A randomized placebo-controlled phase II study of a Pseudomonas vaccine in ventilated ICU patients

Jordi Rello, Claus-Georg Krenn, Gottfried Locker, Ernst Pilger, Christian Madl, Laura Balica, Thierry Dugernier, Pierre-Francois Laterre, Herbert Spapen, Pieter Depuydt, Jean-Louis Vincent, Lajos Bogár, Zsuzsanna Szabó, Barbara Völgyes, Rafael Máñez, Nahit Cakar, Atilla Ramazanoglu, Arzu Topeli, Maria A. Mastruzzo, Abel Jasovich, Christian G. Remolif, Liliana del Carmen Soria, Max A. Andresen Hernandez, Carolina Ruiz Balart, Ildikó Krémer, Zsolt Molnár, Frank von Sonnenburg, Arthur Lyons, Michael Joannidis, Heinz Burgmann, Tobias Welte, Anton Klingler, Romana Hochreiter, Kerstin Westritschnig

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.