6 results on '"Graham, Barney S."'
Search Results
2. Rational Design of an Epstein-Barr Virus Vaccine Targeting the Receptor-Binding Site.
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Kanekiyo, Masaru, Bu, Wei, Joyce, M. Gordon, Meng, Geng, Whittle, James R.R., Baxa, Ulrich, Yamamoto, Takuya, Narpala, Sandeep, Todd, John-Paul, Rao, Srinivas S., McDermott, Adrian B., Koup, Richard A., Rossmann, Michael G., Mascola, John R., Graham, Barney S., Cohen, Jeffrey I., and Nabel, Gary J.
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EPSTEIN-Barr virus , *VIRAL vaccines , *TARGETED drug delivery , *BINDING sites , *CELL receptors - Abstract
Summary Epstein-Barr virus (EBV) represents a major global health problem. Though it is associated with infectious mononucleosis and ∼200,000 cancers annually worldwide, a vaccine is not available. The major target of immunity is EBV glycoprotein 350/220 (gp350) that mediates attachment to B cells through complement receptor 2 (CR2/CD21). Here, we created self-assembling nanoparticles that displayed different domains of gp350 in a symmetric array. By focusing presentation of the CR2-binding domain on nanoparticles, potent neutralizing antibodies were elicited in mice and non-human primates. The structurally designed nanoparticle vaccine increased neutralization 10- to 100-fold compared to soluble gp350 by targeting a functionally conserved site of vulnerability, improving vaccine-induced protection in a mouse model. This rational approach to EBV vaccine design elicited potent neutralizing antibody responses by arrayed presentation of a conserved viral entry domain, a strategy that can be applied to other viruses. PaperClip [ABSTRACT FROM AUTHOR]
- Published
- 2015
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3. Structural Basis for Potent Neutralization of Betacoronaviruses by Single-Domain Camelid Antibodies.
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Wrapp, Daniel, De Vlieger, Dorien, Corbett, Kizzmekia S., Torres, Gretel M., Wang, Nianshuang, Van Breedam, Wander, Roose, Kenny, van Schie, Loes, Hoffmann, Markus, Pöhlmann, Stefan, Graham, Barney S., Callewaert, Nico, Schepens, Bert, Saelens, Xavier, and McLellan, Jason S.
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CELL receptors , *SARS-CoV-2 , *COVID-19 , *IMMUNOGLOBULINS , *MEMBRANE fusion , *BETACORONAVIRUS - Abstract
Coronaviruses make use of a large envelope protein called spike (S) to engage host cell receptors and catalyze membrane fusion. Because of the vital role that these S proteins play, they represent a vulnerable target for the development of therapeutics. Here, we describe the isolation of single-domain antibodies (VHHs) from a llama immunized with prefusion-stabilized coronavirus spikes. These VHHs neutralize MERS-CoV or SARS-CoV-1 S pseudotyped viruses, respectively. Crystal structures of these VHHs bound to their respective viral targets reveal two distinct epitopes, but both VHHs interfere with receptor binding. We also show cross-reactivity between the SARS-CoV-1 S-directed VHH and SARS-CoV-2 S and demonstrate that this cross-reactive VHH neutralizes SARS-CoV-2 S pseudotyped viruses as a bivalent human IgG Fc-fusion. These data provide a molecular basis for the neutralization of pathogenic betacoronaviruses by VHHs and suggest that these molecules may serve as useful therapeutics during coronavirus outbreaks. • VHHs isolated from a llama immunized with prefusion-stabilized coronavirus spikes • Structural characterization of VHHs reveals conserved mechanism of neutralization • SARS-CoV-1 S-directed VHH cross-reacts with SARS-CoV-2 S • Bivalent VHH neutralizes SARS-CoV-2 pseudoviruses Using llamas immunized with prefusion-stabilized betacoronavirus spike proteins, Wrapp et al. identify neutralizing cross-reactive single-domain camelid antibodies, which may serve not only as useful reagents for researchers studying the viruses causing MERS, SARS, and COVID-19, but also potential therapeutic candidates. Crystal structures further reveal how these antibodies bind spike proteins to prevent virus entry into cells. [ABSTRACT FROM AUTHOR]
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- 2020
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4. High-Throughput Mapping of B Cell Receptor Sequences to Antigen Specificity.
