H2N2V1, Main, Exploration, bibRecord, 000355

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

Identifieur interne : 000355 ( Main/Exploration ); précédent : 000354; suivant : 000356

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

Auteurs : Troy C. Sutton [États-Unis] ; Elaine W. Lamirande [États-Unis] ; Kevin W. Bock [États-Unis] ; Ian N. Moore [États-Unis] ; Wouter Koudstaal [Pays-Bas] ; Muniza Rehman [Pays-Bas] ; Gerrit Jan Weverling [Pays-Bas] ; Jaap Goudsmit [Pays-Bas] ; Kanta Subbarao [États-Unis]

Source :

Journal of Virology [ 0022-538X ] ; 2017.

RBID : PMC:5709608

Descripteurs français

English descriptors

KwdEn :
- Animals, Antibodies, Monoclonal (administration & dosage), Antibodies, Monoclonal (genetics), Antibodies, Monoclonal (immunology), Antibodies, Neutralizing (administration & dosage), Antibodies, Neutralizing (genetics), Antibodies, Neutralizing (immunology), Antibodies, Viral (administration & dosage), Antibodies, Viral (immunology), Cross Reactions, Hemagglutinin Glycoproteins, Influenza Virus (immunology), Humans, Influenza A Virus, H2N2 Subtype (immunology), Influenza A Virus, H2N2 Subtype (pathogenicity), Influenza, Human (immunology), Influenza, Human (prevention & control), Mice, Neutralization Tests (standards), Orthomyxoviridae Infections (immunology), Orthomyxoviridae Infections (prevention & control), Receptors, IgG (deficiency), Receptors, IgG (genetics), Receptors, IgG (immunology).
MESH :
- chemical , administration & dosage : Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral.
- chemical , deficiency : Receptors, IgG.
- chemical , genetics : Antibodies, Monoclonal, Antibodies, Neutralizing, Receptors, IgG.
- chemical , immunology : Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Hemagglutinin Glycoproteins, Influenza Virus, Receptors, IgG.
- immunology : Influenza A Virus, H2N2 Subtype, Influenza, Human, Orthomyxoviridae Infections.
- pathogenicity : Influenza A Virus, H2N2 Subtype.
- prevention & control : Influenza, Human, Orthomyxoviridae Infections.
- standards : Neutralization Tests.
- Animals, Cross Reactions, Humans, Mice.

Abstract

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.

IMPORTANCE bNAbs represent a strategy to prevent or treat infection by a wide range of influenza viruses. The evaluation of these antibodies against H2 viruses is important because H2 viruses caused a pandemic in 1957 and could cross into humans again. We demonstrate that CR6261 and CR9114 are effective against infection with H2 viruses of both human and animal origin in mice, despite the finding that CR9114 did not display in vitro neutralizing activity against the human H2 virus. These findings emphasize the importance of in vivo evaluation and testing of bNAbs.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709608

DOI: 10.1128/JVI.01603-17
PubMed: 29046448
PubMed Central: 5709608

Affiliations:

Le document en format XML

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 Neutralization Is Not Predictive of Prophylactic Efficacy of Broadly Neutralizing Monoclonal Antibodies CR6261 and CR9114 against Lethal H2 Influenza Virus Challenge in Mice</title>
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 Neutralization Is Not Predictive of Prophylactic Efficacy of Broadly Neutralizing Monoclonal Antibodies CR6261 and CR9114 against Lethal H2 Influenza Virus Challenge in Mice</title>
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<author><name sortKey="Goudsmit, Jaap" sort="Goudsmit, Jaap" uniqKey="Goudsmit J" first="Jaap" last="Goudsmit">Jaap Goudsmit</name>
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<front><div type="abstract" xml:lang="en"><title>ABSTRACT</title>
<p>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 <italic>in vitro</italic>
 activity against human H2 influenza viruses, but the <italic>in vivo</italic>
 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). <italic>In vitro</italic>
, 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 (<italic>Fcer1g</italic>
<sup>−/−</sup>
) mice, we show that the <italic>in vivo</italic>
 efficacy of CR9114 against AA60 is mediated by Fcγ receptor-dependent mechanisms. Collectively, these findings demonstrate the <italic>in vivo</italic>
 efficacy of CR6261 and CR9114 against H2 viruses and emphasize the need for <italic>in vivo</italic>
 evaluation of bNAbs.</p>
<p><bold>IMPORTANCE</bold>
 bNAbs represent a strategy to prevent or treat infection by a wide range of influenza viruses. The evaluation of these antibodies against H2 viruses is important because H2 viruses caused a pandemic in 1957 and could cross into humans again. We demonstrate that CR6261 and CR9114 are effective against infection with H2 viruses of both human and animal origin in mice, despite the finding that CR9114 did not display <italic>in vitro</italic>
 neutralizing activity against the human H2 virus. These findings emphasize the importance of <italic>in vivo</italic>
 evaluation and testing of bNAbs.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>Pays-Bas</li>
<li>États-Unis</li>
</country>
<region><li>Hollande-Méridionale</li>
<li>Maryland</li>
</region>
<settlement><li>Leyde</li>
</settlement>
</list>
<tree><country name="États-Unis"><region name="Maryland"><name sortKey="Sutton, Troy C" sort="Sutton, Troy C" uniqKey="Sutton T" first="Troy C." last="Sutton">Troy C. Sutton</name>
</region>
<name sortKey="Bock, Kevin W" sort="Bock, Kevin W" uniqKey="Bock K" first="Kevin W." last="Bock">Kevin W. Bock</name>
<name sortKey="Lamirande, Elaine W" sort="Lamirande, Elaine W" uniqKey="Lamirande E" first="Elaine W." last="Lamirande">Elaine W. Lamirande</name>
<name sortKey="Moore, Ian N" sort="Moore, Ian N" uniqKey="Moore I" first="Ian N." last="Moore">Ian N. Moore</name>
<name sortKey="Subbarao, Kanta" sort="Subbarao, Kanta" uniqKey="Subbarao K" first="Kanta" last="Subbarao">Kanta Subbarao</name>
</country>
<country name="Pays-Bas"><region name="Hollande-Méridionale"><name sortKey="Koudstaal, Wouter" sort="Koudstaal, Wouter" uniqKey="Koudstaal W" first="Wouter" last="Koudstaal">Wouter Koudstaal</name>
</region>
<name sortKey="Goudsmit, Jaap" sort="Goudsmit, Jaap" uniqKey="Goudsmit J" first="Jaap" last="Goudsmit">Jaap Goudsmit</name>
<name sortKey="Rehman, Muniza" sort="Rehman, Muniza" uniqKey="Rehman M" first="Muniza" last="Rehman">Muniza Rehman</name>
<name sortKey="Weverling, Gerrit Jan" sort="Weverling, Gerrit Jan" uniqKey="Weverling G" first="Gerrit Jan" last="Weverling">Gerrit Jan Weverling</name>
</country>
</tree>
</affiliations>
</record>

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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

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

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