Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses

Sui, J. et al. Nature structural & molecular biology. 16, 265-273 (2009)

Speaker: Shi-Yu Chao (趙世宇)                           Time: 13:00~14:00, Sep. 16, 2009

Commentator: Dr. Pin Ling (凌斌老師)               Place: Room 601

Abstract:

        Influenza A continuously menaces human health. Seasonal influenza epidemics cause about 250,000-500,000 deaths per year¹. The influenza virus is able to evade the host immune system owing to rapid antigenic drift and shift that can result in reduced vaccine effectiveness². Therefore,there is still no broad and long-term protective vaccine for influenza virus. In this article, authors proposed that human mAb-based immunotherapy could be used in influenza infection. At first, authors fished out ten neutralizing antibodies (nAb) from a human non-immune antibody phage-display library. To identify nAbs binding activity, they examined and found all ten nAbs could bind trimeric H5 hemagglutinin and neutralizing H5 viruses. NAbs also showed the prophylactic and therapeutic efficacy against H5N1 virus infection in a BALB/c mouse model. From these results, authors suggested that the mechanism of neutralization was by nAbs interfering the virus-host membrane fusion rather than by blocking the hemagglutinin bind to cellular receptor. To verify this mechanism, authors solved the H5-nAb complex structure by X-ray crystallography and the structure showed that the nAb interfered H5 by its V_H CDRs directly bound into the HA hydrophobic pocket that located below the receptor binding head. The epitope region contained fusion peptide and helix aA that were required for HA structural reorganization and membrane fusion. Therefore, the nAb binding inhibited HA conformational change and prevented the virus-host membrane fusion. Furthermore, authors aligned all of the available hemagglutinin sequence, and showed that many epitope residues were highly conserved across all 16 hemagglutinin subtypes. In cross-subtype neutralization test, they found that nAbs were able to bind a broad range of group 1 HA subtypes including H5N1, H1N1, H2N2, H6N2, H11N9, H13N6, H16N3 and H9N2 virus strains, because their epitope structures were highly similar. Encouragingly, virus-infected cells were treated with nAbafter three in vitro passages, there did not find any neutralization-escape mutants. This study suggests that we can use in vitro approach to generate new neutralizing antibodies for passive immunotherapy, and we have possible to develop a universal influenza virus vaccine in the future.

References:

1. WHO factsheet 211: influenza (2009) World Health Organization.

2. Carrat, F., and Flahault, A. Influenza vaccine: The challenge of antigenic drift. (2007) Vaccine. 25, 6852-6862.