Article

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.

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    • "Despite rapid worldwide spread, the recent 2009 pandemic was milder in nature than the 1918 pandemic [Franco-Paredes et al., 2009]. Structural analysis of the HA protein of H1N1pdm09 has revealed remarkable similarity to its 1918 counterpart in terms of antigenic epitopes along with dual binding to a2-3 as well as a2-6-linked sialic acid receptors [Ding et al., 2009; Shen et al., 2009; Wei et al., 2010; Xu et al., 2010]. While phylogenetic analysis of the circulating pandemic viruses have revealed genetically homogeneous virus, it is likely that antibody-mediated selection pressure and continuous circulation of H1N1pdm09 in humans may result in altered antigenicity [Morens et al., 2010]. "
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    ABSTRACT: Genetic analysis of pandemic 2009 influenza A (H1N1; H1N1pdm09) virus was undertaken to understand virus evolution during 2009 and 2010 in India. Surveillance of influenza viruses from July 2009 to December 2010 revealed major peaks of circulating H1N1pdm09 viruses in August-September and December-January 2009 and then in August-September 2010. To understand the diversity of the H1N1pdm09 virus, selected specimens (n = 23) from 2009 or 2010 were characterized by nucleotide sequence determination of the HA1 subunit of the HA gene. Phylogenetic analysis revealed that 22 clustered with clade 7 viruses characterized by S203T mutations, whereas one virus from 2010 fell within clade 6. None of the viruses from either 2009 or 2010 formed a monophyletic group, suggesting a continuum of independent introduction of circulating viral strains. Amino acid analysis revealed minor amino acid changes in the antigenic or receptor-binding domains. Importantly, we observed mutations that were also present in 1918 pandemic virus, which includes S183P in 4 and S185T mutation in 3 of 13 viruses analyzed from 2010, while none of the 2009 viruses carried these mutations. Whether antibody-mediated pressure is imposing such changes remains to be determined. Continued genetic surveillance is warranted to monitor pathogenicity as the virus evolves to acquire new features.
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    • "Despite rapid worldwide spread, the recent 2009 pandemic was milder in nature than the 1918 pandemic [Franco-Paredes et al., 2009]. Structural analysis of the HA protein of H1N1pdm09 has revealed remarkable similarity to its 1918 counterpart in terms of antigenic epitopes along with dual binding to a2-3 as well as a2-6-linked sialic acid receptors [Ding et al., 2009; Shen et al., 2009; Wei et al., 2010; Xu et al., 2010]. While phylogenetic analysis of the circulating pandemic viruses have revealed genetically homogeneous virus, it is likely that antibody-mediated selection pressure and continuous circulation of H1N1pdm09 in humans may result in altered antigenicity [Morens et al., 2010]. "
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    • "The studies also revealed that the 2009 HA contains conserved epitopes that existed in the 1918 Spanish flu HA protein [3] [4] [5]. The conservation has explained cross-reactivity of antibodies between the two pandemic viruses and prior immune memory against the current pandemic strain of the older population [5] [6]. "
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