title: Safety and immunogenicity of a novel multivalent OspA vaccine against Lyme borreliosis in healthy adults: a double-blind, randomised, dose-escalation phase 1/2 trial.
abstract: BACKGROUND
  Lyme borreliosis is caused by Borrelia burgdorferi sensu stricto in the USA and by several Borrelia species in Europe and Asia, but no human vaccine is available. We investigated the safety and immunogenicity of adjuvanted and non-adjuvanted vaccines containing protective epitopes from Borrelia species outer surface protein A (OspA) serotypes in healthy adults.
  
  
  METHODS
  Between March 1, 2011, and May 8, 2012, we did a double-blind, randomised, dose-escalation phase 1/2 study at four sites in Austria and Germany. Healthy adults aged 18-70 years who were seronegative for B. burgdorferi sensu lato were eligible for inclusion. Participants were recruited sequentially and randomly assigned to one of six study groups in equal ratios via an electronic data capture system. Participants and investigators were masked to group allocation. Participants received three vaccinations containing 30 μg, 60 μg, or 90 μg OspA antigen with or without an adjuvant, with intervals of 28 days, and a booster 9-12 months after the first immunisation. The coprimary endpoints were the frequency and severity of injection-site and systemic reactions within 7 days of each vaccination, and the antibody responses to OspA serotypes 1-6, as established by ELISA. This study is registered with ClinicalTrials.gov, number NCT01504347.
  
  
  RESULTS
  300 participants were randomly assigned: 151 to adjuvanted vaccines (50 to 30 μg, 51 to 60 μg, and 50 to 90 μg doses), and 149 to non-adjuvanted vaccines (50 to 30 μg, 49 to 60 μg, and 50 to 90 μg doses). Adverse reactions were predominantly mild, and no vaccine-related serious adverse events were reported. The risk of systemic reactions (risk ratio 0·54 [95% CI 0·41-0·70]; p<0·0001) and of moderate or severe systemic reactions (0·35 [0·13-0·92]; p=0·034) was significantly lower for adjuvanted than non-adjuvanted formulations. The 30 μg adjuvanted formulation had the best tolerability profile; only headache (five [10%, 95% CI 4-20] of 50), injection-site pain (16 [32%, 21-45]), and tenderness (17 [34%, 23-47]) affected more than 6% of patients. All doses and formulations induced substantial mean IgG antibody titres against OspA serotypes 1-6 after the first three vaccinations (range 6944-17,321) and booster (19,056-32,824) immunisations. The 30 μg adjuvanted formulation induced the highest antibody titres after the booster: range 26,143 (95% CI 18,906-36,151) to 42,381 (31,288-57,407).
  
  
  CONCLUSIONS
  The novel multivalent OspA vaccine could be an effective intervention for prevention of Lyme borreliosis in Europe and the USA, and possibly worldwide. Larger confirmatory formulation studies will need to be done that include individuals seropositive for Borrelia burgdorferi sensu lato before placebo-controlled phase 3 efficacy studies can begin.
  
  
  BACKGROUND
  Baxter.
authors.affiliation: Vaccine R&D, Baxter BioScience, Vienna, Austria.
authors.forename: Nina
authors.initials: N
authors.lastname: Wressnigg
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Pöllabauer
authors.forename: Gerald
authors.initials: G
authors.lastname: Aichinger
authors.forename: Daniel
authors.initials: D
authors.lastname: Portsmouth
authors.forename: Alexandra
authors.initials: A
authors.lastname: Löw-Baselli
authors.forename: Sandor
authors.initials: S
authors.lastname: Fritsch
authors.forename: Ian
authors.initials: I
authors.lastname: Livey
authors.forename: Brian A
authors.initials: BA
authors.lastname: Crowe
authors.forename: Michael
authors.initials: M
authors.lastname: Schwendinger
authors.forename: Peter
authors.initials: P
authors.lastname: Brühl
authors.forename: Andreas
authors.initials: A
authors.lastname: Pilz
authors.forename: Thomas
authors.initials: T
authors.lastname: Dvorak
authors.forename: Julia
authors.initials: J
authors.lastname: Singer
authors.forename: Clair
authors.initials: C
authors.lastname: Firth
authors.forename: Benjamin
authors.initials: B
authors.lastname: Luft
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schmitt
authors.forename: Markus
authors.initials: M
authors.lastname: Zeitlinger
authors.forename: Markus
authors.initials: M
authors.lastname: Müller
authors.forename: Herwig
authors.initials: H
authors.lastname: Kollaritsch
authors.forename: Maria
authors.initials: M
authors.lastname: Paulke-Korinek
authors.forename: Meral
authors.initials: M
authors.lastname: Esen
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kremsner
authors.forename: Hartmut J
authors.initials: HJ
authors.lastname: Ehrlich
authors.forename: P Noel
authors.initials: PN
authors.lastname: Barrett
mesh_terms: D000276:Adjuvants, Immunologic / Q000009:adverse effects*; D000328:Adult; D000954:Antigens, Surface / Q000009:adverse effects* / Q000276:immunology*; D001425:Bacterial Outer Membrane Proteins / Q000009:adverse effects* / Q000276:immunology*; D001428:Bacterial Vaccines / Q000009:adverse effects* / Q000276:immunology*; D025065:Borrelia burgdorferi / Q000276:immunology*; D004311:Double-Blind Method; D005260:Female; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008074:Lipoproteins / Q000009:adverse effects* / Q000276:immunology*; D022123:Lyme Disease Vaccines / Q000009:adverse effects* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000139:chemically induced; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D000954:Antigens, Surface; D001425:Bacterial Outer Membrane Proteins; D001428:Bacterial Vaccines; D007074:Immunoglobulin G; D008074:Lipoproteins; D022123:Lyme Disease Vaccines; C072045:OspA protein