Targeted selection of HIV-specific antibody mutations by engineering B cell maturation

Saunders, Kevin O.; Wiehe, Kevin; Tian, Ming; Acharya, Priyamvada; Bradley, Todd; Alam, S. Munir; Go, Eden P.; Scearce, Richard M.; Sutherland, Laura L.; Henderson, Rory; Hsu, Allen; Borgnia, Mario J.; Chen, Haiyan; Lu, Xiaozhi; Wu, Nelson R.; Watts, Brian; Jiang, Chuancang; Easterhoff, David; Cheng, Hwei-Ling; McGovern, Kelly; Waddicor, Peyton; Williams, Aimée; Eaton, Amanda; Zhang, Jin Song; Rountree, Wes; Verkoczy, Laurent; Tomai, Mark A.; Lewis, Mark G.; Desaire, Heather; Edwards, Robert J.; Cain, Derek W.; Bonsignori, Mattia; Montefiori, David C.; Alt, Frederick W.; Haynes, Barton F.

doi:10.1126/science.aay7199

Cited by 134 publications

(315 citation statements)

References 95 publications

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“…In the context of a protein subunit vaccine, the ability to drive SHM remains a much larger hurdle. Another issue is that key mutations for development of breadth are not found at traditional AID hotspots and these have been coined improbable mutations that represent hurdles in bnAb development [40,41]*. Potential prime boost strategies can however "shepherd" SHM toward bnAbs, and proof-of-concept was demonstrated a number of years ago [42,43].…”

Section: Somatic Hypermutationmentioning

confidence: 99%

Innovations in structure-based antigen design and immune monitoring for next generation vaccines

Ward

Wilson

2020

Current Opinion in Immunology

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Please cite this article as: Ward AB, Wilson IA, Innovations in structure-based antigen design and immune monitoring for next generation vaccines, J o u r n a l P r e -p r o o f Highligthts Immunofocusing as a strategy for structure-based vaccine design. Structure-based vaccine design for RSV F, influenza HA, HIV-1 Env. Structure-based vaccine design translated into the clinic. AbstractThe recent explosion of atomic-level structures of glycoproteins that comprise the surface antigens of human enveloped viruses, such as RSV, influenza, hepatitis C and HIV, provide tremendous opportunities for rational, structure-based vaccine design. Several concepts in structure-based vaccine design have been put into practice and are are well along preclinical and clinical implementation. Testing of these designed immunogens will provide key insights into the ability to induce the desired immune responses, namely neutralizing antibodies. Many of these immunogens in human clinical trials represent only the first wave of designs and will likely require continued tweaking and elaboration to achieve the ultimate result of ever increasingly breadth and potency. Considerable effort is now being invested in germline targeting, epitope focusing, and improved immune presentation such as multivalent nanoparticle incorporation. This review highlights some of the recent advances in these areas as we prepare for the next generation of immunogens for subsequent rounds of iterative vaccine development.

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Section: Somatic Hypermutationmentioning

confidence: 99%

Innovations in structure-based antigen design and immune monitoring for next generation vaccines

Ward

Wilson

2020

Current Opinion in Immunology

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“…Tetramerized fluorophore-labeled HIV-1 CH848 soluble stabilized Env trimers (SOSIPs) (32), or synthetic HIV-1 Env glycopeptide (Man9-V3) (33) that mimics a V3-glycan bnAb epitope, were used to flow sort SHIV CH848TF-infected macaque lymph node memory B cells at week 52 after infection, as well as blood memory B cells at weeks 52 and 104 after infection. We isolated 173 CH848-Env reactive antibodies (Table S1), including two glycan-dependent neutralizing B cell lineages (DH851 and DH898) from lymph node and blood memory B cells at 52 and 104 weeks post-SHIV infection (Table S2).…”

Section: Shiv-induced Dh851 Fdg Bnab B Cell Lineagementioning

confidence: 99%

“…Like 2G12, DH851 mAbs bound HIV-1 CH848 SOSIP trimers (32) in a glycan-dependent manner; bound Man9-V3 glycopeptide, but not the corresponding non-glycosylated aglycone V3 peptide (33), and bound Candida albicans or Cryptococcus neoformans yeast glycans ( Figure 1C and S2C-F). Both bnAbs 2G12 and IgG DH851.2 cross-blocked each other for binding CH848TF gp120 ( Figure 1D-1E), suggesting that they bound overlapping epitopes.…”

