title: Safety, tolerability, and immunogenicity of a single dose 4-antigen or 3-antigen Staphylococcus aureus vaccine in healthy older adults: Results of a randomised trial.
abstract: The decline in immune function with age is a challenge to vaccine development. Following an initial study in adults aged 18-64years, this study evaluated the safety and immunogenicity of Staphylococcus aureus (S. aureus) 4-antigen (SA4Ag) and 3-antigen (SA3Ag) vaccine in older adults. SA3Ag included capsular polysaccharide serotypes 5 and 8 (CP5 and CP8) conjugated to the nontoxic mutant form of diphtheria toxin (CRM197) and a recombinant version of clumping factor A (ClfA). SA4Ag included these antigens, with the addition of a recombinant manganese transporter C (rP305A or MntC). Both vaccines were unadjuvanted.
  
  
  
  In this double-blind, sponsor-unblinded, placebo-controlled, phase 1/2 study, 284 healthy adults (aged 65-85years) were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A, SA3Ag, or placebo. Functional immune responses were measured using opsonophagocytic activity (OPA) killing and fibrinogen-binding inhibition (FBI) assays; immunogenicity was also assessed using a competitive Luminex® immunoassay (cLIA). T-cell responses were measured in a small subgroup of subjects using intracellular cytokine staining (ICS) assays.
  
  
  
  The results demonstrated rapid and robust functional immune responses to all antigens in healthy older adults. A high proportion of active vaccine recipients met the pre-defined antibody thresholds for each antigen at Day 29. SA4Ag elicited a dose-level response to rP305A with up to a 13-fold rise in cLIA titres at Day 29. Opsonophagocytic activity (OPA) assays showed >50- and >20-fold rises in functional titres using S. aureus strains expressing CP5 and CP8, respectively, at Day 29. T-cell cytokine responses were not substantially above background levels. There were no safety concerns in this study population and no increases in adverse events with higher rP305A dose levels.
  
  
  
  Single-dose vaccination of SA4Ag and SA3Ag in healthy adults aged 65-85years safely induced rapid and robust functional immune responses, supporting further development of SA4Ag for the prevention of S. aureus disease in adults up to age 85years.
  
  
  
  NCT01643941.
authors.affiliation: Vanderbilt Vaccine Research Program, Vanderbilt University School of Medicine, S-2323 MCN, 1161 21st Avenue South, Nashville, TN 37232, United States. Electronic address: Buddy.creech@vanderbilt.edu.
authors.forename: C Buddy
authors.initials: CB
authors.lastname: Creech
authors.affiliation: Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, United States.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Frenck
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 Inc, 500 Arcola Road, Collegeville, PA 19426, United States.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Zito
authors.affiliation: Pfizer Inc, 401 N Middletown Road, Pearl River, NY 10965, United States.
authors.forename: Douglas
authors.initials: D
authors.lastname: Girgenti
authors.affiliation: 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 Inc, 401 N Middletown Road, Pearl River, NY 10965, United States.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Immermann
authors.affiliation: Pfizer Inc, 401 N Middletown Road, Pearl River, NY 10965, United States.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: McNeil
authors.affiliation: Pfizer Inc, 401 N Middletown Road, Pearl River, NY 10965, United States.
authors.forename: David
authors.initials: D
authors.lastname: Cooper
authors.affiliation: 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 Inc, 401 N Middletown Road, Pearl River, NY 10965, United States.
authors.forename: William
authors.initials: W
authors.lastname: Gruber
authors.affiliation: Pfizer Inc, 401 N Middletown Road, Pearl River, NY 10965, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Eiden
authors.affiliation: 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 Australia Pty Ltd, Sydney, 38-42 Wharf Rd, West Ryde, NSW 2114, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Baber
mesh_terms: D000276:Adjuvants, Immunologic / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000907:Antibodies, Bacterial / Q000097:blood; D000942:Antigens, Bacterial / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000032:analysis; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology; D005260:Female; D006801:Humans; 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*; D013601:T-Lymphocytes / Q000276:immunology; D016896:Treatment Outcome; D018074:Vaccines, Conjugate / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D016207:Cytokines; D009895:Opsonin Proteins; D010919:Placebos; D011135:Polysaccharides, Bacterial; D013209:Staphylococcal Vaccines; D018074:Vaccines, Conjugate; C028581:CRM197 (non-toxic variant of diphtheria toxin)
keywords: Capsular polysaccharides; Clumping factor A; Functional antibodies; Manganese transporter C; Staphylococcus aureus; Vaccine