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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
Influenza vaccination and myocarditis among patients receiving immune checkpoint inhibitors.
Awadalla M, Golden DLA, Mahmood SS, Alvi RM, Mercaldo ND, Hassan MZO, Banerji D, Rokicki A, Mulligan C, Murphy SPT, Jones-O'Connor M, Cohen JV, Heinzerling LM, Armanious M, Sullivan RJ, Damrongwatanasuk R, Chen CL, Gupta D, Kirchberger MC, Moslehi JJ, Shah SP, Ganatra S, Thavendiranathan P, Rizvi MA, Sahni G, Lyon AR, Tocchetti CG, Mercurio V, Thuny F, Ederhy S, Mahmoudi M, Lawrence DP, Groarke JD, Nohria A, Fradley MG, Reynolds KL, Neilan TG
(2019) J Immunother Cancer 7: 53
MeSH Terms: Aged, Aged, 80 and over, Antineoplastic Agents, Immunological, Female, Humans, Influenza Vaccines, Influenza, Human, Male, Middle Aged, Myocarditis, Neoplasms, Registries, Vaccination
Show Abstract · Added February 24, 2019
BACKGROUND - Influenza vaccination (FV) is recommended for patients with cancer. Recent data suggested that the administration of the FV was associated with an increase in immune-related adverse events (irAEs) among patients on immune checkpoint inhibitors (ICIs). Myocarditis is an uncommon but serious complication of ICIs and may also result from infection with influenza. There are no data testing the relationship between FV and the development of myocarditis on ICIs.
METHODS - Patients on ICIs who developed myocarditis (n = 101) (cases) were compared to ICI-treated patients (n = 201) without myocarditis (controls). A patient was defined as having the FV if they were administered the FV from 6 months prior to start of ICI to anytime during ICI therapy. Alternate thresholds for FV status were also tested. The primary comparison of interest was the rate of FV between cases and controls. Patients with myocarditis were followed for major adverse cardiac events (MACE), defined as the composite of cardiogenic shock, cardiac arrest, hemodynamically significant complete heart block and cardiovascular death.
RESULTS - The FV was administered to 25% of the myocarditis cases compared to 40% of the non-myocarditis ICI-treated controls (p = 0.01). Similar findings of lower rates of FV administration were noted among myocarditis cases when alternate thresholds were tested. Among the myocarditis cases, those who were vaccinated had 3-fold lower troponin levels when compared to unvaccinated cases (FV vs. No FV: 0.12 [0.02, 0.47] vs. 0.40 [0.11, 1.26] ng/ml, p = 0.02). Within myocarditis cases, those administered the FV also had a lower rate of other irAEs when compared to unvaccinated cases (36 vs. 55% p = 0.10) including lower rates of pneumonitis (12 vs. 36%, p = 0.03). During follow-up (175 [IQR 89, 363] days), 47% of myocarditis cases experienced a MACE. Myocarditis cases who received the FV were at a lower risk of cumulative MACE when compared to unvaccinated cases (24 vs. 59%, p = 0.002).
CONCLUSION - The rate of FV among ICI-related myocarditis cases was lower than controls on ICIs who did not develop myocarditis. In those who developed myocarditis related to an ICI, there was less myocardial injury and a lower risk of MACE among those who were administered the FV.
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13 MeSH Terms
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
Influenza Virus-Specific Human Antibody Repertoire Studies.
Crowe JE
(2019) J Immunol 202: 368-373
MeSH Terms: Antibodies, Viral, Antibody Diversity, Antigenic Variation, Antigens, Viral, B-Lymphocytes, Humans, Influenza A virus, Influenza Vaccines, Influenza, Human, Receptors, Antigen, B-Cell
Show Abstract · Added March 31, 2019
The diversity of Ag-specific adaptive receptors on the surface of B cells and in the population of secreted Abs is enormous, but increasingly, we are acquiring the technical capability to interrogate Ab repertoires in great detail. These Ab technologies have been especially pointed at understanding the complex issues of immunity to infection and disease caused by influenza virus, one of the most common and vexing medical problems in man. Influenza immunity is particularly interesting as a model system because the antigenic diversity of influenza strains and proteins is high and constantly evolving. Discovery of canonical features in the subset of the influenza repertoire response that is broadly reactive for diverse influenza strains has spurred the recent optimism for creating universal influenza vaccines. Using new technologies for sequencing Ab repertoires at great depth is helping us to understand the central features of influenza immunity.
Copyright © 2019 by The American Association of Immunologists, Inc.
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10 MeSH Terms
Is It Possible to Develop a "Universal" Influenza Virus Vaccine? Potential for a Universal Influenza Vaccine.
