Immunization of Noncolonized Cystic Fibrosis Patients against Pseudomonas aeruginosa

Abstract

The long-term safety and immunogenicity of a polyvalent Pseudomonas aeruginosa conjugate vaccine was evaluated in 30 noncolonized cystic fibrosis patients. Four doses were administered over 3 years, and patients were followed for a mean of 38 months. No acute or long-term adverse effects were noted. Immunization engendered a significant antibody response to all vaccine components. A decline in titers during year 3 of observation was associated with a marked rise in the isolation of P. aeruginosa. This organism was isolated repeatedly from the respiratory tract of 4 patients and only once from 7 patients. The remaining patients were repeatedly culture-negative. Only 1 patient showed clinical deterioration associated with multiple isolations of P. aeruginosa.Pseudomonas aeruginosa is the leading cause of bronchopulmonary infection in patients with cystic fibrosis (CF) [1]. A substantial proportion of morbidity and mortality in this patient population is the result of recurrent pulmonary exacerbations subsequent to colonization. Rarely can P. aeruginosa be eradicated through antibiotic treatment. Further complicating treatment is the fact that multiply resistant strains often arise after repeated or prolonged drug therapy or prophylaxis.Colonization of the lower respiratory tract by mucoid variants of P. aeruginosa is preceded by infection of the upper respiratory tract by smooth strains [2]. Such natural exposure to P. aeruginosa stimulates a vigorous humoral antibody response to many somatic and extracellular antigens [3,4]. However, such antibodies do not prevent or even ameliorate subsequent infections. In fact, several laboratories [5,6] have noted a positive correlation between elevated anti-P aeruginosa antibody titers and a more severe disease course. This may be the result ofimmune complexes being deposited in the lungs and other organs.Anti-P. aeruginosa lipopolysaccharide (LPS) antibodies acquired after natural exposure are not effective at promoting opsonophagocytic killing [7]. We have found that anti-P. aeruginosa LPS antibodies acquired subsequent to colonization had very low average affinity constants, which These studies have been expanded to include 30 noncolonized patients followed for an average of38 months after vaccination. Various clinical. serologic, and bacteriologic parameters were analyzed. Materials and MethodsOver 31 months, 30 CF patients (13 males, 17 females) aged 1.6-24.0 years (mean, 8.3) were enrolled. All were in good health and clinically stable and had no history of infection with P. aeruginosa. On entry. sputum or throat swabs (or both) were negative for P. aeruginosa.Patients were immunized intramuscularly at O. 2, 12, and 36 months with a low (12.5 J.lg ofO-PS per serotype, n = 19) or a high (25 J.lg of O-PS per serotype, n = 11) dose of octavalent O-PS-toxin A conjugate vaccine [9] that contained the following International Antigen Typing System (IATS) LPS serotypes: 1.2/5.3.4,6,7. 10, and 16. Patients were observed for 60 min after immunization. For assessment of adverse r...

Pseudomonas aeruginosa lipopolysaccharide: A major virulence factor, initiator of inflammation and target for effective immunity

“…The conjugation process detoxified the exotoxin A. This vaccine was evaluated in a non-blinded, retrospectively controlled trial in CF patients (Cryz et al, 1994(Cryz et al, ,1997Lang et al, 2004;Langford and Hiller, 1984;Schaad et al, 1990) with encouraging reports of efficacy. However, it was recently reported on the Web site of Crucell N.V. (http:// cws.huginonline.com/C/132631/PR/200607/1064252_5_5.html) that a phase III trial involving 476 patients from 46 centers in four European countries did not show efficacy in preventing P. aeruginosa infection in CF patients.…”

Novel conjugate vaccine for the prevention of Pseudomonas aeruginosa infection in cystic fibrosis patients

“…Nine human studies have evaluated the safety and immunogenicity of the vaccine [Cryz et al, 1987c[Cryz et al, ,d, 1989b[Cryz et al, , 1994[Cryz et al, , 1997Schaad et al, 1991;Lang et al, 1995Lang et al, , 2004a. Within those studies, monovalent, heptavalent, and most commonly, octavalent types of the vaccine have been used with dosing regimens that have varied from a single dose to almost yearly immunizations for up to 10 years.…”

“…This small study lacked power to detect clinical significance of high LPS and TA antibody concentrations . As a follow-up to this study, an additional 8 CF patients (30 total) were enrolled to receive either 12.5 or 25 mg of each serotype of the octavalent LPS O-PS-TA vaccine [Cryz et al, 1994]. Patients received the previous regimen and an additional booster at 36 months.…”

“…(Of healthy military volunteers who received one dose of the conjugate vaccine, 75% of those vaccinated experienced tenderness, and more than 30% experienced swelling at injection site [Cryz et al, 1987c[Cryz et al, ,d, 1989[Cryz et al, , 1994[Cryz et al, , 1997Schaad et al, 1991;Lang et al, 1995Lang et al, , 2004a.) Systemic reactions of malaise and headache were noted in 15% of recruits vaccinated; however, no fever or chills were reported.…”

Cellular immunity in healthy volunteers treated with an octavalent conjugatePseudomonas aeruginosavaccine

“…A total of 120 μ g polysaccharide and 182 μ g carrier protein P. aeruginosa exotoxin A was administered. The development and initial evaluation in healthy volunteers and CF patients has been described extensively [3][4][5][6][7][8][9]. Based on previous experience, immunizations were performed on days 1 and 60.…”