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Vaccines and Antiviral Agents

Enhancing Neuraminidase Immunogenicity of Influenza A Viruses by Rewiring RNA Packaging Signals

Allen Zheng, Weina Sun, Xiaoli Xiong, Alec W. Freyn, Julia Peukes, Shirin Strohmeier, Raffael Nachbagauer, John A. G. Briggs, Florian Krammer, Peter Palese
Stacey Schultz-Cherry, Editor
Allen Zheng
aDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Weina Sun
aDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Xiaoli Xiong
bStructural Studies Division, Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom
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Alec W. Freyn
aDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Julia Peukes
bStructural Studies Division, Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom
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Shirin Strohmeier
aDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Raffael Nachbagauer
aDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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John A. G. Briggs
bStructural Studies Division, Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom
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Florian Krammer
aDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Peter Palese
aDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
cDepartment of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Stacey Schultz-Cherry
St. Jude Children's Research Hospital
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DOI: 10.1128/JVI.00742-20
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ABSTRACT

Humoral immune protection against influenza virus infection is mediated largely by antibodies against hemagglutinin (HA) and neuraminidase (NA), the two major glycoproteins on the virus surface. While influenza virus vaccination efforts have focused mainly on HA, NA-based immunity has been shown to reduce disease severity and provide heterologous protection. Current seasonal vaccines do not elicit strong anti-NA responses—in part due to the immunodominance of the HA protein. Here, we demonstrate that by swapping the 5′ and 3′ terminal packaging signals of the HA and NA genomic segments, which contain the RNA promoters, we are able to rescue influenza viruses that express more NA and less HA. Vaccination with formalin-inactivated “rewired” viruses significantly enhances the anti-NA antibody response compared to vaccination with unmodified viruses. Passive transfer of sera from mice immunized with rewired virus vaccines shows better protection against influenza virus challenge. Our results provide evidence that the immunodominance of HA stems in part from its abundance on the viral surface, and that rewiring viral packaging signals—thereby increasing the NA content on viral particles—is a viable strategy for improving the immunogenicity of NA in an influenza virus vaccine.

IMPORTANCE Influenza virus infections are a major source of morbidity and mortality worldwide. Increasing evidence highlights neuraminidase as a potential vaccination target. This report demonstrates the efficacy of rewiring influenza virus packaging signals for creating vaccines with more neuraminidase content which provide better neuraminidase (NA)-based protection.

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Enhancing Neuraminidase Immunogenicity of Influenza A Viruses by Rewiring RNA Packaging Signals
Allen Zheng, Weina Sun, Xiaoli Xiong, Alec W. Freyn, Julia Peukes, Shirin Strohmeier, Raffael Nachbagauer, John A. G. Briggs, Florian Krammer, Peter Palese
Journal of Virology Jul 2020, 94 (16) e00742-20; DOI: 10.1128/JVI.00742-20

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Enhancing Neuraminidase Immunogenicity of Influenza A Viruses by Rewiring RNA Packaging Signals
Allen Zheng, Weina Sun, Xiaoli Xiong, Alec W. Freyn, Julia Peukes, Shirin Strohmeier, Raffael Nachbagauer, John A. G. Briggs, Florian Krammer, Peter Palese
Journal of Virology Jul 2020, 94 (16) e00742-20; DOI: 10.1128/JVI.00742-20
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KEYWORDS

immunodominance
influenza
neuraminidase
packaging signal
vaccine

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