A randomized placebo-controlled phase II study of a Pseudomonas vaccine in ventilated ICU patients.
Currently, no vaccine against Pseudomonas is available. IC43 is a new, recombinant, protein (OprF/I)-based vaccine against the opportunistic pathogen, Pseudomonas aeruginosa, a major cause of serious hospital-acquired infections. IC43 has proven immunogenicity and tolerability in healthy volunteers, patients with burns, and patients with chronic lung diseases. In order to assess the immunogenicity and safety of IC43 in patients who are most at risk of acquiring Pseudomonas infections, it was evaluated in mechanically ventilated ICU patients.



We conducted a randomized, placebo-controlled, partially blinded study in mechanically ventilated ICU patients. The immunogenicity of IC43 at day 14 was determined as the primary endpoint, and safety, efficacy against P. aeruginosa infections, and all-cause mortality were evaluated as secondary endpoints. Vaccinations (100 μg or 200 μg IC43 with adjuvant, or 100 μg IC43 without adjuvant, or placebo) were given twice in a 7-day interval and patients were followed up for 90 days.



Higher OprF/I IgG antibody titers were seen at day 14 for all IC43 groups versus placebo (P < 0.0001). Seroconversion (≥4-fold increase in OprF/I IgG titer from days 0 to 14) was highest with 100 μg IC43 without adjuvant (80.6%). There were no significant differences in P. aeruginosa infection rates, with a low rate of invasive infections (pneumonia or bacteremia) in the IC43 groups (11.2-14.0%). Serious adverse events (SAEs) considered possibly related to therapy were reported by 2 patients (1.9%) in the group of 100 µg IC43 with adjuvant. Both SAEs resolved and no deaths were related to study treatment. Local tolerability symptoms were mild and rare (<5% of patients), a low rate of treatment-related treatment-emergent adverse events (3.1-10.6%) was observed in the IC43 groups.



This phase II study has shown that IC43 vaccination of ventilated ICU patients produced a significant immunogenic effect. P. aeruginosa infection rates did not differ significantly between groups. In the absence of any difference in immune response following administration of 100 μg IC43 without adjuvant compared with 200 μg IC43 with adjuvant, the 100 μg dose without adjuvant was considered for further testing of its possible benefit of improved outcomes. There were no safety or mortality concerns.



