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Editor's Pick Research Article

Influenza Virus Hemagglutinin Stalk-Specific Antibodies in Human Serum are a Surrogate Marker for In Vivo Protection in a Serum Transfer Mouse Challenge Model

Henning Jacobsen, Madhusudan Rajendran, Angela Choi, Haakon Sjursen, Karl A. Brokstad, Rebecca J. Cox, Peter Palese, Florian Krammer, Raffael Nachbagauer
Rino Rappuoli, Editor
Henning Jacobsen
a Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Madhusudan Rajendran
a Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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  • ORCID record for Madhusudan Rajendran
Angela Choi
a Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
b Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Haakon Sjursen
c Influenza Centre, Department of Clinical Science, University of Bergen, Bergen, Norway
d Section for Infectious Diseases, Medical Department, Haukeland University Hospital, Bergen, Norway
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Karl A. Brokstad
e Department of Clinical Science, Broeglemann Research Laboratory, University of Bergen, Bergen, Norway
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Rebecca J. Cox
d Section for Infectious Diseases, Medical Department, Haukeland University Hospital, Bergen, Norway
f KG Jebsen Centre for Influenza Vaccine Research, Department of Clinical Science, University of Bergen, Bergen, Norway
g Department of Research and Development, Haukeland University Hospital, Bergen, Norway
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Peter Palese
a Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Florian Krammer
a Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Raffael Nachbagauer
a Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Rino Rappuoli
GSK Vaccines
Roles: Editor
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Mark Mulligan
Emory University
Roles: Solicited external reviewer
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Daniel Perez
University of Georgia
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DOI: 10.1128/mBio.01463-17
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ABSTRACT

The immunogenicity of current influenza virus vaccines is assessed by measuring an increase of influenza virus-specific antibodies in a hemagglutination inhibition assay. This method exclusively measures antibodies against the hemagglutinin head domain. While this domain is immunodominant, it has been shown that hemagglutination inhibition titers do not always accurately predict protection from disease. In addition, several novel influenza virus vaccines that are currently under development do not target the hemagglutinin head domain, but rather more conserved sites, including the hemagglutinin stalk. Importantly, antibodies against the hemagglutinin stalk do not show activity in hemagglutination inhibition assays and will require different methods for quantification. In this study, we tested human serum samples from a seasonal influenza virus vaccination trial and an avian H5N1 virus vaccination trial for antibody activities in multiple types of assays, including binding assays and also functional assays. We then performed serum transfer experiments in mice which then received an H1N1 virus challenge to assess the in vivo protective effects of the antibodies. We found that hemagglutinin-specific antibody levels measured in an enzyme-linked immunosorbent assay (ELISA) correlated well with protection from weight loss in mice. In addition, we found that weight loss was also inversely correlated with the level of serum antibody-dependent cellular cytotoxicity (ADCC) as measured in a reporter assay. These findings indicate that protection is in part conferred by Fc-dependent mechanisms. In conclusion, ELISAs can be used to measure hemagglutinin-specific antibody levels that could serve as a surrogate marker of protection for universal influenza virus vaccines.

IMPORTANCE Influenza viruses are a serious concern for public health and cause a large number of deaths worldwide every year. Current influenza virus vaccines can confer protection from disease, but they often show low efficacy due to the ever-changing nature of the viruses. Novel vaccination approaches target conserved epitopes of the virus, including the hemagglutinin stalk domain, to elicit universally protective antibodies that also bind to mutated viruses or new subtypes of viruses. Importantly, the hemagglutination inhibition assay—the only assay that has been accepted as a correlate of protection by regulatory authorities—cannot measure antibodies against the hemagglutinin stalk domain. Therefore, novel correlates of protection and assays to measure vaccine immunogenicity need to be developed. In this study, we correlated the results from multiple assays with protection in mice after transfer of human serum and a lethal virus challenge to investigate potential novel serological surrogate markers for protection.

FOOTNOTES

    • Received 15 August 2017
    • Accepted 21 August 2017
    • Published 19 September 2017
  • Copyright © 2017 Jacobsen et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license .

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Influenza Virus Hemagglutinin Stalk-Specific Antibodies in Human Serum are a Surrogate Marker for In Vivo Protection in a Serum Transfer Mouse Challenge Model
Henning Jacobsen, Madhusudan Rajendran, Angela Choi, Haakon Sjursen, Karl A. Brokstad, Rebecca J. Cox, Peter Palese, Florian Krammer, Raffael Nachbagauer
mBio Sep 2017, 8 (5) e01463-17; DOI: 10.1128/mBio.01463-17

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Influenza Virus Hemagglutinin Stalk-Specific Antibodies in Human Serum are a Surrogate Marker for In Vivo Protection in a Serum Transfer Mouse Challenge Model
Henning Jacobsen, Madhusudan Rajendran, Angela Choi, Haakon Sjursen, Karl A. Brokstad, Rebecca J. Cox, Peter Palese, Florian Krammer, Raffael Nachbagauer
mBio Sep 2017, 8 (5) e01463-17; DOI: 10.1128/mBio.01463-17
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KEYWORDS

Antibodies, Viral
Hemagglutinin Glycoproteins, Influenza Virus
Immunization, Passive
Immunogenicity, Vaccine
Influenza A Virus, H1N1 Subtype
Influenza A Virus, H5N1 Subtype
Orthomyxoviridae Infections
ADCC
ELISA
correlate of protection
hemagglutinin
hemagglutinin stalk
influenza
influenza vaccines
surrogate marker
universal influenza virus vaccine

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