Protective efficacy of anti-neuraminidase #monoclonal #antibodies against #H7N9 #influenza virus #infection (Emerg Microbes Infect., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Emerg Microbes Infect. 2020 Dec;9(1):78-87. doi: 10.1080/22221751.2019.1708214.

Protective efficacy of anti-neuraminidase monoclonal antibodies against H7N9 influenza virus infection.

Xiong FF1, Liu XY1, Gao FX1,2, Luo J1, Duan P1, Tan WS2, Chen Z1.

Author information: 1 Shanghai Institute of Biological Products, Shanghai, People’s Republic of China. 2 East China University of Science and Technology, Shanghai, People’s Republic of China.

 

Abstract

The H7N9 influenza virus has been circulating in China for more than six years. The neuraminidase (NA) has gained great concern for the development of antiviral drugs, therapeutic antibodies, and new vaccines. In this study, we screened seven mouse monoclonal antibodies (mAbs) and compared their protective effects against H7N9 influenza virus. The epitope mapping from escape mutants showed that all the seven mAbs could bind to the head region of the N9 NA close to the enzyme activity sites, and four key sites of N9 NA were reported for the first time. The mAbs D3 and 7H2 could simultaneously inhibit the cleavage of the sialic acid of fetuin protein with large molecular weight and NA-XTD with small molecule weight in the NA inhibition experiment, prevent the formation of virus plaque at a low concentration, and effectively protect the mice from the challenge of the lethal dose of H7N9 virus.

KEYWORDS: H7N9 influenza virus; NA epitope; monoclonal antibodies; neuraminidase; protection

PMID: 31894728 DOI: 10.1080/22221751.2019.1708214

Keywords: Avian Influenza; H7N9; Monoclonal antibodies; Animal models.

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Protective Efficacy of #Monoclonal #Antibodies Neutralizing Alpha-Hemolysin and Bicomponent Leukocidins in Rabbit Model of #Staphylococcus aureus Necrotizing #Pneumonia (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Protective Efficacy of Monoclonal Antibodies Neutralizing Alpha-Hemolysin and Bicomponent Leukocidins in Rabbit Model of Staphylococcus aureus Necrotizing Pneumonia

Trang T. T. Vu, Nhu T.Q. Nguyen, Vuvi G. Tran, Emmanuelle Gras, Yanjie Mao, David H. Jung, Christine Tkaczyk, Bret R. Sellman, Binh An Diep

DOI: 10.1128/AAC.02220-19

 

ABSTRACT

Staphylococcus aureus is a major human pathogen, causing a wide range of infections by producing an arsenal of cytotoxins. We found that passive immunization with either a monoclonal antibody (mAb) neutralizing alpha-hemolysin or a broadly cross-reactive mAb that neutralize Panton-Valentine leukocidin, leukocidin ED and gamma-hemolysins HlgAB/HlgCB only conferred partial protection, whereas the combination of those two mAbs conferred significant protection in a rabbit model of necrotizing pneumonia caused by the USA300 MRSA epidemic clone.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Staphylococcus aureus; Monoclonal antibodies; Animal models.

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Molecular #mechanism for #ADE of #coronavirus entry (J Virol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

J Virol. 2019 Dec 11. pii: JVI.02015-19. doi: 10.1128/JVI.02015-19. [Epub ahead of print]

Molecular mechanism for antibody-dependent enhancement of coronavirus entry.

Wan Y1, Shang J1, Sun S, Tai W2, Chen J3, Geng Q1, He L4, Chen Y4, Wu J1, Shi Z3, Zhou Y, Du L5, Li F6.

Author information: 1 Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, USA. 2 Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA. 3 Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei Province, China. 4 Laboratory of infection and immunity, Beijing Institute of Microbiology and Epidemiology, Beijing, China. 5 Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA lifang@umn.edu LDu@nybc.org. 6 Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, USA lifang@umn.edu LDu@nybc.org.

 

Abstract

Antibody-dependent enhancement (ADE) of viral entry has been a major concern for epidemiology, vaccine development and antibody-based drug therapy. However, the molecular mechanism behind ADE is still elusive. Coronavirus spike protein mediates viral entry into cells by first binding to a receptor on host cell surface and then fusing viral and host membranes. Here we investigated how a neutralizing monoclonal antibody (mAb), which targets the receptor-binding domain (RBD) of MERS coronavirus spike, mediates viral entry using pseudovirus entry and biochemical assays. Our results showed that mAb binds to the virus-surface spike, allowing it to undergo conformational changes and become prone to proteolytic activation. Meanwhile, mAb binds to cell-surface IgG Fc receptor, guiding viral entry through canonical viral-receptor-dependent pathways. Our data suggest that the antibody/Fc-receptor complex functionally mimics viral receptor in mediating viral entry. Moreover, we characterized mAb dosages in viral-receptor-dependent, antibody-dependent, and both-receptors-dependent entry pathways, delineating guidelines on mAb usages in treating viral infections. Our study reveals a novel molecular mechanism for antibody-enhanced viral entry and can guide future vaccination and antiviral strategies.

