In vitro neutralization is not predictive of prophylactic efficacy of broadly neutralizing monoclonal antibodies CR6261 and CR9114 against lethal H2 influenza virus challenge in mice

Troy C. Sutton, Elaine W. Lamirande, Kevin W. Bock, Ian N. Moore, Wouter Koudstaal, Muniza Rehman, Gerrit Jan Weverling, Jaap Goudsmit, Kanta Subbarao

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Influenza viruses of the H1N1, H2N2, and H3N2 subtypes have caused previous pandemics. H2 influenza viruses represent a pandemic threat due to continued circulation in wild birds and limited immunity in the human population. In the event of a pandemic, antiviral agents are the mainstay for treatment, but broadly neutralizing antibodies (bNAbs) may be a viable alternative for short-term prophylaxis or treatment. The hemagglutinin stem binding bNAbs CR6261 and CR9114 have been shown to protect mice from severe disease following challenge with H1N1 and H5N1 and with H1N1, H3N2, and influenza B viruses, respectively. Early studies with CR6261 and CR9114 showed weak in vitro activity against human H2 influenza viruses, but the in vivo efficacy against H2 viruses is unknown. Therefore, we evaluated these antibodies against human- and animal-origin H2 viruses A/Ann Arbor/6/1960 (H2N2) (AA60) and A/swine/MO/4296424/ 06 (H2N3) (Sw06). In vitro, CR6261 neutralized both H2 viruses, while CR9114 only neutralized Sw06. To evaluate prophylactic efficacy, mice were given CR6261 or CR9114 and intranasally challenged 24 h later with lethal doses of AA60 or Sw06. Both antibodies reduced mortality, weight loss, airway inflammation, and pulmonary viral load. Using engineered bNAb variants, antibody-mediated cell cytotoxicity reporter assays, and Fcγ receptor-deficient (Fcer1g-/-) mice, we show that the in vivo efficacy of CR9114 against AA60 is mediated by Fcγ receptor-dependent mechanisms. Collectively, these findings demonstrate the in vivo efficacy of CR6261 and CR9114 against H2 viruses and emphasize the need for in vivo evaluation of bNAbs.

Original languageEnglish (US)
Article numbere01603-17
JournalJournal of virology
Volume91
Issue number24
DOIs
StatePublished - Dec 1 2017

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Orthomyxoviridae
Neutralizing Antibodies
neutralizing antibodies
neutralization
monoclonal antibodies
Pandemics
pandemic
Monoclonal Antibodies
Viruses
viruses
Fc Receptors
mice
antibodies
Antibodies
Influenza B virus
antiviral agents
receptors
lethal dose
Hemagglutinins
wild birds

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Sutton, Troy C. ; Lamirande, Elaine W. ; Bock, Kevin W. ; Moore, Ian N. ; Koudstaal, Wouter ; Rehman, Muniza ; Weverling, Gerrit Jan ; Goudsmit, Jaap ; Subbarao, Kanta. / In vitro neutralization is not predictive of prophylactic efficacy of broadly neutralizing monoclonal antibodies CR6261 and CR9114 against lethal H2 influenza virus challenge in mice. In: Journal of virology. 2017 ; Vol. 91, No. 24.
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abstract = "Influenza viruses of the H1N1, H2N2, and H3N2 subtypes have caused previous pandemics. H2 influenza viruses represent a pandemic threat due to continued circulation in wild birds and limited immunity in the human population. In the event of a pandemic, antiviral agents are the mainstay for treatment, but broadly neutralizing antibodies (bNAbs) may be a viable alternative for short-term prophylaxis or treatment. The hemagglutinin stem binding bNAbs CR6261 and CR9114 have been shown to protect mice from severe disease following challenge with H1N1 and H5N1 and with H1N1, H3N2, and influenza B viruses, respectively. Early studies with CR6261 and CR9114 showed weak in vitro activity against human H2 influenza viruses, but the in vivo efficacy against H2 viruses is unknown. Therefore, we evaluated these antibodies against human- and animal-origin H2 viruses A/Ann Arbor/6/1960 (H2N2) (AA60) and A/swine/MO/4296424/ 06 (H2N3) (Sw06). In vitro, CR6261 neutralized both H2 viruses, while CR9114 only neutralized Sw06. To evaluate prophylactic efficacy, mice were given CR6261 or CR9114 and intranasally challenged 24 h later with lethal doses of AA60 or Sw06. Both antibodies reduced mortality, weight loss, airway inflammation, and pulmonary viral load. Using engineered bNAb variants, antibody-mediated cell cytotoxicity reporter assays, and Fcγ receptor-deficient (Fcer1g-/-) mice, we show that the in vivo efficacy of CR9114 against AA60 is mediated by Fcγ receptor-dependent mechanisms. Collectively, these findings demonstrate the in vivo efficacy of CR6261 and CR9114 against H2 viruses and emphasize the need for in vivo evaluation of bNAbs.",
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In vitro neutralization is not predictive of prophylactic efficacy of broadly neutralizing monoclonal antibodies CR6261 and CR9114 against lethal H2 influenza virus challenge in mice. / Sutton, Troy C.; Lamirande, Elaine W.; Bock, Kevin W.; Moore, Ian N.; Koudstaal, Wouter; Rehman, Muniza; Weverling, Gerrit Jan; Goudsmit, Jaap; Subbarao, Kanta.

In: Journal of virology, Vol. 91, No. 24, e01603-17, 01.12.2017.

Research output: Contribution to journalArticle

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AU - Sutton, Troy C.

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