title: Safety and immunogenicity of a plant-produced recombinant monomer hemagglutinin-based influenza vaccine derived from influenza A (H1N1)pdm09 virus: a Phase 1 dose-escalation study in healthy adults.
abstract: BACKGROUND
  Novel influenza viruses continue to pose a potential pandemic threat worldwide. In recent years, plants have been used to produce recombinant proteins, including subunit vaccines. A subunit influenza vaccine, HAC1, based on recombinant hemagglutinin from the 2009 pandemic A/California/04/2009 (H1N1) strain of influenza virus, has been manufactured using a plant virus-based transient expression technology in Nicotiana benthamiana plants and demonstrated to be immunogenic and safe in pre-clinical studies (Shoji et al., 2011).
  
  
  METHODS
  A first-in-human, Phase 1, single-center, randomized, placebo-controlled, single-blind, dose escalation study was conducted to investigate safety, reactogenicity and immunogenicity of an HAC1 formulation at three escalating dose levels (15 μg, 45 μg and 90 μg) with and without Alhydrogel(®), in healthy adults 18-50 years of age (inclusive). Eighty participants were randomized into six study vaccine groups, a saline placebo group and an approved monovalent H1N1 vaccine group. Recipients received two doses of vaccine or placebo (except for the monovalent H1N1 vaccine cohort, which received a single dose of vaccine, later followed by a dose of placebo).
  
  
  RESULTS
  The experimental vaccine was safe and well tolerated, and comparable to placebo and the approved monovalent H1N1 vaccine. Pain and tenderness at the injection site were the only local solicited reactions reported following vaccinations. Nearly all adverse events were mild to moderate in severity. The HAC1 vaccine was also immunogenic, with the highest seroconversion rates, based on serum hemagglutination-inhibition and virus microneutralization antibody titers, in the 90 μg non-adjuvanted HAC1 vaccine group after the second vaccine dose (78% and 100%, respectively).
  
  
  CONCLUSIONS
  This is the first study demonstrating the safety and immunogenicity of a plant-produced subunit H1N1 influenza vaccine in healthy adults. The results support further clinical investigation of the HAC1 vaccine as well as demonstrate the feasibility of the plant-based technology for vaccine antigen production.
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA. Electronic address: james.f.cummings6.mil@mail.mil.
authors.forename: James F
authors.initials: JF
authors.lastname: Cummings
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Guerrero
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Moon
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
authors.forename: Paige
authors.initials: P
authors.lastname: Waterman
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
authors.forename: Robin K
authors.initials: RK
authors.lastname: Nielsen
authors.affiliation: Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: Stacie
authors.initials: S
authors.lastname: Jefferson
authors.affiliation: Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: F Liaini
authors.initials: FL
authors.lastname: Gross
authors.affiliation: Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: Kathy
authors.initials: K
authors.lastname: Hancock
authors.affiliation: Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Katz
authors.affiliation: Fraunhofer USA Center for Molecular Biotechnology, Newark, DE 19711, USA.
authors.forename: Vidadi
authors.initials: V
authors.lastname: Yusibov
mesh_terms: D000328:Adult; D000914:Antibodies, Viral / Q000097:blood; D005260:Female; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D007251:Influenza, Human / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000276:immunology; D016037:Single-Blind Method; D014026:Nicotiana; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000914:Antibodies, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D011994:Recombinant Proteins; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic
keywords: H1N1; Hemagglutinin; Influenza A; Plant-produced; Recombinant vaccine