Inducing Hiv Bnabsmentioning

confidence: 99%

“…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. [32,33]. Based on these animal studies the eDO-GT8 priming immunogen will be tested in a Phase I clinical trial in 2018 to assess its ability to select VRC01-like precursors in humans.…”

Section: Approaches To Design Immunogens Capable Of Inducing Hiv Bnabsmentioning

confidence: 99%

“…Significant progress has been made over the past few years in the generation of immunoglobulin (Ig) knock-in (KI) mouse models that express the pre-rearranged V(D)J-encoding inferred germline genes of HIV bnAbs precursors to evaluate candidate immunogens (Figure 2A) [29,30,32,37,47]. Much of this activity has focused on VRC01-bnAb germline-KI models, but expansion to other bnAb precursors is in progress [37,48].…”

Section: Development Of Animal Models For Vaccine Evaluationmentioning

confidence: 99%

See 4 more Smart Citations

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

Andrabi

Bhiman

Burton

2018

Current Opinion in Immunology

102

100

View full text Add to dashboard Cite

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.

show abstract

Section: Approaches To Design Immunogens Capable Of Inducing Hiv Bnabsmentioning

confidence: 99%

Section: Approaches To Design Immunogens Capable Of Inducing Hiv Bnabsmentioning

confidence: 99%

Section: Approaches To Design Immunogens Capable Of Inducing Hiv Bnabsmentioning

confidence: 99%

Section: Approaches To Design Immunogens Capable Of Inducing Hiv Bnabsmentioning

confidence: 99%

Section: Development Of Animal Models For Vaccine Evaluationmentioning

confidence: 99%

See 3 more Smart Citations

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

Andrabi

Bhiman

Burton

2018

Current Opinion in Immunology

102

100

View full text Add to dashboard Cite

show abstract

Glycosylation as a tool for rational vaccine design

Hariharan

Kane

2020

Biotech & Bioengineering

View full text Add to dashboard Cite

The discovery of broadly neutralizing antibodies that can neutralize multiple strains or subtypes of a pathogen has renewed interest in the development of broadly protective vaccines. To that end, there has been an interest in designing immunofocusing strategies to direct the immune response to specific, conserved regions on antigenic proteins. Modulation of glycosylation is one such immunofocusing strategy; extensive glycosylation is often exploited by pathogens for immune evasion. Masking epitopes on protein immunogens with “self” glycans can also shield the underlying protein surface from humoral immune surveillance. We review recent advances in applying glycosylation as an immunofocusing tool. We also highlight recent interesting work in the HIV‐1 field involving the identification and elicitation of broadly neutralizing antibodies that incorporate glycans into their binding epitopes.

show abstract

Strategies for induction of HIV‐1 envelope‐reactive broadly neutralizing antibodies

et al. 2021

Self Cite

View full text Add to dashboard Cite

IntroductionA primary focus of HIV‐1 vaccine development is the activation of B cell receptors for naïve or precursor broadly neutralizing antibodies (bnAbs), followed by expansion and maturation of bnAb B cell lineage intermediates leading to highly affinity‐matured bnAbs. HIV‐1 envelope (Env) encodes epitopes for bnAbs of different specificities. Design of immunogens to induce bnAb precursors of different specificities and mature them into bnAb status is a goal for HIV‐1 vaccine development. We review vaccine strategies for bnAb lineages development and highlight the immunological barriers that these strategies must overcome to generate bnAbs.MethodsWe provide perspectives based on published research articles and reviews.DiscussionThe recent Antibody Mediated Protection (AMP) trial that tested the protective efficacy of one HIV‐1 Env bnAb specificity demonstrated that relatively high levels of long‐lasting serum titers of multiple specificities of bnAbs will be required for protection from HIV‐1 transmission. Current vaccine efforts for induction of bnAb lineages are focused on immunogens designed to expand naïve HIV‐1 bnAb precursor B cells following the recent success of vaccine‐induction of bnAb precursor B cells in macaques and humans. BnAb precursor B cells serve as templates for priming‐immunogen design. However, design of boosting immunogens for bnAb maturation requires knowledge of the optimal immunogen design and immunological environment for bnAb B cell lineage affinity maturation. BnAb lineages acquire rare genetic changes as mutations during B cell maturation. Moreover, the immunological environment that supports bnAb development during HIV‐1 infection is perturbed with an altered B cell repertoire and dysfunctional immunoregulatory controls, suggesting that in normal settings, bnAb development will be disfavoured. Thus, strategies for vaccine induction of bnAbs must circumvent immunological barriers for bnAb development that normally constrain bnAb B cell affinity maturation.ConclusionsA fully protective HIV‐1 vaccine needs to induce durable high titers of bnAbs that can be generated by a sequential set of Env immunogens for expansion and maturation of bnAb B cell lineages in a permitted immunological environment. Moreover, multiple specificities of bnAbs will be required to be sufficiently broad to prevent the escape of HIV‐1 strains during transmission.

show abstract

Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires

Cited by 217 publications

References 41 publications

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

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

Glycosylation as a tool for rational vaccine design

Strategies for induction of HIV‐1 envelope‐reactive broadly neutralizing antibodies

Contact Info

Product

Resources

About