title: Large-scale analysis of B-cell epitopes on influenza virus hemagglutinin - implications for cross-reactivity of neutralizing antibodies.
abstract: Influenza viruses continue to cause substantial morbidity and mortality worldwide. Fast gene mutation on surface proteins of influenza virus result in increasing resistance to current vaccines and available antiviral drugs. Broadly neutralizing antibodies (bnAbs) represent targets for prophylactic and therapeutic treatments of influenza. We performed a systematic bioinformatics study of cross-reactivity of neutralizing antibodies (nAbs) against influenza virus surface glycoprotein hemagglutinin (HA). This study utilized the available crystal structures of HA complexed with the antibodies for the analysis of tens of thousands of HA sequences. The detailed description of B-cell epitopes, measurement of epitope area similarity among different strains, and estimation of antibody neutralizing coverage provide insights into cross-reactivity status of existing nAbs against influenza virus. We have developed a method to assess the likely cross-reactivity potential of bnAbs for influenza strains, either newly emerged or existing. Our method catalogs influenza strains by a new concept named discontinuous peptide, and then provide assessment of cross-reactivity. Potentially cross-reactive strains are those that share 100% identity with experimentally verified neutralized strains. By cataloging influenza strains and their B-cell epitopes for known bnAbs, our method provides guidance for selection of representative strains for further experimental design. The knowledge of sequences, their B-cell epitopes, and differences between historical influenza strains, we enhance our preparedness and the ability to respond to the emerging pandemic threats.
authors.affiliation: Cancer Vaccine Center, Dana-Farber Cancer Institute, Harvard Medical School , Boston, MA , USA ; Department of Medicine, Harvard Medical School , Boston, MA , USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Cancer Vaccine Center, Dana-Farber Cancer Institute, Harvard Medical School , Boston, MA , USA ; Center for Biological Sequence Analysis, Technical University of Denmark , Lyngby , Denmark.
authors.forename: Ulrich J
authors.initials: UJ
authors.lastname: Kudahl
authors.affiliation: Cancer Vaccine Center, Dana-Farber Cancer Institute, Harvard Medical School , Boston, MA , USA ; Center for Biological Sequence Analysis, Technical University of Denmark , Lyngby , Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Simon
authors.affiliation: School of Life Sciences and Technology, Tongji University , Shanghai , China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Cancer Vaccine Center, Dana-Farber Cancer Institute, Harvard Medical School , Boston, MA , USA ; Department of Medicine, Harvard Medical School , Boston, MA , USA ; Laboratory of Immunobiology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School , Boston, MA , USA.
authors.forename: Ellis L
authors.initials: EL
authors.lastname: Reinherz
authors.affiliation: Cancer Vaccine Center, Dana-Farber Cancer Institute, Harvard Medical School , Boston, MA , USA ; Department of Medicine, Harvard Medical School , Boston, MA , USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Brusic
keywords: B-cell epitope; cross-reactivity; discontinuous peptide; influenza virus; neutralizing antibodies