Human antibodies that neutralize respiratory droplet transmissible H5N1 influenza viruses
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.
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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Brief Report Immunology

Human antibodies that neutralize respiratory droplet transmissible H5N1 influenza viruses

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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Figure 3

Computational modeling of mAb H5.3 complex with VN/1203 HA.

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Computational modeling of mAb H5.3 complex with VN/1203 HA. (A) Model of...
(A) Model of H5.3 in complex with VN/1203 HA overlaid with EM density map in transparent pale blue. VN/1203 HA is shown as a gray ribbon with heavy chain in light blue and light chain in pink. Green spheres show the position of variant mutations in the rdt VN/1203 or Indonesia strains. K193 is shown as magenta spheres. The peptide containing contact residues identified by DXMS is indicated in dark blue, and residues in the receptor-binding site are indicated in orange. The image to the right shows the preferred binding mode with light chain on top (orientation B). (B) Interaction of H5.3 complementarity determining region with VN/1203 HA head domain. The surface of HA is represented with residues of the receptor-binding site colored bright orange, variant mutations from the rdt VN/1203 or Indonesia strains colored green, and residues in the peptide with altered deuterium exchange upon H5.3 binding colored dark blue. Heavy-chain complementarity determining regions (CDRs) are in shades of blue; light-chain CDRs and framework region 3 are in shades of pink. The K193 residue, colored in magenta, interacts with a polar cavity formed by the light chain. Residues 110–111.2 of HCDR3 (IMGT numbering, shown as sticks) insert into the receptor-binding site. The H5.3 footprint avoids significant contact with rdt mutant residues.