Section: Shiv-induced Dh851 Fdg Bnab B Cell Lineagementioning

confidence: 99%

Fab-dimerized glycan-reactive antibodies neutralize HIV and are prevalent in humans and rhesus macaques

Williams

Meyerhoff

Edwards

et al. 2020

Preprint

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SummaryThe HIV-1 envelope (Env) is comprised by mass of over 50% glycans. A goal of HIV-1 vaccine development is the induction of Env glycan-reactive broadly neutralizing antibodies (bnAbs). The 2G12 bnAb recognizes an Env glycan cluster using a unique variable heavy (VH) domain-swapped conformation that results in fragment antigen-binding (Fab) dimerization. Here we describe Fab-dimerized glycan (FDG)-reactive antibodies without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques that neutralized heterologous HIV-1 isolates. FDG precursors were boosted by vaccination in macaques, and were present in HIV-1-naïve humans with an average estimated frequency of one per 340,000 B cells. These data demonstrate frequent HIV-1 Env glycan-reactive bnAb B cell precursors in macaques and humans and reveal a novel strategy for their induction by vaccination.HighlightsDiscovery of Fab-dimerized HIV-1 glycan-reactive antibodies with a non-domain-swapped architectureFab-dimerized antibodies neutralize heterologous HIV-1 isolates.Antibodies with this architecture can be elicited by vaccination in macaques.Fab-dimerized antibodies are found in HIV-1 naïve humans.

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“…The observation that bNAbs arise during natural infection in humans (10)(11)(12)(13)(14)(15)(16)(17), and that they can block SHIV infection in macaques (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28), suggests that a vaccine that elicits such antibodies would be protective. However, with the exception of genetically engineered mice (29)(30)(31), all such efforts have produced only sporadic or less than optimal results with little or no protective activity against heterologous viral strains (32,33). More importantly, it remains unclear which animal model is most relevant to test candidate vaccines.…”

Section: Introductionmentioning

confidence: 99%

A Broadly Neutralizing Macaque Monoclonal Antibody Against the HIV-1 V3-Glycan Patch

Wang

Barnes

Gautam

et al. 2020

Preprint

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A small fraction of HIV-1 infected humans develop potent broadly neutralizing antibodies (bNAbs) against HIV-1 that can protect macaques from infection with simian immunodeficiency HIV chimeric virus (SHIV). Similarly, a small number of macaques infected with SHIVs also develop broadly neutralizing serologic activity, but less is known about the nature of these simian antibodies. Here we report on a monoclonal antibody, Ab1485, isolated from a macaque infected with SHIVAD8 that developed broadly neutralizing serologic activity mapping to the V3-glycan region of HIV-1 Env. Ab1485 neutralizes 38.1 % of HIV-1 isolates in a panel of 42 pseudoviruses with a geometric mean IC50 of 0.055 μg/ml and SHIVAD8 with an IC50 of 0.028 μg/ml. Ab1485 binds to the V3-glycan epitope in a glycan-dependent manner as determined by ELISA and neutralization assays with JRCSF mutant viruses. A 3.5 Å cryo-electron microscopy structure of Ab1485 in complex with a native-like SOSIP Env trimer showed conserved contacts with the N332gp120 glycan and gp120 GDIR peptide motif, but in a distinct Env-binding orientation relative to human V3/N332gp120 glycan-targeting bNAbs. Finally, intravenous infusion of Ab1485 protected macaques from a high dose intrarectal challenge with SHIVAD8. We conclude that macaques can develop bNAbs against the V3-glycan patch that resemble human V3-glycan bNAbs.

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Targeted selection of HIV-specific antibody mutations by engineering B cell maturation

Cited by 134 publications

References 95 publications

Innovations in structure-based antigen design and immune monitoring for next generation vaccines

Innovations in structure-based antigen design and immune monitoring for next generation vaccines

Fab-dimerized glycan-reactive antibodies neutralize HIV and are prevalent in humans and rhesus macaques

A Broadly Neutralizing Macaque Monoclonal Antibody Against the HIV-1 V3-Glycan Patch

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