title: Design and Characterization of a Computationally Optimized Broadly Reactive Hemagglutinin Vaccine for H1N1 Influenza Viruses.
abstract: One of the challenges of developing influenza A vaccines is the diversity of antigenically distinct isolates. Previously, a novel hemagglutinin (HA) for H5N1 influenza was derived from a methodology termed computationally optimized broadly reactive antigen (COBRA). This COBRA HA elicited a broad antibody response against H5N1 isolates from different clades. We now report the development and characterization of a COBRA-based vaccine for both seasonal and pandemic H1N1 influenza virus isolates. Nine prototype H1N1 COBRA HA proteins were developed and tested in mice using a virus-like particle (VLP) format for the elicitation of broadly reactive, functional antibody responses and protection against viral challenge. These candidates were designed to recognize H1N1 viruses isolated within the last 30 years. In addition, several COBRA candidates were designed based on sequences of H1N1 viruses spanning the past 100 years, including modern pandemic H1N1 isolates. Four of the 9 H1N1 COBRA HA proteins (X1, X3, X6, and P1) had the broadest hemagglutination inhibition (HAI) activity against a panel of 17 H1N1 viruses. These vaccines were used in cocktails or prime-boost combinations. The most effective regimens that both elicited the broadest HAI response and protected mice against a pandemic H1N1 challenge were vaccines that contained the P1 COBRA VLP and either the X3 or X6 COBRA VLP vaccine. These mice had little or no detectable viral replication, comparable to that observed with a matched licensed vaccine. This is the first report describing a COBRA-based HA vaccine strategy that elicits a universal, broadly reactive, protective response against seasonal and pandemic H1N1 isolates.
  
  
  OBJECTIVE
  Universal influenza vaccine approaches have the potential to be paradigm shifting for the influenza vaccine field, with the goal of replacing the current standard of care with broadly cross-protective vaccines. We have used COBRA technology to develop an HA head-based strategy that elicits antibodies against many H1 strains that have undergone genetic drift and has potential as a "subtype universal" vaccine. Nine HA COBRA candidates were developed, and these vaccines were used alone, in cocktails or in prime-boost combinations. The most effective regimens elicited the broadest hemagglutination inhibition (HAI) response against a panel of H1N1 viruses isolated over the past 100 years. This is the first report describing a COBRA-based HA vaccine strategy that elicits a broadly reactive response against seasonal and pandemic H1N1 isolates.
authors.affiliation: Center for Vaccines and Immunology, Department of Infectious Diseases, University of Georgia, Athens, Georgia, USA.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Carter
authors.affiliation: Center for Vaccines and Immunology, Department of Infectious Diseases, University of Georgia, Athens, Georgia, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Darby
authors.affiliation: Center for Vaccines and Immunology, Department of Infectious Diseases, University of Georgia, Athens, Georgia, USA.
authors.forename: Bradford C
authors.initials: BC
authors.lastname: Lefoley
authors.affiliation: Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida, USA.
authors.forename: Corey J
authors.initials: CJ
authors.lastname: Crevar
authors.affiliation: Sanofi Pasteur, Cambridge, Massachusetts, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Alefantis
authors.affiliation: Sanofi Pasteur, Cambridge, Massachusetts, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Oomen
authors.affiliation: Sanofi Pasteur, Cambridge, Massachusetts, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Anderson
authors.affiliation: Sanofi Pasteur, Cambridge, Massachusetts, USA.
authors.forename: Tod
authors.initials: T
authors.lastname: Strugnell
authors.affiliation: Sanofi Pasteur, Cambridge, Massachusetts, USA.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Cortés-Garcia
authors.affiliation: Sanofi Pasteur, Cambridge, Massachusetts, USA.
authors.forename: Thorsten U
authors.initials: TU
authors.lastname: Vogel
authors.affiliation: Sanofi Pasteur, Cambridge, Massachusetts, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Parrington
authors.affiliation: Sanofi Pasteur, Cambridge, Massachusetts, USA.
authors.forename: Harold
authors.initials: H
authors.lastname: Kleanthous
authors.affiliation: Center for Vaccines and Immunology, Department of Infectious Diseases, University of Georgia, Athens, Georgia, USA tedross@uga.edu.
authors.forename: Ted M
authors.initials: TM
authors.lastname: Ross
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D000914:Antibodies, Viral / Q000276:immunology / Q000378:metabolism; D000956:Antigens, Viral / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D004195:Disease Models, Animal; D006385:Hemagglutination Inhibition Tests; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007114:Immunization; D053118:Influenza A Virus, H1N1 Subtype / Q000145:classification / Q000235:genetics / Q000276:immunology* / Q000648:ultrastructure; D007252:Influenza Vaccines / Q000276:immunology*; D007251:Influenza, Human / Q000517:prevention & control; D051379:Mice; D008958:Models, Molecular; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000517:prevention & control; D010802:Phylogeny; D011485:Protein Binding / Q000276:immunology; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D058425:Vaccines, Virus-Like Particle / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D000956:Antigens, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D058425:Vaccines, Virus-Like Particle