Cross-neutralization of 1918 and 2009 influenza viruses: role of glycans in viral evolution and vaccine design.

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-3005, USA.
Science translational medicine (Impact Factor: 14.41). 03/2010; 2(24):24ra21. DOI: 10.1126/scitranslmed.3000799
Source: PubMed

ABSTRACT New strains of H1N1 influenza virus have emerged episodically over the last century to cause human pandemics, notably in 1918 and recently in 2009. Pandemic viruses typically evolve into seasonal forms that develop resistance to antibody neutralization, and cross-protection between strains separated by more than 3 years is uncommon. Here, we define the structural basis for cross-neutralization between two temporally distant pandemic influenza viruses--from 1918 and 2009. Vaccination of mice with the 1918 strain protected against subsequent lethal infection by 2009 virus. Both were resistant to antibodies directed against a seasonal influenza, A/New Caledonia/20/1999 (1999 NC), which was insensitive to antisera to the pandemic strains. Pandemic strain-neutralizing antibodies were directed against a subregion of the hemagglutinin (HA) receptor binding domain that is highly conserved between the 1918 and the 2009 viruses. In seasonal strains, this region undergoes amino acid diversification but is shielded from antibody neutralization by two highly conserved glycosylation sites absent in the pandemic strains. Pandemic HA trimers modified by glycosylation at these positions were resistant to neutralizing antibodies to wild-type HA. Yet, antisera generated against the glycosylated HA mutant neutralized it, suggesting that the focus of the immune response can be selectively changed with this modification. Collectively, these findings define critical determinants of H1N1 viral evolution and have implications for vaccine design. Immunization directed to conserved receptor binding domain subregions of pandemic viruses could potentially protect against similar future pandemic viruses, and vaccination with glycosylated 2009 pandemic virus may limit its further spread and transformation into a seasonal influenza.

1 Bookmark
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The location and number of glycosylation in HA proteins exhibit large variations among H5 subtype avian influenza viruses (AIVs). To investigate the effect of glycosylation in the globular head of HA on the pathogenicity and antigenicity of H5N1 AIVs, seven rescued AIVs differing in their glycosylation patterns (144N, 158N and 169N) within the HA globular head of A/Mallard/Huadong/S/2005 were generated using site directed mutagenesis. Results showed that loss of glycosylation 158N was the prerequisite for H5 AIV binding to the α2,6-linked receptor. Only in conjunction with the removal of the 158N glycosylation, the H5 AIVs harboring both 144N and 169N glycosylations obtained an optimal binding preference to the α2,6-linked receptor. Compared with the wild-type virus, growth of viruses lacking glycosylation at either 158N or 169N was significantly reduced both in MDCK and A549 cells, while replication of viruses with additional glycosylation 144N was significantly promoted. Mutant viruses with loss of 158N or 169N glycosylation sites showed increased pathogenicity, systemic spread and pulmonary inflammation in mice compared to the wild-type H5N1 virus. In addition, chicken studies demonstrated that inactivated de-glycosylation 169N mutant induced cross-reaction HI and neutralization antibody against various clades of H5N1 AIVs. Moreover, this type of glycan pattern vaccine virus provided better cross-protection in chickens compared to wild-type vaccine virus. Thus, the glycosylation alteration of HA should be considered in the global surveillance and vaccine design of H5 subtype AIVs. Copyright © 2014 Elsevier B.V. All rights reserved.
    Veterinary Microbiology 12/2014; 175(2-4). DOI:10.1016/j.vetmic.2014.12.011 · 2.73 Impact Factor
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: Prior immunity against influenza A viruses generates sterilizing immunity against matched (homologous) viruses and varying levels of protection against mismatched (heterologous) viruses of the same or different subtypes. Natural immunity carries the risk of high morbidity and mortality, therefore immunization offers the best preventative measure. Antibody responses against the viral hemagglutinin protein correlate with protection in humans and evidence increasingly supports a role for robust cellular immune responses. By exploiting mismatched immunity, current conventional and experimental vaccine candidates can improve the generation of cross-protective immune responses against heterologous viruses. Experimental vaccines such as virus-like particles, DNA vectors, viral vectors and broadly neutralizing antibodies are able to expand cross-protection through mismatched B- and T-cell responses. However, the generation of mismatched immune responses can also have the opposite effect and impair protective immunity. This review discusses mismatched immunity in the context of natural infection and immunization. Additionally, we discuss strategies to exploit mismatched immunity in order to improve current conventional and experimental influenza A virus vaccines.
    Future Virology 11/2012; 7(11):1065-1076. DOI:10.2217/fvl.12.105 · 1.00 Impact Factor

Full-text (2 Sources)

Available from
Jun 2, 2014