Conserved Neutralization Epitope on the Hemagglutinins of Avian and Human Influenza A Viruses belonging to Group 1
Session VI – Ruben O. Donis
Title of Contribution: Conserved Neutralization Epitope on the Hemagglutinins of Avian and Human Influenza A Viruses belonging to Group 1
Author(s): Jianhua Sui 1, William C. Hwang 2, Sandra Perez 3, Ge Wei 2, Daniel Aird 1, Li-mei Chen 3, Eugenio Santelli 2, Boguslaw Stec 2, Greg Cadwell 2, Maryam Ali 1, Hongquan Wan 3, Akikazu Murakami 1, Anuradha Yammanuru 1, Thomas Han 1, Nancy J. Cox3, Laurie A. Bankston 2, Ruben O. Donis 3, Robert C. Liddington 2 and Wayne A. Marasco 1
Affiliation(s): 1Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
2Infectious and Inflammatory Disease Center, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
3Influenza Division, Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases, Atlanta, GA 30333, USA.
Presenting author: Underlined. Email: rdonis@cdc.gov
Session: Later Breaker Abstracts; Vaccinology and Prevention
Abstract: Human monoclonal antibodies (mAb) to recombinant H5 hemagglutinin (HA) ectodomain identified from a phage display library neutralized a remarkably broad range of avian and human influenza viruses with HA subtypes belonging to Group 1, including highly pathogenic H5N1 viruses from a variety of clades as well as pseudotyped 1918 H1N1 pandemic virus. In a micro-neutralization assay, the mAbs also neutralized contemporary H1N1 viruses and viruses of the H2N2, H6N1, H6N2, H8N4, and H9N2subtypes. These mAbs also neutralized H2-, H6- and H11-pseudotyped virus infections. However, none of the mAbs neutralized Group 2 viruses, e.g., H3N2 and H7N7.
The crystal structure of mAb F10 complexed with H5 HA revealed that the epitope is located in the stem region, below the globular head. The IgG heavy chain of mAb F10 inserts into a highly conserved pocket in the HA stem, inhibiting conformational changes required for membrane fusion, blocking infection. The F10 epitope residues involved in atomic contacts with the mAb are strictly conserved among all HA subtypes in Group 1, including H5 HAs belonging to multiple clades.
Mice treated with three mAb IgG1s before or after lethal viral challenge with A/Vietnam/1203/04 (H5N1, Clade 1) or A/HongKong/483/97 (H5N1, Clade 0) viruses were effectively protected (80-100%) and showed minimal body weight loss over the 2-week observation period. mAB treatment caused significantly reduced viral replication in the lungs as well as reducing spleen virus titers by ≥ 1000-fold.
Our studies raise the possibility that neutralizing Abs targeting this epitope could provide broad protection against seasonal and pandemic influenza A infections caused by viruses with Group 1 hemagglutinins.