ClinicalTrials.gov, NCT00876252 . Registered on 3 April 2009.
Hospital Universitari Joan XXIII, C. Dr. Mallafrè Guasch 4, 43007, Tarragona, Spain. jrello@crips.es.|CIBERES, Hospital Universitari Vall d'Hebron, Passeig Vall d'Hebron, 119, 08035, Barcelona, Spain. jrello@crips.es.|Universitat Autonoma de Barcelona, Barcelona, Spain. jrello@crips.es.
Jordi
0000-0003-0676-6210
J
Rello
Medical University of Vienna, Intensive Care 13C1, Währinger Gürtel 18 - 20, 1090, Vienna, Austria.
Claus-Georg
CG
Krenn
Department of Internal Medicine I, Medical University of Vienna, Intensive Care 13I2, Währinger Gürtel 18 - 20, 1090, Vienna, Austria.
Gottfried
G
Locker
Intensive Care, Department of Internal Medicine, University Hospital Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
Ernst
E
Pilger
Department of Internal Medicine III, Intensive Care 13H1, Medical University of Vienna, Währinger Gürtel 18 - 20, 1090, Vienna, Austria.
Christian
C
Madl
Emergency Clinical Hospital Bucharest, Toxicology - ICU, 8 Floreasca Street, 01446, Bucharest, Romania.
Laura
L
Balica
Clinique St. Pierre, Intensive Care Department, Avenue Reine Fabiola 9, 1340, Ottignies, Belgium.
Thierry
T
Dugernier
Department of CCM, St. Luc University Hospital UCL, Université Catholique de Louvain, Avenue Hippocrate 10, 1200, Brussels, Belgium.
Pierre-Francois
PF
Laterre
University Hospital Vrije Universiteit Brussels, Laarbeeklaan 101, 1090, Brussels, Belgium.
Herbert
H
Spapen
UZ Gent, De Pintelaan 185, 9000, Gent, Belgium.
Pieter
P
Depuydt
Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium.
Jean-Louis
JL
Vincent
University of Pécs Anesthesiology and Intensive Care Department, Ifjúság ut 13, 7624, Pécs, Hungary.
Lajos
L
Bogár
Uzsoki Hospital, Uzsoki u. 29, 1145, Budapest, Hungary.
Zsuzsanna
Z
Szabó
Bajcsy Zsilinszky Hospital and Polyclinic, Intensive Care Unit, Maglodi út 89-91, 1106, Budapest, Hungary.
Barbara
B
Völgyes
Department for Critical Care Medicine, Bellvitge University Hospital, Feixa Llarga s/n, 08907, L'Hospitalet de Llobregat, Barcelona, Spain.
Rafael
R
Máñez
Department of Anesthesiology and Reanimation, Istanbul University Capa Medical Faculty, 34390, Istanbul, Turkey.
Nahit
N
Cakar
Department of Anesthesiology, Dumlupinar Bulvari Kampus Antalya, Akdeniz University, Faculty of Medicine Hospital, 07070, Antalya, Turkey.
Atilla
A
Ramazanoglu
Department of Internal Medicine, Intensive Care Unit, Hacettepe University Hospital, 06100, Ankara, Turkey.
Arzu
A
Topeli
Hospital Dr. Carlos Bocalandro, Ruta 8 No. 9100, B1657BHD Loma Hermosa, Partido 3 de Febrero, Buenos Aires, Argentina.
Maria A
MA
Mastruzzo
Sanatorio Güemes, Av. Roque Sanchez Pena 811 5°C, C1035AAP, Buenos Aires, Argentina.
Abel
A
Jasovich
Hospital "Heroes de Malvinas", Av. Ricardo Balbín 1910, B1721FJN Merlo, Buenos Aires, Argentina.
Christian G
CG
Remolif
Hospital Central Mendoza, Alem y Salta, M5500GKO, Ciudad de Mendoza, Argentina.
Liliana
L
Del Carmen Soria
Hospital Clinico, Facultad de Medicina Pontificia, Universidad Católica de Chile, Marcoleta 367, Santiago, Chile.
Max A
MA
Andresen Hernandez
Hospital Dr. Sótero del Rio, Unidad de Cuidado Intensivo, Departamento de Medicina Intensiva, Escuela de Medicina, Pontificia Universidad Católica de Chile, Avenida Concha y Toro, 3459, Puente Alto, Santiago, Chile.
Carolina
C
Ruiz Balart
Flor Ferenc County Hospital, Semmelweis tér 1, 2143, Kistarcsa, Hungary.
Ildikó
I
Krémer
Department of Anaesthesia and Intensive Care, University of Szeged, Semmelweis u. 6, 6720, Szeged, Hungary.
Zsolt
Z
Molnár
Department of Infectious Diseases and Tropical Medicine, University of Munich, Georgenstr. 5, 80799, Munich, Germany.
Frank
F
von Sonnenburg
Clinical Research Department, Division of Virus Diseases, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD, 20910, USA.
Arthur
A
Lyons
Department of Internal Medicine, Division of Intensive Care and Emergency Medicine, Medical University of Innsbruck, Anichstr. 35, 6020, Innsbruck, Austria.
Michael
M
Joannidis
Department of Internal Medicine I, Division of Infectious Diseases, Medical University of Vienna, Währinger Gürtel 18 - 20, 1090, Vienna, Austria.
Heinz
H
Burgmann
Department of Respiratory Medicine, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
Tobias
T
Welte
Assign Data Management and Biostatistics GmbH, Stadlweg 23, 6020, Innsbruck, Austria.
Anton
A
Klingler
Valneva Austria GmbH, Campus Vienna Biocenter 3, 1030, Vienna, Austria.
Romana
R
Hochreiter
Valneva Austria GmbH, Campus Vienna Biocenter 3, 1030, Vienna, Austria.
Kerstin
K
Westritschnig
D000328:Adult; D000368:Aged; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007362:Intensive Care Units / Q000458:organization & administration; D008297:Male; D008875:Middle Aged; D010919:Placebos; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000517:prevention & control*; D054406:Pseudomonas Vaccines / Q000494:pharmacology* / Q000627:therapeutic use; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity; D012121:Respiration, Artificial / Q000379:methods; D018805:Sepsis / Q000517:prevention & control
D010919:Placebos; D054406:Pseudomonas Vaccines
Bacterial infections; Immunity; Immunocompromised host; Mortality; Pseudomonas aeruginosa; Vaccination