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: 15.84). 03/2010; 2(24):24ra21. DOI: 10.1126/scitranslmed.3000799
Source: PubMed


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.

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Available from: Wing Pui Kong
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    • "The relevance of this work is further reinforced by recent studies , suggesting that the addition of glycosite on the H1 of H1N1pdm09 could allow the resulting variants to efficiently and rapidly escape from neutralizing antibodies (Job et al., 2013; Medina et al., 2013; Wei et al., 2010). "
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    • "Because of the high morbidity and mortality due to influenza epidemics, monitoring of the accumulated antigenic variations in circulating influenza viruses is important for predicting epidemics, severity, and for the design of future vaccines [7]. Glycosylation at antigenic sites is an important mechanism of immune evasion by influenza virus [2,8,9]. In fact, the well-known seasonal drift of influenza virus antigenicity accounts for the absence of long-term immune protection in previously infected individuals. "
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    ABSTRACT: We present major results concerning isolation and determination of the nucleotide sequence of hemagglutinin (HA1) of the pandemic (H1N1)pdm09 influenza viruses found in Tunisia. Amino acid analysis revealed minor amino acid changes in the antigenic or receptor-binding domains. We found mutations that were also present in 1918 pandemic virus, which includes S183P in 4 and S185T mutation in 19 of 27 viruses analyzed from 2011, while none of the 2009 viruses carried these mutations. Also two specific amino acid differences into N-glycosylation sites (N288T and N276H) were detected. The phylogenetic analysis revealed that the majority of the Tunisian isolates clustered with clade A/St. Petersburg/27/2011 viruses characterized by D97N and S185T mutations. However it also reveals a trend of 2010 strains to accumulate amino acid variation and form new phylogenetic clade with three specific amino acid substitutions: V47I, E172K and K308E.
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    • "The lack of protein bands with molecular weight higher than that of HA0 under reducing conditions indicates that the oligomeric forms observed under non-reducing conditions were disulfide-linked. The A/California/07/2009 HA0 band migrated slightly faster than the HA0 comparators, possibly because A/California/07/2009 HA protein has only a single glycosylation site in the globular head (total five glycosylation sites) in contrast to the nine sites identified in the HA from A/Brisbane/59/2007 H1N1 virus [14,15]. In addition, less cleavage of A/California/07/2009 HA0 into HA1 and HA2 was observed. "
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