 

Significance

Antibody-dependent enhancement (ADE) of viral entry has been observed for many viruses. It was shown that antibodies target one serotype of viruses but only sub-neutralize another, leading to ADE of the latter viruses. Here we identify a novel mechanism for ADE: a neutralizing antibody binds to the virus-surface spike protein of coronaviruses like a viral receptor, triggers a conformational change of the spike, and mediates viral entry into IgG-Fc-receptor-expressing cells through canonical viral-receptor-dependent pathways. We further evaluated how antibody dosages impacted viral entry into cells expressing viral receptor, Fc receptor, or both receptors. This study reveals complex roles of antibodies in viral entry and can guide future vaccine design and antibody-based drug therapy.

Copyright © 2019 American Society for Microbiology.

PMID: 31826992 DOI: 10.1128/JVI.02015-19

Keywords: Coronavirus; MERS-CoV; Monoclonal antibodies; ADE.

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Mapping of a Novel #H3-Specific Broadly Neutralizing #Monoclonal #Antibody Targeting the #Hemagglutinin Globular Head Isolated from an Elite #Influenza Virus-Immunized Donor Exhibiting Serological Breadth (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Mapping of a Novel H3-Specific Broadly Neutralizing Monoclonal Antibody Targeting the Hemagglutinin Globular Head Isolated from an Elite Influenza Virus-Immunized Donor Exhibiting Serological Breadth

Yu Qiu, Svetlana Stegalkina, Jianxin Zhang, Ekaterina Boudanova, Anna Park, Yanfeng Zhou, Ponraj Prabakaran, Svetlana Pougatcheva, Irina V. Ustyugova, Thorsten U. Vogel, Sophia T. Mundle, Ray Oomen, Simon Delagrave, Ted M. Ross, Harry Kleanthous, Huawei Qiu

DOI: 10.1128/JVI.01035-19

 

ABSTRACT

The discovery of potent and broadly protective influenza epitopes could lead to improved vaccines that are resistant to antigenic drift. Here, we describe human antibody C585, isolated from a vaccinee with remarkable serological breadth as measured by hemagglutinin inhibition (HAI). C585 binds and neutralizes multiple H3N2 strains isolated between 1968 and 2016, including strains which emerged up to four years after B cells were isolated from the vaccinated donor. The crystal structure of C585 Fab in complex with the HA from A/Switzerland/9715293/2013 (H3N2) shows that the antibody binds to a novel and well-conserved epitope on the globular head of H3 HA, and differs from other antibodies not only in its epitope but in its binding geometry and hypermutated framework 3 region, thereby explaining its breadth and ability to mediate hemagglutination inhibition across decades of H3N2 strains. The existence of epitopes such as the one elucidated by C585 has implications for rational vaccine design.

 

Importance

Influenza viruses escape immunity through continuous antigenic changes that occur predominantly on the viral hemagglutinin (HA). Induction of broadly neutralizing antibodies (bnAb) targeting conserved epitopes following vaccination is a goal of universal influenza vaccines and advantageous to protecting hosts against virus evolution and antigenic drift. To date, most of the discovered bnAbs bind either to conserved sites in the stem region or to the sialic acid-binding pocket. Generally, antibodies targeting the stem region offer broader breadth with low potency; while antibodies targeting the sialic acid-binding pocket cover narrower breadth but usually have higher potency. In this study, we identified a novel neutralizing epitope in the head region recognized by a broadly neutralizing human antibody against a broad range of H3N2 with high potency. This epitope may provide insights for future universal vaccine design.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Influenza A; H3N2; Monoclonal antibodies.

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Synthetic nucleic acid #antibody #prophylaxis confers rapid and durable protective immunity against #Zika virus challenge (Hum Vaccin Immunother., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Hum Vaccin Immunother. 2019 Dec 4:1-12. doi: 10.1080/21645515.2019.1688038. [Epub ahead of print]

Synthetic nucleic acid antibody prophylaxis confers rapid and durable protective immunity against Zika virus challenge.

