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Title: Broadly Reactive Human Monoclonal Antibodies Elicited following Pandemic H1N1 Influenza Virus Exposure Protect Mice against Highly Pathogenic H5N1 Challenge

Abstract

ABSTRACT Broadly cross-reactive antibodies (Abs) that recognize conserved epitopes within the influenza virus hemagglutinin (HA) stalk domain are of particular interest for their potential use as therapeutic and prophylactic agents against multiple influenza virus subtypes, including zoonotic virus strains. Here, we characterized four human HA stalk-reactive monoclonal antibodies (MAbs) for their binding breadth and affinity,in vitroneutralization capacity, andin vivoprotective potential against an highly pathogenic avian influenza virus. The monoclonal antibodies were isolated from individuals shortly following infection with (70-1F02 and 1009-3B05) or vaccination against (05-2G02 and 09-3A01) A(H1N1)pdm09. Three of the MAbs bound HAs from multiple strains of group 1 viruses, and one MAb, 05-2G02, bound to both group 1 and group 2 influenza A virus HAs. All four antibodies prophylactically protected mice against a lethal challenge with the highly pathogenic A/Vietnam/1203/04 (H5N1) strain. Two MAbs, 70-1F02 and 09-3A01, were further tested for their therapeutic efficacy against the same strain and showed good efficacy in this setting as well. One MAb, 70-1F02, cocrystallized with H5 HA and showed heavy-chain-only interactions similar to those seen with the previously described CR6261 anti-stalk antibody. Finally, we show that antibodies that compete with these MAbs are prevalent in serum from an individual recently infectedmore » with the A(H1N1)pdm09 virus. The antibodies described here can be developed into broad-spectrum antiviral therapeutics that could be used to combat infections by zoonotic or emerging pandemic influenza viruses. IMPORTANCEThe rise in zoonotic infections of humans by emerging influenza viruses is a worldwide public health concern. The majority of recent zoonotic human influenza cases were caused by H7N9 and H5Nx viruses and were associated with high morbidity and mortality. In addition, seasonal influenza viruses are estimated to cause up to 650,000 deaths annually worldwide. Currently available antiviral treatment options include only neuraminidase inhibitors, but some influenza viruses are naturally resistant to these drugs, and others quickly develop resistance-conferring mutations. Alternative therapeutics are urgently needed. Broadly protective antibodies that target the conserved “stalk” domain of the hemagglutinin represent potential potent antiviral prophylactic and therapeutic agents that can assist pandemic preparedness. Here, we describe four human monoclonal antibodies that target conserved regions of influenza HA and characterize their binding spectrum as well as their protective capacity in prophylactic and therapeutic settings against a lethal challenge with a zoonotic influenza virus.« less

