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

Vaccine. 2017 Jan 5;35(2):375-384. doi: 10.1016/j.vaccine.2016.11.010. Epub 2016 Dec 1.

Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Trial registration number: NCT01364571.

Keywords: Capsular polysaccharide; 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

  • Aged
  • Aged, 80 and over
  • Antibodies, Bacterial / blood
  • Antigens, Bacterial / immunology*
  • Bacterial Proteins / immunology
  • Dose-Response Relationship, Immunologic
  • Double-Blind Method
  • Drug-Related Side Effects and Adverse Reactions / epidemiology
  • Female
  • Healthy Volunteers
  • Humans
  • Immunoassay
  • 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*
  • Vaccines, Synthetic / administration & dosage
  • Vaccines, Synthetic / immunology

Substances

  • Antibodies, Bacterial
  • Antigens, Bacterial
  • Bacterial Proteins
  • Opsonin Proteins
  • Placebos
  • Polysaccharides, Bacterial
  • Staphylococcal Vaccines
  • Vaccines, Synthetic

Associated data

  • ClinicalTrials.gov/NCT01364571