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Analysis of a Therapeutic Antibody Cocktail Reveals Determinants for Cooperative and Broad Ebolavirus Neutralization.
Gilchuk P, Murin CD, Milligan JC, Cross RW, Mire CE, Ilinykh PA, Huang K, Kuzmina N, Altman PX, Hui S, Gunn BM, Bryan AL, Davidson E, Doranz BJ, Turner HL, Alkutkar T, Flinko R, Orlandi C, Carnahan R, Nargi R, Bombardi RG, Vodzak ME, Li S, Okoli A, Ibeawuchi M, Ohiaeri B, Lewis GK, Alter G, Bukreyev A, Saphire EO, Geisbert TW, Ward AB, Crowe JE
(2020) Immunity 52: 388-403.e12
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Cell Line, Disease Models, Animal, Drug Therapy, Combination, Ebolavirus, Epitopes, Female, Glycoproteins, Hemorrhagic Fever, Ebola, Humans, Immunoglobulin Fab Fragments, Macaca mulatta, Male, Mice, Mice, Inbred BALB C, Molecular Mimicry, Protein Conformation
Show Abstract · Added March 31, 2020
Structural principles underlying the composition of protective antiviral monoclonal antibody (mAb) cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a therapeutic mAb cocktail against Ebola virus. We systematically analyzed the antibody repertoire in human survivors and identified a pair of potently neutralizing mAbs that cooperatively bound to the ebolavirus glycoprotein (GP). High-resolution structures revealed that in a two-antibody cocktail, molecular mimicry was a major feature of mAb-GP interactions. Broadly neutralizing mAb rEBOV-520 targeted a conserved epitope on the GP base region. mAb rEBOV-548 bound to a glycan cap epitope, possessed neutralizing and Fc-mediated effector function activities, and potentiated neutralization by rEBOV-520. Remodeling of the glycan cap structures by the cocktail enabled enhanced GP binding and virus neutralization. The cocktail demonstrated resistance to virus escape and protected non-human primates (NHPs) against Ebola virus disease. These data illuminate structural principles of antibody cooperativity with implications for development of antiviral immunotherapeutics.
Copyright © 2020 Elsevier Inc. All rights reserved.
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20 MeSH Terms
Identification and Characterization of Unique Neutralizing Antibodies to Mouse EGF Receptor.
Jae Huh W, Niitsu H, Carney B, McKinley ET, Houghton JL, Coffey RJ
(2020) Gastroenterology 158: 1500-1502
MeSH Terms: Animals, Antibodies, Monoclonal, Humanized, Antibodies, Neutralizing, Azoxymethane, Carcinogens, Cells, Cultured, Colonic Neoplasms, Dextran Sulfate, Disease Models, Animal, ErbB Receptors, Gastritis, Hypertrophic, Genes, Reporter, Hepatocytes, Humans, Mice, Mice, Transgenic, Primary Cell Culture
Added January 31, 2020
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17 MeSH Terms
Mechanism of differential Zika and dengue virus neutralization by a public antibody lineage targeting the DIII lateral ridge.
Zhao H, Xu L, Bombardi R, Nargi R, Deng Z, Errico JM, Nelson CA, Dowd KA, Pierson TC, Crowe JE, Diamond MS, Fremont DH
(2020) J Exp Med 217:
MeSH Terms: Aedes, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Cell Line, Tumor, Chlorocebus aethiops, Cross Reactions, Crystallography, X-Ray, Dengue, Dengue Virus, Epitopes, HEK293 Cells, Humans, Hydrogen Bonding, Immunoglobulin Fab Fragments, Protein Binding, Protein Conformation, Protein Domains, Vero Cells, Viral Envelope Proteins, Zika Virus, Zika Virus Infection
Show Abstract · Added March 31, 2020
We previously generated a panel of human monoclonal antibodies (mAbs) against Zika virus (ZIKV) and identified one, ZIKV-116, that shares germline usage with mAbs identified in multiple donors. Here we show that ZIKV-116 interferes with ZIKV infection at a post-cellular attachment step by blocking viral fusion with host membranes. ZIKV-116 recognizes the lateral ridge of envelope protein domain III, with one critical residue varying between the Asian and African strains responsible for differential binding affinity and neutralization potency (E393D). ZIKV-116 also binds to and cross-neutralizes some dengue virus serotype 1 (DENV1) strains, with genotype-dependent inhibition explained by variation in a domain II residue (R204K) that potentially modulates exposure of the distally located, partially cryptic epitope. The V-J reverted germline configuration of ZIKV-116 preferentially binds to and neutralizes an Asian ZIKV strain, suggesting that this epitope may optimally induce related B cell clonotypes. Overall, these studies provide a structural and molecular mechanism for a cross-reactive mAb that uniquely neutralizes ZIKV and DENV1.
