Table 1.

Active immunization clinical trials against P. aeruginosa infections.

Immunogen	Clinical Trial	Immunization Protocol	Results		References
			Pros	Cons
Pseudostat (Paraformaldehyde-killed P. aeruginosa)	(Phase 1): Safety and immunogenicity test of a vaccine administered to healthy human subjects	Healthy volunteers (18–50 years of age) Oral dose (150 mg), 2 doses (day 0 and 28). Serological follow-up to 56-days post-vaccination.	Immunogenic in humans. Pooled sera collected after immunization had higher capacity to promote opsonophagocytotic killing (OPK) of P. aeruginosa.	Some neurological, gastrointestinal, and respiratory disorders were detected	[43]
Pseudogen (Heptavalent O-antigen)	(Phase 2): Efficacy evaluation of the vaccine in patients with acute leukemia and CF.	Intramuscular (IM) administration of 6–12 µg/kg.	Efficacy in preventing fatal P. aeruginosa infections in cancer and burn patients.	No benefit for leukemia and CF patients. Limited use due to their toxicity in 92% of patients tested.	[45]
PEV-01 (Polyvalent LPS extracts)	(Phase 2): Prospective, controlled study of a polyvalent vaccine in CF.	Three doses, SC, 1 month apart and the dose 4 after 1 year. 0.25 mL for CF patients under 12 years of age and 0.5 mL for patients over 12.		No benefit for CF patients.	[46]
Aerugen (Octavalent OPS-Toxin A conjugate)	(Phase 3): Analysis of the serological response after 10 years of repeated immunization of children with CF and efficacy on prevention of P. aeruginosa colonization.	Initial inoculations were given at 0, 2 and 12 months, and annual booster doses after the third year.	Increase of IgG levels to all vaccine components. Has a good safety profile for long-term use. The incidence of P. aeruginosa infection was lower compared with the non-vaccinated group.	Later unpublished results from a prospective trial of this vaccine in Europe did not show a delay in colonization and this vaccine was abandoned.	[47]
Bivalent FliC	(Phase 3): Immunization of CF patients not colonized with P. aeruginosa to evaluate its safety and efficacy.	Double-blind, placebo-controlled, multicenter trial. IM; 40 µg in CF patients (2–18 years of age), 4 doses, administrated each dose with 4 weeks apart and a booster dose after 1 year. Addition of adjuvant Al(OH)3, thiomersal.	Vaccine well tolerated. Active immunization of CF patients delayed the onset of chronic infection with P. aeruginosa, resulting in longer survival of these patients. High serum IgG titers to flagella vaccine subtypes.		[33]
CFC-101 (OMP extracted from 4 P. aeruginosa strains)	(Phase 2): Analysis of 2 immunization schedules of the OMP vaccine in burn patients.	Double-blind, randomized and placebo-controled trial. Adult patients with burn injuries in greater than 10% total body surface. IM; 3 doses (0.5 or 1.0 mg) with 3- or 7-day intervals.	The vaccine was safe and highly immunogenic in burn patients, especially with 1 mg doses at 3-day intervals.		[48]
IC43 (OprF/I)	NCT00778388 (Phase 1): Against P. aeruginosa in healthy volunteers	Placebo controlled, double-blind, multi-center, randomized trial. Four different doses (50–200 mcg) administered intramuscularly (IM) to healthy adults (18–65 years of age), with 2 doses given 7 days apart	No serious adverse effect. IC43 doses ≥50 mcg were sufficient to induce plateau of IgG antibody responses in healthy volunteers. At day 90, titers declined but remained higher than the placebo group for up to 6 months.	Higher doses, whether adjuvanted or not, were not more effective.	[37,38,49]
	NCT00876252 (Phase 2): Immunogenicity of IC43 in ICU admitted patients requiring MV	Patients were randomized to receive 3 different vaccine doses (100 mcg or 200 mcg IC43 with adjuvant, or 100 mcg without adjuvant) or placebo IM at days 0 and 7. Evaluation for 90 days.	At day 14 all IC43 administered groups had higher anti-OprF/I titers. Lower mortality in patients immunized with IC43 compared with placebo.	No statistical difference in P. aeruginosa infection rates between patients vaccinated with IC43 and placebo. However, most P. aeruginosa infections occurred before 14 days.
	NCT01563263 (Phase 2/3): Confirmatory study assessing efficacy, immunogenicity and safety of IC43 vaccine in intensive care unit (ICU) patients	Placebo controlled, double-blind, multi-center, randomized trial. ICU patients requiring MV for more than 48 h, age 18–80 years. Patients were randomized to receive an IM injection of 100 mcg of IC43 or placebo on days 0 and 7.	Vaccine was well tolerated in the large population of medically ill, MV patients. The vaccine achieved high immunogenicity.	However, no clinical benefit over placebo was provided in terms of overall mortality.