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Setliff, Ian, Shiakolas, Andrea R., Pilewski, Kelsey A., Murji, Amyn A., Mapengo, Rutendo E., Janowska, Katarzyna, Richardson, Simone, Oosthuysen, Charissa, Raju, Nagarajan, Ronsard, Larance, Kanekiyo, Masaru, Qin, Juliana S., Kramer, Kevin J., Greenplate, Allison R., McDonnell, Wyatt J., Graham, Barney S., Connors, Mark, Lingwood, Daniel, Acharya, Priyamvada, and Morris, Lynn
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B cell receptors , *ANTIGEN receptors , *HIV antibodies , *B cells , *IMMUNE response , *VACCINE effectiveness - Abstract
B cell receptor (BCR) sequencing is a powerful tool for interrogating immune responses to infection and vaccination, but it provides limited information about the antigen specificity of the sequenced BCRs. Here, we present LIBRA-seq (linking B cell receptor to antigen specificity through sequencing), a technology for high-throughput mapping of paired heavy- and light-chain BCR sequences to their cognate antigen specificities. B cells are mixed with a panel of DNA-barcoded antigens so that both the antigen barcode(s) and BCR sequence are recovered via single-cell next-generation sequencing. Using LIBRA-seq, we mapped the antigen specificity of thousands of B cells from two HIV-infected subjects. The predicted specificities were confirmed for a number of HIV- and influenza-specific antibodies, including known and novel broadly neutralizing antibodies. LIBRA-seq will be an integral tool for antibody discovery and vaccine development efforts against a wide range of antigen targets. • LIBRA-seq: high-throughput mapping of BCR sequence to antigen specificity • Identified HIV- and influenza-specific B cells in two HIV-infected subjects • Predicted antigen reactivity for thousands of single B cells • Identified a previously unknown broadly neutralizing HIV antibody LIBRA-seq enables high-throughput mapping of B cell receptor sequence to antigen specificity at the single-cell level. [ABSTRACT FROM AUTHOR]
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- 2019
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5. Fc Glycan-Mediated Regulation of Placental Antibody Transfer.
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Jennewein, Madeleine F., Goldfarb, Ilona, Dolatshahi, Sepideh, Cosgrove, Cormac, Noelette, Francesca J., Krykbaeva, Marina, Das, Jishnu, Sarkar, Aniruddh, Gorman, Matthew J., Fischinger, Stephanie, Boudreau, Carolyn M., Brown, Joelle, Cooperrider, Jennifer H., Aneja, Jasneet, Suscovich, Todd J., Graham, Barney S., Lauer, Georg M., Goetghebuer, Tessa, Marchant, Arnaud, and Lauffenburger, Douglas
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MATERNALLY acquired immunity , *KILLER cells , *IMMUNE complexes , *IMMUNOGLOBULINS , *IMMUNE system , *IMMUNE response - Abstract
Despite the worldwide success of vaccination, newborns remain vulnerable to infections. While neonatal vaccination has been hampered by maternal antibody-mediated dampening of immune responses, enhanced regulatory and tolerogenic mechanisms, and immune system immaturity, maternal pre-natal immunization aims to boost neonatal immunity via antibody transfer to the fetus. However, emerging data suggest that antibodies are not transferred equally across the placenta. To understand this, we used systems serology to define Fc features associated with antibody transfer. The Fc-profile of neonatal and maternal antibodies differed, skewed toward natural killer (NK) cell-activating antibodies. This selective transfer was linked to digalactosylated Fc-glycans that selectively bind FcRn and FCGR3A, resulting in transfer of antibodies able to efficiently leverage innate immune cells present at birth. Given emerging data that vaccination may direct antibody glycosylation, our study provides insights for the development of next-generation maternal vaccines designed to elicit antibodies that will most effectively aid neonates. • NK cell-activating antibodies are selectively transferred across the placenta • Digalactosylated Fc glycans are preferentially transferred across the placenta • Digalactosylated antibodies bind more effectively to FcRn and FCGR3A • Although immature, neonatal NK cells are highly responsive to immune complexes Antibodies with a specific glycan modification and with the ability to activate NK cells are selectively transferred across the placenta to the neonate. [ABSTRACT FROM AUTHOR]
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- 2019
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6. Cross-Neutralizing and Protective Human Antibody Specificities to Poxvirus Infections.
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Gilchuk, Iuliia, Gilchuk, Pavlo, Sapparapu, Gopal, Lampley, Rebecca, Singh, Vidisha, Kose, Nurgun, Blum, David L., Hughes, Laura J., Satheshkumar, Panayampalli S., Townsend, Michael B., Kondas, Ashley V., Reed, Zachary, Weiner, Zachary, Olson, Victoria A., Hammarlund, Erika, Raue, Hans-Peter, Slifka, Mark K., Slaughter, James C., Graham, Barney S., and Edwards, Kathryn M.
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POXVIRUS diseases , *ANTIBODY specificity , *CROSS reactions (Immunology) , *BIOTERRORISM , *VACCINIA diseases , *MONOCLONAL antibodies , *MONKEYPOX , *PREVENTION , *IMMUNOLOGY - Abstract
Summary Monkeypox (MPXV) and cowpox (CPXV) are emerging agents that cause severe human infections on an intermittent basis, and variola virus (VARV) has potential for use as an agent of bioterror. Vaccinia immune globulin (VIG) has been used therapeutically to treat severe orthopoxvirus infections but is in short supply. We generated a large panel of orthopoxvirus-specific human monoclonal antibodies (Abs) from immune subjects to investigate the molecular basis of broadly neutralizing antibody responses for diverse orthopoxviruses. Detailed analysis revealed the principal neutralizing antibody specificities that are cross-reactive for VACV, CPXV, MPXV, and VARV and that are determinants of protection in murine challenge models. Optimal protection following respiratory or systemic infection required a mixture of Abs that targeted several membrane proteins, including proteins on enveloped and mature virion forms of virus. This work reveals orthopoxvirus targets for human Abs that mediate cross-protective immunity and identifies new candidate Ab therapeutic mixtures to replace VIG. [ABSTRACT FROM AUTHOR]
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- 2016
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