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Vaccines and Antiviral Agents

Neuraminidase-Inhibiting Antibody Titers Correlate with Protection from Heterologous Influenza Virus Strains of the Same Neuraminidase Subtype

Lisa Walz, Sarah-Katharina Kays, Gert Zimmer, Veronika von Messling
Stacey Schultz-Cherry, Editor
Lisa Walz
aVeterinary Medicine Division, Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Langen, Germany
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Sarah-Katharina Kays
aVeterinary Medicine Division, Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Langen, Germany
bGerman Centre for Infection Research (DZIF), TTU Emerging Infections, Langen, Germany
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Gert Zimmer
cInstitute of Virology and Immunology, Mittelhäusern, Switzerland
dDepartment of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Veronika von Messling
aVeterinary Medicine Division, Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Langen, Germany
bGerman Centre for Infection Research (DZIF), TTU Emerging Infections, Langen, Germany
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Stacey Schultz-Cherry
St. Jude Children's Research Hospital
Roles: Editor
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DOI: 10.1128/JVI.01006-18
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ABSTRACT

Immune responses induced by currently licensed inactivated influenza vaccines are mainly directed against the hemagglutinin (HA) glycoprotein, the immunodominant antigen of influenza viruses. The resulting antigenic drift of HA requires frequent updating of the vaccine composition and annual revaccination. On the other hand, the levels of antibodies directed against the neuraminidase (NA) glycoprotein, the second major influenza virus antigen, vary greatly. To investigate the potential of the more conserved NA protein for the induction of subtype-specific protection, vesicular stomatitis virus-based replicons expressing a panel of N1 proteins from prototypic seasonal and pandemic H1N1 strains and human H5N1 and H7N9 isolates were generated. Immunization of mice and ferrets with the replicon carrying the matched N1 protein resulted in robust humoral and cellular immune responses and protected against challenge with the homologous influenza virus with an efficacy similar to that of the matched HA protein, illustrating the potential of the NA protein as a vaccine antigen. The extent of protection after immunization with mismatched N1 proteins correlated with the level of cross-reactive neuraminidase-inhibiting antibody titers. Passive serum transfer experiments in mice confirmed that these functional antibodies determine subtype-specific cross-protection. Our findings illustrate the potential of NA-specific immunity for achieving broader protection against antigenic drift variants or newly emerging viruses carrying the same NA but a different HA subtype.

IMPORTANCE Despite the availability of vaccines, annual influenza virus epidemics cause 250,000 to 500,000 deaths worldwide. Currently licensed inactivated vaccines, which are standardized for the amount of the hemagglutinin (HA) antigen, primarily induce strain-specific antibodies, whereas the immune response to the neuraminidase (NA) antigen, which is also present on the viral surface, is usually low. Using NA-expressing single-cycle vesicular stomatitis virus replicons, we show that the NA antigen conferred protection of mice and ferrets against not only the matched influenza virus strains but also viruses carrying NA proteins from other strains of the same subtype. The extent of protection correlated with the level of cross-reactive NA-inhibiting antibodies. This highlights the potential of the NA antigen for the development of more broadly protective influenza vaccines. Such vaccines may also provide partial protection against newly emerging strains with the same NA but a different HA subtype.

FOOTNOTES

    • Received 8 June 2018.
    • Accepted 10 June 2018.
    • Accepted manuscript posted online 20 June 2018.
  • Address correspondence to Veronika von Messling, veronika.vonmessling{at}pei.de.
  • Citation Walz L, Kays S-K, Zimmer G, von Messling V. 2018. Neuraminidase-inhibiting antibody titers correlate with protection from heterologous influenza virus strains of the same neuraminidase subtype. J Virol 92:e01006-18. https://doi.org/10.1128/JVI.01006-18.

  • Copyright © 2018 American Society for Microbiology.

All Rights Reserved.

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Neuraminidase-Inhibiting Antibody Titers Correlate with Protection from Heterologous Influenza Virus Strains of the Same Neuraminidase Subtype
Lisa Walz, Sarah-Katharina Kays, Gert Zimmer, Veronika von Messling
Journal of Virology Aug 2018, 92 (17) e01006-18; DOI: 10.1128/JVI.01006-18

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Neuraminidase-Inhibiting Antibody Titers Correlate with Protection from Heterologous Influenza Virus Strains of the Same Neuraminidase Subtype
Lisa Walz, Sarah-Katharina Kays, Gert Zimmer, Veronika von Messling
Journal of Virology Aug 2018, 92 (17) e01006-18; DOI: 10.1128/JVI.01006-18
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KEYWORDS

correlates of protection
functional antibodies
influenza A virus
neuraminidase protein
VSV replicon vaccine platform

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