Crowe JE
(2018) Cold Spring Harb Perspect Biol 10:
MeSH Terms: Antibodies, Neutralizing, Antibodies, Viral, Hemagglutinins, Humans, Influenza Vaccines, Influenza, Human
Show Abstract · Added March 14, 2018
Development of optimal vaccines for influenza is challenging, in part as a result of the high antigenic variability in field strains associated with genetic shift from reassortment and genetic drift from point mutations. Discovery of conserved antigenic sites on the hemagglutinin (HA) protein for neutralizing antibodies suggested the possibility that influenza vaccines could be developed that induce focused antibody responses to the conserved neutralizing determinants, especially the HA stem region. Recent studies have focused on the antigenicity and immunogenicity of such domains, using monoclonal antibodies and candidate-engineered HA stem-based vaccines. Much progress has been made, but we still do not fully understand the biology of the immune response to this unique antigenic region.
Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.
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6 MeSH Terms
Proteomics show antigen presentation processes in human immune cells after AS03-H5N1 vaccination.
Galassie AC, Goll JB, Samir P, Jensen TL, Hoek KL, Howard LM, Allos TM, Niu X, Gordy LE, Creech CB, Hill H, Joyce S, Edwards KM, Link AJ
(2017) Proteomics 17:
MeSH Terms: Adjuvants, Immunologic, Antigen Presentation, B-Lymphocytes, Cells, Cultured, Humans, Influenza A Virus, H5N1 Subtype, Influenza Vaccines, Influenza, Human, Killer Cells, Natural, Monocytes, Neutrophils, Protein Interaction Maps, Proteome, Proteomics, T-Lymphocytes
Show Abstract · Added August 15, 2017
Adjuvants enhance immunity elicited by vaccines through mechanisms that are poorly understood. Using a systems biology approach, we investigated temporal protein expression changes in five primary human immune cell populations: neutrophils, monocytes, natural killer cells, T cells, and B cells after administration of either an Adjuvant System 03 adjuvanted or unadjuvanted split-virus H5N1 influenza vaccine. Monocytes demonstrated the strongest differential signal between vaccine groups. On day 3 post-vaccination, several antigen presentation-related pathways, including MHC class I-mediated antigen processing and presentation, were enriched in monocytes and neutrophils and expression of HLA class I proteins was increased in the Adjuvant System 03 group. We identified several protein families whose proteomic responses predicted seroprotective antibody responses (>1:40 hemagglutination inhibition titer), including inflammation and oxidative stress proteins at day 1 as well as immunoproteasome subunit (PSME1 and PSME2) and HLA class I proteins at day 3 in monocytes. While comparison between temporal proteomic and transcriptomic results showed little overlap overall, enrichment of the MHC class I antigen processing and presentation pathway in monocytes and neutrophils was confirmed by both approaches.
© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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15 MeSH Terms
Cell-Based Systems Biology Analysis of Human AS03-Adjuvanted H5N1 Avian Influenza Vaccine Responses: A Phase I Randomized Controlled Trial.
Howard LM, Hoek KL, Goll JB, Samir P, Galassie A, Allos TM, Niu X, Gordy LE, Creech CB, Prasad N, Jensen TL, Hill H, Levy SE, Joyce S, Link AJ, Edwards KM
(2017) PLoS One 12: e0167488
MeSH Terms: Adjuvants, Immunologic, Adolescent, Adult, Antibodies, Viral, Antibody Formation, Antigen Presentation, Chemokine CXCL10, Dendritic Cells, Double-Blind Method, Female, Hemagglutination Inhibition Tests, Humans, Influenza A Virus, H5N1 Subtype, Influenza Vaccines, Influenza, Human, Interleukin-6, Killer Cells, Natural, Male, Middle Aged, Monocytes, Neutrophils, Systems Biology, Vaccination, Young Adult
Show Abstract · Added May 3, 2017
BACKGROUND - Vaccine development for influenza A/H5N1 is an important public health priority, but H5N1 vaccines are less immunogenic than seasonal influenza vaccines. Adjuvant System 03 (AS03) markedly enhances immune responses to H5N1 vaccine antigens, but the underlying molecular mechanisms are incompletely understood.
OBJECTIVE AND METHODS - We compared the safety (primary endpoint), immunogenicity (secondary), gene expression (tertiary) and cytokine responses (exploratory) between AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 influenza vaccines. In a double-blinded clinical trial, we randomized twenty adults aged 18-49 to receive two doses of either AS03-adjuvanted (n = 10) or unadjuvanted (n = 10) H5N1 vaccine 28 days apart. We used a systems biology approach to characterize and correlate changes in serum cytokines, antibody titers, and gene expression levels in six immune cell types at 1, 3, 7, and 28 days after the first vaccination.
RESULTS - Both vaccines were well-tolerated. Nine of 10 subjects in the adjuvanted group and 0/10 in the unadjuvanted group exhibited seroprotection (hemagglutination inhibition antibody titer > 1:40) at day 56. Within 24 hours of AS03-adjuvanted vaccination, increased serum levels of IL-6 and IP-10 were noted. Interferon signaling and antigen processing and presentation-related gene responses were induced in dendritic cells, monocytes, and neutrophils. Upregulation of MHC class II antigen presentation-related genes was seen in neutrophils. Three days after AS03-adjuvanted vaccine, upregulation of genes involved in cell cycle and division was detected in NK cells and correlated with serum levels of IP-10. Early upregulation of interferon signaling-related genes was also found to predict seroprotection 56 days after first vaccination.
