title: Safety, tolerability, and immunogenicity of a 4-antigen Staphylococcus aureus vaccine (SA4Ag): Results from a first-in-human randomised, placebo-controlled phase 1/2 study.
abstract: A prophylactic Staphylococcus aureus four-antigen vaccine (SA4Ag) is under development for prevention of invasive S. aureus disease. A preliminary S. aureus three-antigen vaccine (SA3Ag) was reformulated to include a novel manganese transporter protein (MntC or rP305A). This study describes the first-in-human dose-finding, safety, and immunogenicity results for SA4Ag.
  
  
  
  In this double-blind, sponsor-unblind, placebo-controlled, phase 1/2 study, 454 healthy adults aged 18-64years were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A or placebo. Functional immune responses were measured using opsonophagocytic activity (OPA) killing and fibrinogen-binding inhibition (FBI) assays; antigen-specific immunogenicity was assessed using a four-plex competitive Luminex® immunoassay (cLIA).
  
  
  
  A high proportion of SA4Ag recipients met the pre-defined antibody thresholds for each antigen at Day 29. A substantial and dose-level dependent immune response was observed for rP305A, with up to 18-fold rises in cLIA titres at Day 29. Robust functional responses were demonstrated, with >80-fold and >20-fold rises in OPA assay titres at Day 29 using S. aureus strains expressing capsular polysaccharide serotypes 5 and 8, respectively. Durable antibody responses were observed through month 12, gradually waning from peak levels achieved by days 11-15. SA4Ag was well tolerated, and no vaccine-related serious adverse events were reported.
  
  
  
  Single-dose vaccination of SA4Ag in healthy adults aged 18-64years safely induced rapid and robust functional immune responses that were durable through month 12, supporting further development of this vaccine.
  
  
  
  NCT01364571.
authors.affiliation: Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, United States. Electronic address: robert.frenck@cchmc.org.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Frenck
authors.affiliation: Vanderbilt Vaccine Research Program, Vanderbilt University School of Medicine, S-2323 MCN, 1161 21st Avenue South, Nashville, TN 37232, United States.
authors.forename: C Buddy
authors.initials: CB
authors.lastname: Creech
authors.affiliation: Miami Research Associates, 6141 Sunset Dr., South Miami, FL 33143, United States.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Sheldon
authors.affiliation: Broward Research Group, 7261 Sheridan Street, Suite 210, Hollywood, FL 33024, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Seiden
authors.affiliation: Vince and Associates Clinical Research, 10103 Metcalf Ave, Overland Park, KS 66212, United States.
authors.forename: Martin K
authors.initials: MK
authors.lastname: Kankam
authors.affiliation: Pfizer Australia Pty Ltd, Sydney, 38-42 Wharf Rd, West Ryde, NSW 2114, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Baber
authors.affiliation: Pfizer Vaccine Research and Development, Pfizer Inc, 500 Arcola Road, Collegeville, PA 19426, United States.
authors.forename: Edward
authors.initials: E
authors.lastname: Zito
authors.affiliation: Pfizer Vaccine Research and Development, Pfizer Inc, 500 Arcola Road, Collegeville, PA 19426, United States.
authors.forename: Robin
authors.initials: R
authors.lastname: Hubler
authors.affiliation: Pfizer Vaccine Research and Development, Pfizer Inc, 401 N Middletown Road, Pearl River, NY 10965, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Eiden
authors.affiliation: Pfizer Vaccine Research and Development, Pfizer Inc, 401 N Middletown Road, Pearl River, NY 10965, United States.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Severs
authors.affiliation: Pfizer Vaccine Research and Development, Pfizer Inc, 401 N Middletown Road, Pearl River, NY 10965, United States.
authors.forename: Shite
authors.initials: S
authors.lastname: Sebastian
authors.affiliation: Pfizer Vaccine Research and Development, Pfizer Inc, 401 N Middletown Road, Pearl River, NY 10965, United States.
authors.forename: Jasdeep
authors.initials: J
authors.lastname: Nanra
authors.affiliation: Pfizer Vaccine Research and Development, Pfizer Inc, 401 N Middletown Road, Pearl River, NY 10965, United States.
authors.forename: Kathrin U
authors.initials: KU
authors.lastname: Jansen
authors.affiliation: Pfizer Vaccine Research and Development, Pfizer Inc, 401 N Middletown Road, Pearl River, NY 10965, United States.
authors.forename: William C
authors.initials: WC
authors.lastname: Gruber
authors.affiliation: Pfizer Vaccine Research and Development, Pfizer Inc, 401 N Middletown Road, Pearl River, NY 10965, United States.
authors.forename: Annaliesa S
authors.initials: AS
authors.lastname: Anderson
authors.affiliation: Pfizer Vaccine Research and Development, Pfizer Inc, 401 N Middletown Road, Pearl River, NY 10965, United States.
authors.forename: Douglas
authors.initials: D
authors.lastname: Girgenti
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000907:Antibodies, Bacterial / Q000097:blood; D000942:Antigens, Bacterial / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007118:Immunoassay; D008297:Male; D009895:Opsonin Proteins / Q000097:blood; D010587:Phagocytosis; D010919:Placebos / Q000008:administration & dosage; D011135:Polysaccharides, Bacterial / Q000276:immunology; D013209:Staphylococcal Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D009895:Opsonin Proteins; D010919:Placebos; D011135:Polysaccharides, Bacterial; D013209:Staphylococcal Vaccines; D014614:Vaccines, Synthetic
keywords: Capsular polysaccharide; Clumping factor A; Functional antibodies; Manganese transporter C; Staphylococcus aureus; Vaccine