Preparing for the worst
H5N1 is a highly pathogenic variant of avian influenza that has a high mortality rate in humans that have contracted the disease. Currently, H5N1 transmission is limited to people that have had direct contact with infected birds; however, resent controversial studies have revealed that a small number of mutations in the viral gene encoding hemagglutin (HA) render the virus transmissible between ferrets via respiratory droplets. Should H5N1 become transmissible between humans, vaccines will be critical for preventing a pandemic. Natalie Thornburg and colleagues at Vanderbilt University, identified antibodies from people that had previously received a vaccine containing various H5N1 HAs that were able to bind to and neutralize both the WT and respiratory transmissible HA. The most effective antibodies bound HA at the head region and blocked the receptor-binding site of both the respiratory transmissible HA and WT HA. This study indicates that this critical antigenic site should be incorporated in the development of future H5N1 vaccines. The above image is a computational model of one of the mABs identified by Thornburg and colleagues in complex with WT H5N1 HA. H5N1 HA is shown as a gray ribbon and the mAb heavy chain is aqua and the mAb light chain is pink. Green spheres show the position of respiratory droplet transmissible variant mutations. The magenta spheres represent another common H5N1 HA variant. The peptide containing identified contact residues is indicated in dark blue, and residues in the HA receptor-binding site are indicated in orange.
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Abstract
Recent studies described the experimental adaptation of influenza H5 HAs that confers respiratory droplet transmission (rdt) to influenza virus in ferrets. Acquisition of the ability to transmit via aerosol may lead to the development of a highly pathogenic pandemic H5 virus. Vaccines are predicted to play an important role in H5N1 control should the virus become readily transmissible between humans. We obtained PBMCs from patients who received an A/Vietnam/1203/2004 H5N1 subunit vaccine. Human hybridomas were then generated and characterized. We identified antibodies that bound the HA head domain and recognized both WT and rdt H5 HAs. We used a combination of structural techniques to define a mechanism of antibody recognition of an H5 HA receptor–binding site that neutralized H5N1 influenza viruses and pseudoviruses carrying the HA rdt variants that have mutations near the receptor-binding site. Incorporation or retention of this critical antigenic site should be considered in the design of novel H5 HA immunogens to protect against mammalian-adapted H5N1 mutants.
Authors
Natalie J. Thornburg, David P. Nannemann, David L. Blum, Jessica A. Belser, Terrence M. Tumpey, Shyam Deshpande, Gloria A. Fritz, Gopal Sapparapu, Jens C. Krause, Jeong Hyun Lee, Andrew B. Ward, David E. Lee, Sheng Li, Katie L. Winarski, Benjamin W. Spiller, Jens Meiler, James E. Crowe Jr.
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ISSN: 0021-9738 (print), 1558-8238 (online)