tetano
Editor, Senior Moderator
J Virol. 2019 Aug 2. pii: JVI.00840-19. doi: 10.1128/JVI.00840-19. [Epub ahead of print]
[h=1]Extending the stalk enhances immunogenicity of the influenza virus neuraminidase.[/h] Broecker F[SUP]1[/SUP], Zheng A[SUP]1[/SUP], Suntrongwong N[SUP]2[/SUP], Sun W[SUP]1[/SUP], Bailey MJ[SUP]1[/SUP], Krammer F[SUP]1[/SUP], Palese P[SUP]3,[/SUP][SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Influenza viruses express two surface glycoproteins, the hemagglutinin (HA) and the neuraminidase (NA). Anti-NA antibodies protect from lethal influenza virus challenge in the mouse model and correlate inversely with virus shedding and symptoms in humans. Consequently, the NA is a promising target for influenza virus vaccine design. Current seasonal vaccines, however, poorly induce anti-NA antibodies, partly because of the immunodominance of the HA over the NA when both glycoproteins are closely associated. To address this issue, we here investigated whether extending the stalk domain of the NA could render it more immunogenic on virus particles. Two recombinant influenza viruses based on the H1N1 strain A/Puerto Rico/8/1934 (PR8) were rescued with NA stalk domains extended by 15 or 30 amino acids. Formalin-inactivated viruses expressing wild type NA or the stalk-extended NA variants were used to vaccinate mice. Compared to the wild type PR8 virus, the virus with the 30 amino acid stalk extension induced significantly higher anti-NA IgG responses characterized by increased in vitro antibody-dependent cellular cytotoxicity (ADCC) activity, while anti-HA IgG levels were unaffected. Similarly, extending the stalk domain of the NA of a recent H3N2 virus enhanced the induction of anti-NA IgGs in mice. Based on these results we hypothesize that the subdominance of the NA can be modulated if the protein is modified such that it surpasses the height of the HA on the viral membrane. Extending the stalk domain of NA may help to enhance its immunogenicity in influenza virus vaccines without compromising antibody responses to HA.IMPORTANCE The efficacy of influenza virus vaccines could be improved by enhancing the immunogenicity of the NA protein. One of the reasons for its poor immunogenicity is the immunodominance of the HA over the NA in many seasonal influenza virus vaccines. Here we demonstrate that, in the mouse model, extending the stalk domain of the NA protein can enhance its immunogenicity on virus particles and overcome the immunodominance of the HA without affecting antibody responses to the HA. The antibody repertoire is broadened by the extended NA and includes additional ADCC-active antibodies. Our findings may assist in the efforts towards more effective influenza virus vaccines.
Copyright ? 2019 American Society for Microbiology.
PMID: 31375573 DOI: 10.1128/JVI.00840-19
[h=1]Extending the stalk enhances immunogenicity of the influenza virus neuraminidase.[/h] Broecker F[SUP]1[/SUP], Zheng A[SUP]1[/SUP], Suntrongwong N[SUP]2[/SUP], Sun W[SUP]1[/SUP], Bailey MJ[SUP]1[/SUP], Krammer F[SUP]1[/SUP], Palese P[SUP]3,[/SUP][SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Influenza viruses express two surface glycoproteins, the hemagglutinin (HA) and the neuraminidase (NA). Anti-NA antibodies protect from lethal influenza virus challenge in the mouse model and correlate inversely with virus shedding and symptoms in humans. Consequently, the NA is a promising target for influenza virus vaccine design. Current seasonal vaccines, however, poorly induce anti-NA antibodies, partly because of the immunodominance of the HA over the NA when both glycoproteins are closely associated. To address this issue, we here investigated whether extending the stalk domain of the NA could render it more immunogenic on virus particles. Two recombinant influenza viruses based on the H1N1 strain A/Puerto Rico/8/1934 (PR8) were rescued with NA stalk domains extended by 15 or 30 amino acids. Formalin-inactivated viruses expressing wild type NA or the stalk-extended NA variants were used to vaccinate mice. Compared to the wild type PR8 virus, the virus with the 30 amino acid stalk extension induced significantly higher anti-NA IgG responses characterized by increased in vitro antibody-dependent cellular cytotoxicity (ADCC) activity, while anti-HA IgG levels were unaffected. Similarly, extending the stalk domain of the NA of a recent H3N2 virus enhanced the induction of anti-NA IgGs in mice. Based on these results we hypothesize that the subdominance of the NA can be modulated if the protein is modified such that it surpasses the height of the HA on the viral membrane. Extending the stalk domain of NA may help to enhance its immunogenicity in influenza virus vaccines without compromising antibody responses to HA.IMPORTANCE The efficacy of influenza virus vaccines could be improved by enhancing the immunogenicity of the NA protein. One of the reasons for its poor immunogenicity is the immunodominance of the HA over the NA in many seasonal influenza virus vaccines. Here we demonstrate that, in the mouse model, extending the stalk domain of the NA protein can enhance its immunogenicity on virus particles and overcome the immunodominance of the HA without affecting antibody responses to the HA. The antibody repertoire is broadened by the extended NA and includes additional ADCC-active antibodies. Our findings may assist in the efforts towards more effective influenza virus vaccines.
Copyright ? 2019 American Society for Microbiology.
PMID: 31375573 DOI: 10.1128/JVI.00840-19