Choi H1, Kudchodkar SB1, Reuschel EL1, Asija K1, Borole P1, Agarwal S1, Van Gorder L1, Reed CC2, Gulendran G3, Ramos S2, Broderick KE2, Kim JJ2, Ugen KE4, Kobinger G5, Siegel DL3, Weiner DB1, Muthumani K1.

Author information: 1 Vaccine & Immunotherapy Center, The Wistar Institute, Philadelphia, PA, USA. 2 R&D, Inovio Pharmaceuticals, Plymouth Meeting, PA, USA. 3 Department of Pathology & Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, PA, USA. 4 Department of Molecular Medicine, University of South Florida Morsani College of Medicine, Tampa, FL, USA. 5 Université Laval, Quebec City, QC, Canada.

 

Abstract

Significant concerns have arisen over the past 3 y from the increased global spread of the mosquito-borne flavivirus, Zika. Accompanying this spread has been an increase in cases of the devastating birth defect microcephaly as well as of Guillain-Barré syndrome in adults in many affected countries. Currently there is no vaccine or therapy for this infection; however, we sought to develop a combination approach that provides more rapid and durable protection than traditional vaccination alone. A novel immune-based prophylaxis/therapy strategy entailing the facilitated delivery of a synthetic DNA consensus prME vaccine along with DNA-encoded anti-ZIKV envelope monoclonal antibodies (dMAb) were developed and evaluated for antiviral efficacy. This immediate and persistent protection strategy confers the ability to overcome shortcomings inherent with conventional active vaccination or passive immunotherapy. A collection of novel dMAbs were developed which were potent against ZIKV and could be expressed in serum within 24-48 h of in vivo administration. The DNA vaccine, from a previous development, was potent after adaptive immunity was developed, protecting against infection, brain and testes pathology in relevant mouse challenge models and in an NHP challenge. Delivery of potent dMAbs protected mice from the same murine viral challenge within days of delivery. Combined injection of dMAb and the DNA vaccine afforded rapid and long-lived protection in this challenge model, providing an important demonstration of the advantage of this synergistic approach to pandemic outbreaks.

KEYWORDS: DNA vaccine; Zika virus; antibodies; dMAb-DNA encoded monoclonal antibodies; immunotherapy; vaccination

PMID: 31799896 DOI: 10.1080/21645515.2019.1688038

Keywords: Zika Virus; Vaccines; Monoclonal antibodies; Immunotherapy; Animal models.

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#Monoclonal #antibodies with neutralizing activity and Fc-effector functions against the #Machupo virus glycoprotein (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Monoclonal antibodies with neutralizing activity and Fc-effector functions against the Machupo virus glycoprotein

Fatima Amanat, James Duehr, Cheng Huang, Slobodan Paessler, Gene Tan, Florian Krammer

DOI: 10.1128/JVI.01741-19

 

ABSTRACT

Machupo virus (MACV), the causative agent of Bolivian hemorrhagic fever (BHF), is a New World arenavirus that was first isolated in Bolivia from a human spleen in 1963. Due to the lack of a specific vaccine or therapy, this virus is considered a major risk to public health and is classified as a Category A Priority Pathogen by the US National Institutes of Health. In this study, we used DNA vaccination against the MACV glycoprotein precursor complex (GPC) and murine hybridoma technology to generate 25 mouse monoclonal antibodies (mAbs) against the GPC of MACV. Out of 25, five mAbs were found to have potent neutralization activity in vitro against a recombinant vesicular stomatitis virus expressing MACV GPC (VSV-MACV) as well as authentic MACV. Furthermore, the five neutralizing mAbs exhibited strong antibody-dependent cellular cytotoxicity (ADCC) activity in a reporter assay. When tested in vivo using VSV-MACV in a Stat2-/- mouse model, three mAbs significantly lowered viral loads in the spleen. Our work provides valuable insights into epitopes targeted by neutralizing antibodies that could be potent targets for vaccines and therapeutics, and shed light towards the importance of effector functions in immunity against MACV.

 

Significance

MACV infections are a significant public health concern and lead to high case fatality rates. No specific treatment or vaccine for MACV infections exist. However, cases of Junin virus infection, a related virus, can be treated with convalescent serum. This indicates, that a mAb-based therapy for MACV could be effective. Here, we describe several mAbs that neutralize MACV and could be used for this purpose.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Arenavirus; Machupo virus; Monoclonal antibodies; Bolivian Hemorrhagic Fever.