CONCLUSIONS - Using this cell-based systems approach, novel mechanisms of action for AS03-adjuvanted pandemic influenza vaccination were observed.
TRIAL REGISTRATION - ClinicalTrials.gov NCT01573312.
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24 MeSH Terms
Vaccine-Induced Antibodies that Neutralize Group 1 and Group 2 Influenza A Viruses.
Joyce MG, Wheatley AK, Thomas PV, Chuang GY, Soto C, Bailer RT, Druz A, Georgiev IS, Gillespie RA, Kanekiyo M, Kong WP, Leung K, Narpala SN, Prabhakaran MS, Yang ES, Zhang B, Zhang Y, Asokan M, Boyington JC, Bylund T, Darko S, Lees CR, Ransier A, Shen CH, Wang L, Whittle JR, Wu X, Yassine HM, Santos C, Matsuoka Y, Tsybovsky Y, Baxa U, NISC Comparative Sequencing Program, Mullikin JC, Subbarao K, Douek DC, Graham BS, Koup RA, Ledgerwood JE, Roederer M, Shapiro L, Kwong PD, Mascola JR, McDermott AB
(2016) Cell 166: 609-623
MeSH Terms: Adult, Amino Acid Sequence, Antibodies, Neutralizing, Antibodies, Viral, B-Lymphocytes, Epitopes, B-Lymphocyte, Female, Gene Rearrangement, B-Lymphocyte, Heavy Chain, Humans, Immunologic Memory, Influenza A Virus, H5N1 Subtype, Influenza A virus, Influenza Vaccines, Male, Middle Aged, Models, Molecular, Protein Structure, Tertiary, Structure-Activity Relationship, Young Adult
Show Abstract · Added May 3, 2017
Antibodies capable of neutralizing divergent influenza A viruses could form the basis of a universal vaccine. Here, from subjects enrolled in an H5N1 DNA/MIV-prime-boost influenza vaccine trial, we sorted hemagglutinin cross-reactive memory B cells and identified three antibody classes, each capable of neutralizing diverse subtypes of group 1 and group 2 influenza A viruses. Co-crystal structures with hemagglutinin revealed that each class utilized characteristic germline genes and convergent sequence motifs to recognize overlapping epitopes in the hemagglutinin stem. All six analyzed subjects had sequences from at least one multidonor class, and-in half the subjects-multidonor-class sequences were recovered from >40% of cross-reactive B cells. By contrast, these multidonor-class sequences were rare in published antibody datasets. Vaccination with a divergent hemagglutinin can thus increase the frequency of B cells encoding broad influenza A-neutralizing antibodies. We propose the sequence signature-quantified prevalence of these B cells as a metric to guide universal influenza A immunization strategies.
Published by Elsevier Inc.
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19 MeSH Terms
H7N9 influenza virus neutralizing antibodies that possess few somatic mutations.
Thornburg NJ, Zhang H, Bangaru S, Sapparapu G, Kose N, Lampley RM, Bombardi RG, Yu Y, Graham S, Branchizio A, Yoder SM, Rock MT, Creech CB, Edwards KM, Lee D, Li S, Wilson IA, García-Sastre A, Albrecht RA, Crowe JE
(2016) J Clin Invest 126: 1482-94
MeSH Terms: Adult, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Binding Sites, Antibody, Epitope Mapping, Epitopes, Female, Humans, Influenza A Virus, H7N9 Subtype, Influenza Vaccines, Male, Mice, Middle Aged, Mutation
Show Abstract · Added May 4, 2016
Avian H7N9 influenza viruses are group 2 influenza A viruses that have been identified as the etiologic agent for a current major outbreak that began in China in 2013 and may pose a pandemic threat. Here, we examined the human H7-reactive antibody response in 75 recipients of a monovalent inactivated A/Shanghai/02/2013 H7N9 vaccine. After 2 doses of vaccine, the majority of donors had memory B cells that secreted IgGs specific for H7 HA, with dominant responses against single HA subtypes, although frequencies of H7-reactive B cells ranged widely between donors. We isolated 12 naturally occurring mAbs with low half-maximal effective concentrations for binding, 5 of which possessed neutralizing and HA-inhibiting activities. The 5 neutralizing mAbs exhibited narrow breadth of reactivity with influenza H7 strains. Epitope-mapping studies using neutralization escape mutant analysis, deuterium exchange mass spectrometry, and x-ray crystallography revealed that these neutralizing mAbs bind near the receptor-binding pocket on HA. All 5 neutralizing mAbs possessed low numbers of somatic mutations, suggesting the clones arose from naive B cells. The most potent mAb, H7.167, was tested as a prophylactic treatment in a mouse intranasal virus challenge study, and systemic administration of the mAb markedly reduced viral lung titers.
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16 MeSH Terms