© 2019 Zhao et al.
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23 MeSH Terms
Influenza H7N9 Virus Neuraminidase-Specific Human Monoclonal Antibodies Inhibit Viral Egress and Protect from Lethal Influenza Infection in Mice.
Gilchuk IM, Bangaru S, Gilchuk P, Irving RP, Kose N, Bombardi RG, Thornburg NJ, Creech CB, Edwards KM, Li S, Turner HL, Yu W, Zhu X, Wilson IA, Ward AB, Crowe JE
(2019) Cell Host Microbe 26: 715-728.e8
MeSH Terms: Animals, Antibodies, Heterophile, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Birds, Epitopes, Humans, Influenza A Virus, H7N9 Subtype, Influenza Vaccines, Influenza in Birds, Influenza, Human, Mice, Neuraminidase, Orthomyxoviridae Infections, Pre-Exposure Prophylaxis, Vaccination, Vaccines, Inactivated, Viral Proteins, Virus Release
Show Abstract · Added March 31, 2020
H7N9 avian influenza virus causes severe infections and might have the potential to trigger a major pandemic. Molecular determinants of human humoral immune response to N9 neuraminidase (NA) proteins, which exhibit unusual features compared with seasonal influenza virus NA proteins, are ill-defined. We isolated 35 human monoclonal antibodies (mAbs) from two H7N9 survivors and two vaccinees. These mAbs react to NA in a subtype-specific manner and recognize diverse antigenic sites on the surface of N9 NA, including epitopes overlapping with, or distinct from, the enzyme active site. Despite recognizing multiple antigenic sites, the mAbs use a common mechanism of action by blocking egress of nascent virions from infected cells, thereby providing an antiviral prophylactic and therapeutic protection in vivo in mice. Studies of breadth, potency, and diversity of antigenic recognition from four subjects suggest that vaccination with inactivated adjuvanted vaccine induce NA-reactive responses comparable to that of H7N9 natural infection.
Copyright © 2019 Elsevier Inc. All rights reserved.
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20 MeSH Terms
Structural Basis of Protection against H7N9 Influenza Virus by Human Anti-N9 Neuraminidase Antibodies.
Zhu X, Turner HL, Lang S, McBride R, Bangaru S, Gilchuk IM, Yu W, Paulson JC, Crowe JE, Ward AB, Wilson IA
(2019) Cell Host Microbe 26: 729-738.e4
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Antiviral Agents, Cryoelectron Microscopy, Epitopes, Humans, Influenza A Virus, H7N9 Subtype, Influenza Vaccines, Neuraminidase, Orthomyxoviridae Infections, Viral Proteins
Show Abstract · Added March 31, 2020
Influenza virus neuraminidase (NA) is a major target for small-molecule antiviral drugs. Antibodies targeting the NA surface antigen could also inhibit virus entry and egress to provide host protection. However, our understanding of the nature and range of target epitopes is limited because of a lack of human antibody structures with influenza neuraminidase. Here, we describe crystal and cryogenic electron microscopy (cryo-EM) structures of NAs from human-infecting avian H7N9 viruses in complex with five human anti-N9 antibodies, systematically defining several antigenic sites and antibody epitope footprints. These antibodies either fully or partially block the NA active site or bind to epitopes distant from the active site while still showing neuraminidase inhibition. The inhibition of antibodies to NAs was further analyzed by glycan array and solution-based NA activity assays. Together, these structural studies provide insights into protection by anti-NA antibodies and templates for the development of NA-based influenza virus vaccines and therapeutics.
Copyright © 2019 Elsevier Inc. All rights reserved.
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13 MeSH Terms
Early Human B Cell Response to Ebola Virus in Four U.S. Survivors of Infection.
