title: Robust mucosal-homing antibody-secreting B cell responses induced by intramuscular administration of adjuvanted bivalent human norovirus-like particle vaccine.
abstract: BACKGROUND
  Two major antigenically heterogenous norovirus genogroups (GI and GII) commonly infect humans and are the leading cause of foodborne, viral gastrointestinal infections in adults.
  
  
  METHODS
  We assessed B cell responses in participants in a double-blind, placebo-controlled, dose-escalation phase 1 study of the safety and immunogenicity of an intramuscular bivalent norovirus virus-like particle (VLP) vaccine. The vaccine contained a GI.1 VLP (Norwalk) and a consensus GII.4 VLP, representing the two major genotypes that cause human disease, and was administered on days 0 and 28 to healthy adults aged 18-49 years. Four separate cohorts received increasing doses of 5 μg, 15 μg, 50 μg, and 150 μg of each VLP adjuvanted in monophosphoryl lipid A and alum. PBMCs were analyzed for B cell activation and mucosal homing markers (flow cytometry) and VLP-specific and total IgG and IgA Ab-secreting cells (ASCs); and serum titers of VLP-specific IgG, IgA, and Pan-Ig were determined.
  
  
  RESULTS
  The vaccine elicited CD27+ CD38+ plasmablasts and high frequencies of ASCs specific for both VLP antigens in the peripheral blood at 7 days after the first dose. The plasmablasts exhibited a mucosal-homing phenotype and included a high proportion of IgA ASCs. Serum antibodies increased as early as 7 days after the first immunization.
  
  
  CONCLUSIONS
  The data suggest that a single dose of the IM bivalent norovirus vaccine is effective in activating pre-existing B cell memory. The rapid B cell response and the mucosal homing phenotype of induced ASCs are consistent with anamnestic responses in subjects primed by prior oral norovirus infection. This study is registered at ClinicalTrials.gov Identifier NCT01609257.
authors.affiliation: Center for Vaccine Biology & Immunology, Department of Microbiology & Immunology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 609, Rochester, NY 14642, USA.
authors.forename: Aarthi
authors.initials: A
authors.lastname: Sundararajan
authors.affiliation: Center for Vaccine Biology & Immunology, Department of Microbiology & Immunology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 609, Rochester, NY 14642, USA.
authors.forename: Mark Y
authors.initials: MY
authors.lastname: Sangster
authors.affiliation: Saint Louis University, School of Medicine, 1402 South Grand Boulevard, St. Louis, MO 63104, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Frey
authors.affiliation: Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Atmar
authors.affiliation: Center for Vaccine Development, The University of Maryland Medical School, 685 West Baltimore Street, Room 480, Baltimore, MD 21201, USA.
authors.forename: Wilbur H
authors.initials: WH
authors.lastname: Chen
authors.affiliation: The EMMES Corporation, 401 North Washington Street, Suite 700, Rockville, MD 20850, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ferreira
authors.affiliation: Takeda Vaccines (Montana), Inc., 2155 Analysis Drive, Bozeman, MT 59718, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Bargatze
authors.affiliation: Takeda Vaccines (Montana), Inc., 2155 Analysis Drive, Bozeman, MT 59718, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Mendelman
authors.affiliation: Division of Infectious Disease, Department of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 689, Rochester, NY 14642, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Treanor
authors.affiliation: Center for Vaccine Biology & Immunology, Department of Microbiology & Immunology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 609, Rochester, NY 14642, USA. Electronic address: david_topham@urmc.rochester.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Topham
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000293:Adolescent; D000328:Adult; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D018928:Immunity, Mucosal; D007114:Immunization / Q000379:methods; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007273:Injections, Intramuscular; D008297:Male; D008875:Middle Aged; D029322:Norovirus / Q000276:immunology*; D010919:Placebos / Q000008:administration & dosage; D016896:Treatment Outcome; D058425:Vaccines, Virus-Like Particle / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014765:Viral Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D010919:Placebos; D058425:Vaccines, Virus-Like Particle; D014765:Viral Vaccines
keywords: Antibody; B cell; Mucosal; Norovirus; Vaccine