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

Abstract

BackgroundCurrently, 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.MethodsWe 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.ResultsHigher 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.ConclusionThis 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 registrationClinicalTrials.gov, NCT00876252. Registered on 3 April 2009.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-017-1601-9) contains supplementary material, which is available to authorized users.

The protective effects of nasal PcrV‐CpG oligonucleotide vaccination against Pseudomonas aeruginosa pneumonia

“…Although many other P. aeruginosa vaccine candidates, such as exotoxin A , outer membrane proteins including a recombinant OprF/I conjugate , flagella and alginate , have been investigated, there is no licensed vaccine for P. aeruginosa as yet. In the current study, we found that intranasal administration of a PcrV‐CpG‐based vaccine provides effective protection against virulent P. aeruginosa pneumonia in mice.…”

Efficacy, immunogenicity, and safety of IC43 recombinant Pseudomonas aeruginosa vaccine in mechanically ventilated intensive care patients—a randomized clinical trial

“…In the phase 2 study, IC43 demonstrated a significant immunogenic effect in ventilated ICU patients without safety concerns. In addition, all-cause mortality was reduced versus placebo (more pronounced in patients with infections), although there were no significant differences in P. aeruginosa infection rates [13].…”

“…Vaccination strategies that may confer long-lived adaptive immunity against multidrug-resistant, gram-negative bacterial infections have produced mixed results [12]. However, the investigational vaccine IC43 appeared to be promising based on the favorable safety and immunogenicity profile from previous phase 1/2 studies [13,14]. In the phase 2 study, IC43 demonstrated a significant immunogenic effect in ventilated ICU patients without safety concerns.…”

Meeting report: Global vaccine and immunization research forum, 2018

“…Ongoing activities aligned with the U.S. National Action Plan for Combating Antibiotic-Resistant Bacteria are expanding funding opportunities for vaccines targeting antimicrobial-resistant pathogens and highlighting the value of vaccines in addressing AMR. As presented at GVIRF, new vaccines targeting Pseudomonas, Staphylococcus aureus, and uropathogenic E. coli are in development to prevent human diseases that drive antibiotic use [59][60][61]. Participants observed that identifying and reaching the appropriate target populations for such vaccines may be challenging, especially given the low coverage achieved for well-established vaccines such as influenza.…”