Williamson LE, Flyak AI, Kose N, Bombardi R, Branchizio A, Reddy S, Davidson E, Doranz BJ, Fusco ML, Saphire EO, Halfmann PJ, Kawaoka Y, Piper AE, Glass PJ, Crowe JE
(2019) J Virol 93:
MeSH Terms: Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, B-Lymphocytes, Ebolavirus, Female, Hemorrhagic Fever, Ebola, Humans, Immunologic Memory, Male, Survivors, United States, Viral Envelope Proteins
Show Abstract · Added March 31, 2019
The human B cell response to natural filovirus infections early after recovery is poorly understood. Previous serologic studies suggest that some Ebola virus survivors exhibit delayed antibody responses with low magnitude and quality. Here, we sought to study the population of individual memory B cells induced early in convalescence. We isolated monoclonal antibodies (MAbs) from memory B cells from four survivors treated for Ebola virus disease (EVD) 1 or 3 months after discharge from the hospital. At the early time points postrecovery, the frequency of Ebola-specific B cells was low and dominated by clones that were cross-reactive with both Ebola glycoprotein (GP) and with the secreted GP (sGP) form. Of 25 MAbs isolated from four donors, only one exhibited neutralization activity. This neutralizing MAb, designated MAb EBOV237, recognizes an epitope in the glycan cap of the surface glycoprotein. murine lethal challenge studies showed that EBOV237 conferred protection when given prophylactically at a level similar to that of the ZMapp component MAb 13C6. The results suggest that the human B cell response to EVD 1 to 3 months postdischarge is characterized by a paucity of broad or potent neutralizing clones. However, the neutralizing epitope in the glycan cap recognized by EBOV237 may play a role in the early human antibody response to EVD and should be considered in rational design strategies for new Ebola virus vaccine candidates. The pathogenesis of Ebola virus disease (EVD) in humans is complex, and the mechanisms contributing to immunity are poorly understood. In particular, it appears that the quality and magnitude of the human B cell response early after recovery from EVD may be reduced compared to most viral infections. Here, we isolated human monoclonal antibodies from B cells of four survivors of EVD at 1 or 3 months after hospital discharge. Ebola-specific memory B cells early in convalescence were low in frequency, and the antibodies they encoded demonstrated poor neutralizing potencies. One neutralizing antibody that protected mice from lethal infection, EBOV237, was identified in the panel of 25 human antibodies isolated. Recognition of the glycan cap epitope recognized by EBOV237 suggests that this antigenic site should be considered in vaccine design and treatment strategies for EVD.
Copyright © 2019 American Society for Microbiology.
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13 MeSH Terms
Dengue and Zika Virus Cross-Reactive Human Monoclonal Antibodies Protect against Spondweni Virus Infection and Pathogenesis in Mice.
Salazar V, Jagger BW, Mongkolsapaya J, Burgomaster KE, Dejnirattisai W, Winkler ES, Fernandez E, Nelson CA, Fremont DH, Pierson TC, Crowe JE, Screaton GR, Diamond MS
(2019) Cell Rep 26: 1585-1597.e4
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Cells, Cultured, Cross Reactions, Dengue Virus, Female, Flavivirus Infections, Humans, Male, Mice, Mice, Inbred C57BL, Zika Virus
Show Abstract · Added March 31, 2019
Spondweni virus (SPOV) is the flavivirus that is most closely related to Zika virus (ZIKV). Although SPOV causes sporadic human infections in Africa, recently it was found in Culex mosquitoes in Haiti. To investigate the pathogenic spectrum of SPOV, we developed infection models in mice. Although two SPOV strains failed to cause disease in immunocompetent mice, each accumulated in the brain, spleen, eye, testis, and kidney when type I interferon signaling was blocked and unexpectedly caused infection, immune cell infiltration, and swelling in the ankle. In pregnant mice, SPOV replicated in the placenta and fetus but did not cause placental insufficiency or microcephaly. We identified human antibodies from ZIKV or DENV immune subjects that neutralized SPOV infection and protected against lethal challenge. Our experiments describe similarities and differences in clinical syndromes between SPOV and ZIKV and suggest that their serological relatedness has implications for antibody therapeutics and flavivirus vaccine development.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
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14 MeSH Terms
Potent anti-influenza H7 human monoclonal antibody induces separation of hemagglutinin receptor-binding head domains.
