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

Vaccine. 2017 Jan 5;35(2):385-394. doi: 10.1016/j.vaccine.2016.11.032. Epub 2016 Nov 17.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Trial registration number: NCT01643941.

Keywords: Capsular polysaccharides; Clumping factor A; Functional antibodies; Manganese transporter C; Staphylococcus aureus; Vaccine.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / metabolism
  • Aged
  • Aged, 80 and over
  • Antibodies, Bacterial / blood
  • Antigens, Bacterial / immunology*
  • Bacterial Proteins / immunology
  • Bacterial Proteins / metabolism
  • Cytokines / analysis
  • Double-Blind Method
  • Drug-Related Side Effects and Adverse Reactions / epidemiology
  • Female
  • Humans
  • Male
  • Opsonin Proteins / blood
  • Phagocytosis
  • Placebos / administration & dosage
  • Polysaccharides, Bacterial / immunology
  • Staphylococcal Vaccines / administration & dosage
  • Staphylococcal Vaccines / adverse effects*
  • Staphylococcal Vaccines / immunology*
  • Staphylococcus aureus / immunology*
  • T-Lymphocytes / immunology
  • Treatment Outcome
  • Vaccines, Conjugate / administration & dosage
  • Vaccines, Conjugate / immunology

Substances

  • Adjuvants, Immunologic
  • Antibodies, Bacterial
  • Antigens, Bacterial
  • Bacterial Proteins
  • Cytokines
  • Opsonin Proteins
  • Placebos
  • Polysaccharides, Bacterial
  • Staphylococcal Vaccines
  • Vaccines, Conjugate
  • CRM197 (non-toxic variant of diphtheria toxin)

Associated data

  • ClinicalTrials.gov/NCT01643941