title: Recognition of influenza H3N2 variant virus by human neutralizing antibodies.
abstract: Since 2011, over 300 human cases of infection, especially in exposed children, with the influenza A H3N2 variant (H3N2v) virus that circulates in swine in the US have been reported. The structural and genetic basis for the lack of protection against H3N2v induced by vaccines containing seasonal H3N2 antigens is poorly understood. We isolated 17 human monoclonal antibodies (mAbs) that neutralized H3N2v virus from subjects experimentally immunized with an H3N2v candidate vaccine. Six mAbs exhibited very potent neutralizing activity (IC50< 200 ng/ml) against the H3N2v virus but not against current human H3N2 circulating strains. Fine epitope mapping and structural characterization of antigen-antibody complexes revealed that H3N2v specificity was attributable to amino acid polymorphisms in the 150-loop and the 190-helix antigenic sites on the hemagglutinin protein. H3N2v-specific antibodies also neutralized human H3N2 influenza strains naturally circulating between 1995 and 2005. These results reveal a high level of antigenic relatedness between the swine H3N2v virus and previously circulating human strains, consistent with the fact that early human H3 seasonal strains entered the porcine population in the 1990s and reentered the human population, where they had not been circulating, as H3N2v about a decade later. The data also explain the increased susceptibility to H3N2v viruses in young children, who lack prior exposure to human seasonal strains from the 1990s.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Bangaru
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Travis
authors.initials: T
authors.lastname: Nieusma
authors.affiliation: Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Nurgun
authors.initials: N
authors.lastname: Kose
authors.affiliation: Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Thornburg
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Finn
authors.affiliation: Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Bryan S
authors.initials: BS
authors.lastname: Kaplan
authors.affiliation: Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Hannah G
authors.initials: HG
authors.lastname: King
authors.affiliation: Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Vidisha
authors.initials: V
authors.lastname: Singh
authors.affiliation: Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Lampley
authors.affiliation: Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Gopal
authors.initials: G
authors.lastname: Sapparapu
authors.affiliation: Chemical and Physical Biology Program, Vanderbilt University University, Nashville, Tennessee, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Cisneros
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Edwards
authors.affiliation: Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Slaughter
authors.affiliation: The Hope Clinic of Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA; Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Srilatha
authors.initials: S
authors.lastname: Edupuganti
authors.affiliation: The Hope Clinic of Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA; Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Lilin
authors.initials: L
authors.lastname: Lai
authors.affiliation: College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, USA.
authors.forename: Juergen A
authors.initials: JA
authors.lastname: Richt
authors.affiliation: Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Webby
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Ward
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Crowe