Turner HL, Pallesen J, Lang S, Bangaru S, Urata S, Li S, Cottrell CA, Bowman CA, Crowe JE, Wilson IA, Ward AB
(2019) PLoS Biol 17: e3000139
MeSH Terms: Amino Acid Sequence, Animals, Antibodies, Neutralizing, Antibody Specificity, Baculoviridae, Binding Sites, Cloning, Molecular, Cryoelectron Microscopy, Gene Expression, Hemagglutinin Glycoproteins, Influenza Virus, Hydrogen Bonding, Immunoglobulin Fab Fragments, Influenza A virus, Molecular Docking Simulation, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Recombinant Proteins, Sequence Alignment, Sequence Homology, Amino Acid, Sf9 Cells, Spodoptera
Show Abstract · Added March 31, 2019
Seasonal influenza virus infections can cause significant morbidity and mortality, but the threat from the emergence of a new pandemic influenza strain might have potentially even more devastating consequences. As such, there is intense interest in isolating and characterizing potent neutralizing antibodies that target the hemagglutinin (HA) viral surface glycoprotein. Here, we use cryo-electron microscopy (cryoEM) to decipher the mechanism of action of a potent HA head-directed monoclonal antibody (mAb) bound to an influenza H7 HA. The epitope of the antibody is not solvent accessible in the compact, prefusion conformation that typifies all HA structures to date. Instead, the antibody binds between HA head protomers to an epitope that must be partly or transiently exposed in the prefusion conformation. The "breathing" of the HA protomers is implied by the exposure of this epitope, which is consistent with metastability of class I fusion proteins. This structure likely therefore represents an early structural intermediate in the viral fusion process. Understanding the extent of transient exposure of conserved neutralizing epitopes also may lead to new opportunities to combat influenza that have not been appreciated previously.
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Antibody Determinants of Influenza Immunity.
Crowe JE
(2019) J Infect Dis 219: S21-S29
MeSH Terms: Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Antigens, Viral, B-Lymphocytes, Cross Reactions, Genetic Drift, Hemagglutinin Glycoproteins, Influenza Virus, Humans, Immunologic Memory, Influenza A virus, Influenza Vaccines, Influenza, Human, Neuraminidase, Point Mutation, Vaccination, Vaccines, Inactivated
Show Abstract · Added March 31, 2019
Understanding antigenic variation in influenza virus strains and how the human immune system recognizes strains are central challenges for vaccinologists. Antibodies directed to the 2 major viral surface membrane proteins, hemagglutinin (HA) and neuraminidase (NA), mediate protection against reinfection following natural infection or vaccination, but HA and NA protein sequences in field strains are highly variable. The central questions are how to achieve protective antibody responses in a higher proportion of individuals and how to induce responses with more breadth and durability. Studies using isolation of human monoclonal antibodies followed by structural and functional characterization revealed conserved antigenic sites recognized by broadly cross-reactive antibodies. The antigenic landscape on HA and NA proteins is coming into focus to inform studies of the correlates and mechanisms of immunity. Understanding the antibody determinants of influenza immunity points the way toward development and testing of next-generation vaccines with potential to confer broadly protective immunity.
© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
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17 MeSH Terms
Structural basis of a potent human monoclonal antibody against Zika virus targeting a quaternary epitope.
Long F, Doyle M, Fernandez E, Miller AS, Klose T, Sevvana M, Bryan A, Davidson E, Doranz BJ, Kuhn RJ, Diamond MS, Crowe JE, Rossmann MG
(2019) Proc Natl Acad Sci U S A 116: 1591-1596
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Cryoelectron Microscopy, Disease Models, Animal, Epitopes, Humans, Male, Mice, Mice, Inbred C57BL, Vaccination, Viral Envelope Proteins, Zika Virus, Zika Virus Infection
Show Abstract · Added March 31, 2019
Zika virus (ZIKV) is a major human pathogen and member of the genus in the Flaviviridae family. In contrast to most other insect-transmitted flaviviruses, ZIKV also can be transmitted sexually and from mother to fetus in humans. During recent outbreaks, ZIKV infections have been linked to microcephaly, congenital disease, and Guillain-Barré syndrome. Neutralizing antibodies have potential as therapeutic agents. We report here a 4-Å-resolution cryo-electron microscopy structure of the ZIKV virion in complex with Fab fragments of the potently neutralizing human monoclonal antibody ZIKV-195. The footprint of the ZIKV-195 Fab fragment expands across two adjacent envelope (E) protein protomers. ZIKV neutralization by this antibody is presumably accomplished by cross-linking the E proteins, which likely prevents formation of E protein trimers required for fusion of the viral and cellular membranes. A single dose of ZIKV-195 administered 5 days after virus inoculation showed marked protection against lethality in a stringent mouse model of infection.
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