title: Development of an Alternative Modified Live Influenza B Virus Vaccine.
abstract: Influenza B virus (IBV) is considered a major human pathogen, responsible for seasonal epidemics of acute respiratory illness. Two antigenically distinct IBV hemagglutinin (HA) lineages cocirculate worldwide with little cross-reactivity. Live attenuated influenza virus (LAIV) vaccines have been shown to provide better cross-protective immune responses than inactivated vaccines by eliciting local mucosal immunity and systemic B cell- and T cell-mediated memory responses. We have shown previously that incorporation of temperature-sensitive (ts) mutations into the PB1 and PB2 subunits along with a modified HA epitope tag in the C terminus of PB1 resulted in influenza A viruses (IAV) that are safe and effective as modified live attenuated (att) virus vaccines (IAVatt). We explored whether analogous mutations in the IBV polymerase subunits would result in a stable virus with anattphenotype. The PB1 subunit of the influenza B/Brisbane/60/2008 strain was used to incorporatetsmutations and a C-terminal HA tag. Such modifications resulted in a B/Brisattstrain withtscharacteristicsin vitroand anattphenotypein vivoVaccination studies in mice showed that a single dose of the B/Brisattcandidate stimulated sterilizing immunity against lethal homologous challenge and complete protection against heterologous challenge. These studies show the potential of an alternative LAIV platform for the development of IBV vaccines.IMPORTANCEA number of issues with regard to the effectiveness of the LAIV vaccine licensed in the United States (FluMist) have arisen over the past three seasons (2013-2014, 2014-2015, and 2015-2016). While the reasons for the limited robustness of the vaccine-elicited immune response remain controversial, this problem highlights the critical importance of continued investment in LAIV development and creates an opportunity to improve current strategies so as to develop more efficacious vaccines. Our laboratory has developed an alternative strategy, the incorporation of 2 amino acid mutations and a modified HA tag at the C terminus of PB1, which is sufficient to attenuate the IBV. As a LAIV, this novel vaccine provides complete protection against IBV strains. The availability of attenuated IAV and IBV backbones based on contemporary strains offers alternative platforms for the development of LAIVs that may overcome current limitations.
authors.affiliation: Department of Population Health, Poultry Diagnostic and Research Center, University of Georgia, Athens, Georgia, USA.|Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland, USA.
authors.forename: Jefferson J S
authors.identifier: http://orcid.org/0000-0001-5895-4163
authors.initials: JJS
authors.lastname: Santos
authors.affiliation: Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Finch
authors.affiliation: Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland, USA.
authors.forename: Troy
authors.initials: T
authors.lastname: Sutton
authors.affiliation: Department of Population Health, Poultry Diagnostic and Research Center, University of Georgia, Athens, Georgia, USA.|Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland, USA.
authors.forename: Adebimpe
authors.initials: A
authors.lastname: Obadan
authors.affiliation: Department of Population Health, Poultry Diagnostic and Research Center, University of Georgia, Athens, Georgia, USA.
authors.forename: Isabel
authors.initials: I
authors.lastname: Aguirre
authors.affiliation: Department of Population Health, Poultry Diagnostic and Research Center, University of Georgia, Athens, Georgia, USA.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Wan
authors.affiliation: Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Lopez
authors.affiliation: Department of Population Health, Poultry Diagnostic and Research Center, University of Georgia, Athens, Georgia, USA.
authors.forename: Ginger
authors.initials: G
authors.lastname: Geiger
authors.affiliation: Department of Population Health, Poultry Diagnostic and Research Center, University of Georgia, Athens, Georgia, USA.|Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland, USA.
authors.forename: Ana Silvia
authors.initials: AS
authors.lastname: Gonzalez-Reiche
authors.affiliation: Department of Population Health, Poultry Diagnostic and Research Center, University of Georgia, Athens, Georgia, USA.
authors.forename: Lucas
authors.initials: L
authors.lastname: Ferreri
authors.affiliation: Department of Population Health, Poultry Diagnostic and Research Center, University of Georgia, Athens, Georgia, USA dperez1@uga.edu.|Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland, USA.
authors.forename: Daniel R
authors.identifier: http://orcid.org/0000-0002-6569-5689
authors.initials: DR
authors.lastname: Perez
mesh_terms: D000596:Amino Acids / Q000235:genetics; D000818:Animals; D000940:Antigenic Variation / Q000235:genetics / Q000276:immunology; D016679:Genome, Viral; D006801:Humans; D056724:Immunity, Humoral; D009981:Influenza B virus / Q000201:enzymology / Q000276:immunology*; D007252:Influenza Vaccines / Q000235:genetics / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D008168:Lung / Q000473:pathology / Q000821:virology; D051379:Mice; D009154:Mutation; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology; D014613:Vaccines, Attenuated / Q000276:immunology; D015164:Vaccines, Inactivated / Q000276:immunology
chemical_list: D000596:Amino Acids; D007252:Influenza Vaccines; D014613:Vaccines, Attenuated; D015164:Vaccines, Inactivated
keywords: T cell immunity; antigenic variation; humoral immunity; influenza B; influenza vaccines; live vector vaccines; orthomyxovirus; viral immunity