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Therapeutic #monoclonal #antibody #treatment protects nonhuman #primates from severe Venezuelan #equine #encephalitis virus disease after aerosol exposure (PLOS Pathog., abstract)

[Source: PLOS Pathogens, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Therapeutic monoclonal antibody treatment protects nonhuman primates from severe Venezuelan equine encephalitis virus disease after aerosol exposure

Crystal W. Burke, Jeffery W. Froude, Franco Rossi, Charles E. White, Crystal L. Moyer, Jane Ennis, M. Louise Pitt, Stephen Streatfield, R. Mark Jones, Konstantin Musiychuk, Jukka Kervinen, Larry Zeitlin, Vidadi Yusibov, Pamela J. Glass

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Published: December 2, 2019 / DOI: https://doi.org/10.1371/journal.ppat.1008157 / This is an uncorrected proof.

 

Abstract

There are no FDA licensed vaccines or therapeutics for Venezuelan equine encephalitis virus (VEEV) which causes a debilitating acute febrile illness in humans that can progress to encephalitis. Previous studies demonstrated that murine and macaque monoclonal antibodies (mAbs) provide prophylactic and therapeutic efficacy against VEEV peripheral and aerosol challenge in mice. Additionally, humanized versions of two neutralizing mAbs specific for the E2 glycoprotein, 1A3B-7 and 1A4A-1, administered singly protected mice against aerosolized VEEV. However, no studies have demonstrated protection in nonhuman primate (NHP) models of VEEV infection. Here, we evaluated a chimeric antibody 1A3B-7 (c1A3B-7) containing mouse variable regions on a human IgG framework and a humanized antibody 1A4A-1 containing a serum half-life extension modification (Hu-1A4A-1-YTE) for their post-exposure efficacy in NHPs exposed to aerosolized VEEV. Approximately 24 hours after exposure, NHPs were administered a single bolus intravenous mAb. Control NHPs had typical biomarkers of VEEV infection including measurable viremia, fever, and lymphopenia. In contrast, c1A3B-7 treated NHPs had significant reductions in viremia and lymphopenia and on average approximately 50% reduction in fever. Although not statistically significant, Hu-1A4A-1-YTE administration did result in reductions in viremia and fever duration. Delay of treatment with c1A3B-7 to 48 hours post-exposure still provided NHPs protection from severe VEE disease through reductions in viremia and fever. These results demonstrate that post-exposure administration of c1A3B-7 protected macaques from development of severe VEE disease even when administered 48 hours following aerosol exposure and describe the first evaluations of VEEV-specific mAbs for post-exposure prophylactic use in NHPs. Viral mutations were identified in one NHP after c1A3B-7 treatment administered 24 hrs after virus exposure. This suggests that a cocktail-based therapy, or an alternative mAb against an epitope that cannot mutate without resulting in loss of viral fitness may be necessary for a highly effective therapeutic.

 

Author summary

Endemic in the Americas, Venezuelan equine encephalitis virus (VEEV) can be transmitted to humans, horses, and other animals through the bite of a mosquito. Beyond its natural prevalence, VEEV was previously developed as a biological weapon making the development of vaccines and therapeutics of the upmost importance. Despite over 60 years of research to identify effective therapeutics for VEEV disease, to-date no anti-VEEV therapeutics have progressed beyond pre-clinical testing in a mouse model. Here, we present the first evaluation of an anti-VEEV therapeutic in a nonhuman primate (NHP). We found that a monoclonal antibody given either one or two days after an aerosol exposure to VEEV protected from severe VEE disease. We also found the level of in vitro virus neutralization by a given antibody did not predict efficacy in NHPs. Importantly, we identified viral escape mutations in one NHP after treatment, highlighting the need for development of novel antibodies for inclusion in cocktail-based therapy against VEEV.

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Citation: Burke CW, Froude JW, Rossi F, White CE, Moyer CL, Ennis J, et al. (2019) Therapeutic monoclonal antibody treatment protects nonhuman primates from severe Venezuelan equine encephalitis virus disease after aerosol exposure. PLoS Pathog 15(12): e1008157. https://doi.org/10.1371/journal.ppat.1008157

Editor: Mehul Suthar, Emory University, UNITED STATES

Received: July 31, 2019; Accepted: October 23, 2019; Published: December 2, 2019

This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Data Availability: All relevant data are within the manuscript and its supporting information files.

Funding: This was supported by the Joint Science and Technology Office for Chemical and Biological Defense Program CB3957 to PJG and Contract HDTRA1-14-C-0115 to LZ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: JWF, MLP, KM, JK, YV, and PJG have filled a patent application on c1A3B-7. CLM and JE are employees of Mapp Biopharmaceutical. LZ is an employee and co-owner of Mapp. This does not alter our adherence to all PLOS Pathogens policies on sharing data and materials.

Keywords: Venezuelan Equine Encephalitis; Monoclonal antibodies; Animal models.

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