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Induction of broadly-reactive anti-hemagglutinin stalk antibodies by an H5N1 vaccine in humans

Raffael Nachbagauer, Teddy John Wohlbold, Ariana Hirsh, Rong Hai, Haakon Sjursen, Peter Palese, Rebecca J. Coxand, Florian Krammer
Raffael Nachbagauer
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Teddy John Wohlbold
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Ariana Hirsh
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Rong Hai
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Haakon Sjursen
3The Influenza Centre, Department of Clinical Science, University of Bergen, Norway
4Section for Infectious Diseases, Medical Department, Haukeland University Hospital, Bergen, Norway
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Peter Palese
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
5Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Rebecca J. Coxand
3The Influenza Centre, Department of Clinical Science, University of Bergen, Norway
6Jebsen Centre for Influenza Vaccine Research, Department of Clinical Science, University of Bergen, Bergen, Norway
7Department of Research and Development, Haukeland University Hospital, Bergen, Norway
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  • For correspondence: florian.krammer@mssm.edu Rebecca.Cox@gades.uib.no
Florian Krammer
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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  • For correspondence: florian.krammer@mssm.edu Rebecca.Cox@gades.uib.no
DOI: 10.1128/JVI.02133-14
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ABSTRACT

Influenza virus infections are a major public health concern and cause significant morbidity and mortality worldwide. Current vaccines are effective but strain specific due to their focus on the immunodominant globular head domain of the hemagglutinin. It has been hypothesized that sequential exposure of humans to hemagglutinins with divergent globular head domains but conserved stalk domains could refocus the immune response to broadly neutralizing epitopes in the stalk. Humans have pre-existing immunity against H1 (group 1 hemagglutinin) and vaccination with H5 HA (also group 1) – which has a divergent globular head domain but a similar stalk domain – represents one such sequential exposure scenario. To test this hypothesis, we used novel reagents based on chimeric hemagglutinins to screen sera from an H5N1 clinical trial for induction of stalk-specific antibodies by quantitative ELISA and neutralization assays. Importantly, we also investigated the biological activity of these antibodies in a passive transfer in a mouse challenge model. We found that the H5N1 vaccine induced high titers of stalk-reactive antibodies which were biologically active and protective in the passive transfer experiment. The induced response showed exceptional breadth towards divergent group 1 hemagglutinins but did not extend to group 2 hemagglutinins. This data provides evidence for the hypothesis that sequential exposure to hemagglutinins with divergent globular head domains but conserved stalk domains can refocus the immune response towards the conserved stalk domain. Furthermore, the results support the concept of a chimeric hemagglutinin universal influenza virus vaccine strategy that is based on the same principle.

Significance Influenza virus vaccines have to be re-formulated and re-administered on an annual basis. The development of a universal influenza virus vaccine could abolish the need for this cumbersome and costly process and would also enhance our pandemic preparedness. This study addressed the following questions that are essential for the development of a hemagglutinin stalk based universal influenza virus vaccine: 1) Can stalk-reactive antibodies be boosted by vaccination with divergent HAs that share conserved epitopes? 2) How long-lived are these vaccine induced stalk-reactive antibody responses? 3) What is the breadth of this reactivity. 4) Are these antibodies functional and protective? Our results further strengthen the concept of induction of stalk-reactive antibodies by sequential exposure to hemagglutinin immunogens with conserved stalk and divergent head domains. A universal influenza virus vaccine based on the same principles seems possible and might have a significant impact on global human health.

FOOTNOTES

  • ↵* To whom correspondence should be addressed: florian.krammer{at}mssm.edu and Rebecca.Cox{at}gades.uib.no
  • Copyright © 2014, American Society for Microbiology. All Rights Reserved.
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Induction of broadly-reactive anti-hemagglutinin stalk antibodies by an H5N1 vaccine in humans
Raffael Nachbagauer, Teddy John Wohlbold, Ariana Hirsh, Rong Hai, Haakon Sjursen, Peter Palese, Rebecca J. Coxand, Florian Krammer
Journal of Virology Sep 2014, JVI.02133-14; DOI: 10.1128/JVI.02133-14

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Induction of broadly-reactive anti-hemagglutinin stalk antibodies by an H5N1 vaccine in humans
Raffael Nachbagauer, Teddy John Wohlbold, Ariana Hirsh, Rong Hai, Haakon Sjursen, Peter Palese, Rebecca J. Coxand, Florian Krammer
Journal of Virology Sep 2014, JVI.02133-14; DOI: 10.1128/JVI.02133-14
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