Authors:
ORCiD logo; ; ; ; ; ORCiD logo; ; ; ; ; ORCiD logo; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIAID
OSTI Identifier:
1479030
Resource Type:
Journal Article
Journal Name:
Journal of Virology
Additional Journal Information:
Journal Volume: 92; Journal Issue: 16; Journal ID: ISSN 0022-538X
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Nachbagauer, Raffael, Shore, David, Yang, Hua, Johnson, Scott K., Gabbard, Jon D., Tompkins, S. Mark, Wrammert, Jens, Wilson, Patrick C., Stevens, James, Ahmed, Rafi, Krammer, Florian, Ellebedy, Ali H., and Schultz-Cherry, Stacey. Broadly Reactive Human Monoclonal Antibodies Elicited following Pandemic H1N1 Influenza Virus Exposure Protect Mice against Highly Pathogenic H5N1 Challenge. United States: N. p., 2018. Web. doi:10.1128/JVI.00949-18.
Nachbagauer, Raffael, Shore, David, Yang, Hua, Johnson, Scott K., Gabbard, Jon D., Tompkins, S. Mark, Wrammert, Jens, Wilson, Patrick C., Stevens, James, Ahmed, Rafi, Krammer, Florian, Ellebedy, Ali H., & Schultz-Cherry, Stacey. Broadly Reactive Human Monoclonal Antibodies Elicited following Pandemic H1N1 Influenza Virus Exposure Protect Mice against Highly Pathogenic H5N1 Challenge. United States. https://doi.org/10.1128/JVI.00949-18
Nachbagauer, Raffael, Shore, David, Yang, Hua, Johnson, Scott K., Gabbard, Jon D., Tompkins, S. Mark, Wrammert, Jens, Wilson, Patrick C., Stevens, James, Ahmed, Rafi, Krammer, Florian, Ellebedy, Ali H., and Schultz-Cherry, Stacey. Wed . "Broadly Reactive Human Monoclonal Antibodies Elicited following Pandemic H1N1 Influenza Virus Exposure Protect Mice against Highly Pathogenic H5N1 Challenge". United States. https://doi.org/10.1128/JVI.00949-18.
@article{osti_1479030,
title = {Broadly Reactive Human Monoclonal Antibodies Elicited following Pandemic H1N1 Influenza Virus Exposure Protect Mice against Highly Pathogenic H5N1 Challenge},
author = {Nachbagauer, Raffael and Shore, David and Yang, Hua and Johnson, Scott K. and Gabbard, Jon D. and Tompkins, S. Mark and Wrammert, Jens and Wilson, Patrick C. and Stevens, James and Ahmed, Rafi and Krammer, Florian and Ellebedy, Ali H. and Schultz-Cherry, Stacey},
abstractNote = {ABSTRACT Broadly cross-reactive antibodies (Abs) that recognize conserved epitopes within the influenza virus hemagglutinin (HA) stalk domain are of particular interest for their potential use as therapeutic and prophylactic agents against multiple influenza virus subtypes, including zoonotic virus strains. Here, we characterized four human HA stalk-reactive monoclonal antibodies (MAbs) for their binding breadth and affinity,in vitroneutralization capacity, andin vivoprotective potential against an highly pathogenic avian influenza virus. The monoclonal antibodies were isolated from individuals shortly following infection with (70-1F02 and 1009-3B05) or vaccination against (05-2G02 and 09-3A01) A(H1N1)pdm09. Three of the MAbs bound HAs from multiple strains of group 1 viruses, and one MAb, 05-2G02, bound to both group 1 and group 2 influenza A virus HAs. All four antibodies prophylactically protected mice against a lethal challenge with the highly pathogenic A/Vietnam/1203/04 (H5N1) strain. Two MAbs, 70-1F02 and 09-3A01, were further tested for their therapeutic efficacy against the same strain and showed good efficacy in this setting as well. One MAb, 70-1F02, cocrystallized with H5 HA and showed heavy-chain-only interactions similar to those seen with the previously described CR6261 anti-stalk antibody. Finally, we show that antibodies that compete with these MAbs are prevalent in serum from an individual recently infected with the A(H1N1)pdm09 virus. The antibodies described here can be developed into broad-spectrum antiviral therapeutics that could be used to combat infections by zoonotic or emerging pandemic influenza viruses. IMPORTANCEThe rise in zoonotic infections of humans by emerging influenza viruses is a worldwide public health concern. The majority of recent zoonotic human influenza cases were caused by H7N9 and H5Nx viruses and were associated with high morbidity and mortality. In addition, seasonal influenza viruses are estimated to cause up to 650,000 deaths annually worldwide. Currently available antiviral treatment options include only neuraminidase inhibitors, but some influenza viruses are naturally resistant to these drugs, and others quickly develop resistance-conferring mutations. Alternative therapeutics are urgently needed. Broadly protective antibodies that target the conserved “stalk” domain of the hemagglutinin represent potential potent antiviral prophylactic and therapeutic agents that can assist pandemic preparedness. Here, we describe four human monoclonal antibodies that target conserved regions of influenza HA and characterize their binding spectrum as well as their protective capacity in prophylactic and therapeutic settings against a lethal challenge with a zoonotic influenza virus.},
doi = {10.1128/JVI.00949-18},
url = {https://www.osti.gov/biblio/1479030}, journal = {Journal of Virology},
issn = {0022-538X},
number = 16,
volume = 92,
place = {United States},
year = {2018},
month = {6}
}

Works referenced in this record:

Neuraminidase inhibitors: who, when, where?
journal, March 2015


Structure and Receptor binding properties of a pandemic H1N1 virus hemagglutinin
journal, March 2010


Refinement of Macromolecular Structures by the Maximum-Likelihood Method
journal, May 1997


Drug resistance in influenza A virus: the epidemiology and management
journal, January 2017


Preliminary Epidemiologic Assessment of Human Infections With Highly Pathogenic Avian Influenza A(H5N6) Virus, China
journal, May 2017


Monoclonal Antibodies for Emerging Infectious Diseases — Borrowing from History
journal, April 2018


Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins
journal, September 2016


Oseltamivir-Resistant Influenza Virus A (H1N1), Europe, 2007–08 Season
journal, April 2009


