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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov, NCT00876252 . Registered on 3 April 2009.

Keywords: Bacterial infections; Immunity; Immunocompromised host; Mortality; Pseudomonas aeruginosa; Vaccination.

Figures

Fig. 1

Study design. *Day 0 assessments were in the intensive care unit (ICU). Subsequent visits were performed in the ICU, hospital, or outpatient setting. Key study visits were at days 0, 7, 14, and 90, and ICU discharge. Optional study visits were performed on days 28, 42, 56, and 70, and only if the patient was still in the ICU or hospital. The total number of visits was dependent on the length of hospital stay (maximum 9 visits). The day-90 visit was considered essential; if patients were not able to attend in person, a telephone call for safety assessment was conducted. The primary endpoint (immunogenicity assessment) was outer membrane protein (OprF/I)-specific immunoglobulin G (IgG) antibody titer at day 14. †Surveillance cultures for Pseudomonas aeruginosa (P. aeruginosa) diagnosis were taken from blood, wounds (if applicable), respiratory tract, urine, and central venous catheter at visits conducted in the ICU. In between these visits, and at other visits up to day 90, cultures for P. aeruginosa diagnosis were taken at the investigator’s discretion, if medically indicated

Fig. 2

Patient disposition. *Dosage deviations were reported in 9 (2.5%), 11 (3.0%), 12 (3.2%), and 16 (4.5%) patients, in the IC43 100 μg with adjuvant, 100 μg without adjuvant, 200 μg with adjuvant, and placebo groups, respectively. Treatment assignment deviations were reported in 2 (0.6%), 5 (1.4%), 3 (0.8%), and 2 (0.6%) patients, respectively. †Early study terminations due to patient deaths, as documented in the case report form. In addition, a further patient from the group randomized to IC43 100 μg without adjuvant who died, and for whom the date and primary cause of death was missing, is not included in this figure. f/up follow up, ITT intention-to-treat, W/d withdrawn, w/o adj without aluminum hydroxide adjuvant, with adj with aluminum hydroxide adjuvant

Fig. 3

Outer membrane protein F/I hybrid vaccine (OprF/I)-specific IgG antibody geometric mean titers (GMT) (U/ml) (intention-to-treat (ITT) population). Note, on day 14 (primary endpoint), there was a statistically significant difference in the OprF/I-specific IgG antibody titer in all IC43 groups compared with placebo (all P < 0.0001). In addition, there were statistically significant differences between all IC43 groups versus placebo on days 28, 42, 56, and 70 (P ≤ 0.0119). At baseline (day 0), 25 subjects had a detectable OprF/I IgG titer >350 U/ml; none of these patients had a baseline infection. *Statistically significant difference between 200 μg and 100 μg IC43 with adjuvant (P = 0.0344). †Two outliers representing measurements in six subjects (11,582 and 7,935 U/ml). ‡Optional visit. w/o without aluminum hydroxide adjuvant, ANOVA analysis of variance

Fig. 4

Survival curve: time until death by treatment group. In the group randomized to 100 μg IC43 without adjuvant, there was statistically significantly lower mortality versus placebo by day 28 (P = 0.0099, log-rank and Cox regression analysis) and significantly longer survival during the study versus placebo (P = 0.0196, Cox regression analysis). w/o without aluminum hydroxide adjuvant