Contemporary North American influenza H7 viruses possess human receptor specificity: Implications for virus transmissibility
journal, May 2008


Influenza virus hemagglutinin stalk-based antibodies and vaccines
journal, October 2013


Pandemic H1N1 influenza vaccine induces a recall response in humans that favors broadly cross-reactive memory B cells
journal, May 2012


Direct Observation of an Enamine Intermediate in Amine Catalysis
journal, December 2009


Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection
journal, January 2011


MolProbity: all-atom contacts and structure validation for proteins and nucleic acids
journal, May 2007


Induction of broadly cross-reactive antibody responses to the influenza HA stem region following H5N1 vaccination in humans
journal, August 2014


Antibody Recognition of a Highly Conserved Influenza Virus Epitope
journal, April 2009


Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp
journal, August 2014


Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses
journal, February 2009


A Highly Conserved Neutralizing Epitope on Group 2 Influenza A Viruses
journal, July 2011


A Pan-H1 Anti-Hemagglutinin Monoclonal Antibody with Potent Broad-Spectrum Efficacy In Vivo
journal, April 2012


Efficacy and Safety of Treatment With an Anti-M2e Monoclonal Antibody in Experimental Human Influenza
journal, October 2014


Inference of Macromolecular Assemblies from Crystalline State
journal, September 2007


Efficient Transmission of Pandemic H1N1 Influenza Viruses with High-Level Oseltamivir Resistance
journal, February 2012


Increase in Human Infections with Avian Influenza A(H7N9) Virus During the Fifth Epidemic — China, October 2016–February 2017
journal, March 2017


Comparing influenza vaccine efficacy against mismatched and matched strains: a systematic review and meta-analysis
journal, June 2013


Human infections with recently-emerging highly pathogenic H7N9 avian influenza virus in China
journal, July 2017


Flexible Label-Free Quantitative Assay for Antibodies to Influenza Virus Hemagglutinins
journal, July 2010


Highly Pathogenic Avian Influenza A(H7N3) Virus in Poultry Workers, Mexico, 2012
journal, September 2013


Induction of Broadly Reactive Anti-Hemagglutinin Stalk Antibodies by an H5N1 Vaccine in Humans
journal, September 2014


Influenza: old and new threats
journal, November 2004


IGHV1-69 polymorphism modulates anti-influenza antibody repertoires, correlates with IGHV utilization shifts and varies by ethnicity
journal, February 2016


Origin and Molecular Characteristics of a Novel 2013 Avian Influenza A(H6N1) Virus Causing Human Infection in Taiwan
journal, November 2013


H5 influenza, a global update
journal, February 2017


The Hemagglutinin Stem-Binding Monoclonal Antibody VIS410 Controls Influenza Virus-Induced Acute Respiratory Distress Syndrome
journal, January 2016


Universal influenza virus vaccines and therapeutic antibodies
journal, April 2017


Emerging influenza viruses and the prospect of a universal influenza virus vaccine
journal, March 2015


Influenza A(H7N9) virus gains neuraminidase inhibitor resistance without loss of in vivo virulence or transmissibility
journal, December 2013


Features and development of Coot
journal, March 2010


Immune history profoundly affects broadly protective B cell responses to influenza
journal, December 2015


Defining the antibody cross-reactome directed against the influenza virus surface glycoproteins
journal, February 2017


Both Neutralizing and Non-Neutralizing Human H7N9 Influenza Vaccine-Induced Monoclonal Antibodies Confer Protection
journal, June 2016


Structure and Receptor Specificity of the Hemagglutinin from an H5N1 Influenza Virus
journal, March 2006


Highly Conserved Protective Epitopes on Influenza B Viruses
journal, August 2012


Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome
journal, January 2004


Hemagglutinin stalk antibodies elicited by the 2009 pandemic influenza virus as a mechanism for the extinction of seasonal H1N1 viruses
journal, January 2012


A Simple Method of Estimating Fifty per cent Endpoints12
journal, May 1938


[20] Processing of X-ray diffraction data collected in oscillation mode
book, January 1997


Human Illness from Avian Influenza H7N3, British Columbia
journal, December 2004


New Class of Monoclonal Antibodies against Severe Influenza: Prophylactic and Therapeutic Efficacy in Ferrets
journal, February 2010


Phaser crystallographic software
journal, July 2007


Human Infection with a Novel Avian-Origin Influenza A (H7N9) Virus
journal, May 2013


Advances in the development of influenza virus vaccines
journal, February 2015