Keywords::
Cystic fibrosis
In patients with cystic fibrosis (CF), life-threatening bacterial lung infections are the leading cause of morbidity and mortality Citation[1], and more than 80% of adult patients with CF are infected with the major pathogen Pseudomonas aeruginosa Citation[2]. The high prevalence of infections is linked to mutations in the epithelial chloride channel, CF transmembrane conductance regulator, which impair various mechanisms of innate immunity Citation[3]. A phenotypic switch from genetically homogenous, nonmucoid P. aeruginosa cells to large mucoid aggregates, known as biofilms, is believed to be an important cause for the inability of the host to control chronic pulmonary infections Citation[4]. Once biofilm formation has occurred, antibiotics are much less efficacious in eradicating P. aeruginosa from the patient's airways, and antibiotic-resistant strains evolve. In addition to P. aeruginosa, other pathogens, including strict anaerobic species, are also present in the patients' sputa Citation[5–7]. Although the prevalence of chronic P. aeruginosa lung infection in CF has decreased in some countries because of early antibiotic therapy Citation[8,9], it is difficult to imagine that all patients with CF will benefit from this treatment strategy and that we will not see chronic P. aeruginosa lung infection in CF any more. Antibiotics used to treat patients with CF frequently also cause side effects such as allergy and sometimes impairment of renal function or hearing loss. Therefore, on the basis of the high impact that P. aeruginosa has on patients with CF, the development of immunization strategies against P. aeruginosa is of major importance.
Pseudomonas vaccine development
Various P. aeruginosa vaccine candidates have been tested in the past Citation[10]. A conjugated polysaccharide vaccine, Aerugen® Citation[11], and a bivalent flagella vaccine Citation[12] have been studied in double-blind, randomized, placebo-controlled multicenter Phase III trials. The Aerugen trial, however, was prematurely terminated in 2006 by the manufacturer, Crucell (Berne, Switzerland). Unfortunately, results from this study have not been published yet, and it is therefore difficult to understand the exact reasons for the negative outcome.
The rationale for flagella antigens in a P. aeruginosa vaccine is that P. aeruginosa strains that initially colonize patients with CF are generally flagella positive and composed of ‘a’ or ‘b’ or both flagella subtypes Citation[13]; the efficacy of various flagella vaccines in animals challenged with P. aeruginosa was generally high Citation[13]; and a Phase I study demonstrated that intramuscular immunization in healthy human adults results in high and long-lasting serum IgG flagella antibody titers and IgG, IgA and secretory IgA isotypes in the secretory immune system Citation[14]. In a Phase III trial, including 483 European patients with CF without previous P. aeruginosa colonization, most patients developed high serum IgG titers to the flagella ‘a’ and ‘b’ antigens after the first vaccination Citation[12]. The end point ‘first positive P. aeruginosa culture' was missed in the intention-to-treat group; however, a significant reduction in the number of immunized patients with a first positive culture for P. aeruginosa was obtained in the per-protocol group. On the basis of the relative risk, the degree of protection against P. aeruginosa infection was calculated as 34%. The majority of P. aeruginosa isolates from patients were flagella positive. P. aeruginosa strains exhibiting flagella subtypes included in the vaccine were less frequently isolated from vaccinated patients than from patients in the placebo group Citation[12].
However, the second primary end point in this study, that is, prevention of chronic P. aeruginosa infection, was achieved neither in the intention-to-treat nor in the per-protocol study group because of a much lower than expected rate of development of chronic infection in the placebo group. How could that have happened? The expected rate was based on data observed in European patients with CF in the 1990s. In the decade 1990–2000, however, many CF centers participating in the flagella vaccine trial used antibiotics to successfully eradicate P. aeruginosa immediately after its first detection and thus markedly reduced chronic P. aeruginosa infection rates in patients with CF Citation[8,9,15]. The Aerugen trial may have run into the same problem. Nevertheless, calculated from the relative risk in the per-protocol group, the degree of protection against chronic P. aeruginosa infection was 51% Citation[12].
Although the flagella vaccine trial Citation[12] established early immunization as a reasonable strategy for patients with CF, the bivalent flagella vaccine may not be optimal. Molecular analysis of the flagella types in P. aeruginosa isolates from vaccinated patients suggested that some strains of P. aeruginosa express flagella antigens not included in the vaccine. Therefore, the inclusion of other P. aeruginosa flagella types in a multivalent vaccine preparation may improve protection against P. aeruginosa in patients with CF. However, since the termination of the bivalent flagella trial in 2002, such an improved vaccine has not been constructed. What are the reasons for this sad situation?
CF is an orphan disease and needs the commitment of pharmaceutical companies more than diseases with larger patient numbers. Although such a commitment for CF has been evidenced in other areas of drug development, P. aeruginosa vaccine development has staggered largely. Furthermore, the enormous efficacy of early eradication therapy may hamper future vaccine trials enrolling European CF patient cohorts if the end point ‘chronic P. aeruginosa infection’ is used in the study design. Still both hurdles may be overcome with some courage, intellect and financial support from sources other than academia and industry. In this context, a positive sign has been given by the EU, which has funded the IMPACT trial in which daily gargling with IgY is used against P. aeruginosa infection in patients with CF Citation[16].
The Cochrane report
Despite the encouraging results of the Phase III flagella study Citation[12], a Cochrane report has expressed a negative opinion that may influence the whole field of P. aeruginosa vaccine development Citation[17]. The reviewers commented that “because seven years passed before the trial was published in 2007, the analyses could have been more powerful if the authors had used survival analysis and followed the patients up for longer, rather than reporting a relative risk after only two years.” Although that in theory may be right, booster doses of vaccination may be needed if antibody responses decline; however, such a study design was not considered when the flagella vaccination study was planned independent of the cost aspect for such an extension. Furthermore, to follow up a large patient cohort that is widespread in Europe over such a long time is difficult. The reviewers then concluded that “vaccines against P. aeruginosa cannot be recommended,” despite the positive results of the study. Furthermore, the review stated that “additional basic research is needed to further increase our understanding of those elements of the immune response to P. aeruginosa that could potentially have a protective effect.” The flagella study clearly revealed that distinct flagella subtypes should be included in a multivalent flagella vaccine preparation. Thus, it remains unclear what the reviewers mean by “additional basic research is needed.” What has not yet been studied is whether a mucosal route of immunization would be more protective as has been developed for protection against viral infections Citation[18]. They further commented that “the risk of inducing immunologically mediated damage following vaccination must be considered in all trials, and long-term follow-up of all trial patients will be necessary to adequately address this issue when new vaccines have been developed.” This verdict is similarly difficult to understand: do the reviewers indeed think that successful vaccination leading to eradication of the pathogen will create such a high burden of immune complexes that the patients’ health will be compromised by the vaccination? With this argument, many approved vaccines may have to be taken off the market. Or do they think that such a scenario will occur if vaccination does not eradicate the pathogen? Given the high antibody response to many different P. aeruginosa antigens in chronically infected patients with CF who have not been vaccinated, the initial antibody titers against flagella antigens in vaccinated, noninfected patients would soon be largely overcome upon infection by high titers against P. aeruginosa lipopolysaccharides and other potent antigens. The reasons for this warning are unclear in the author's opinion and may unfortunately signal ethics committees to negatively vote against a future vaccine proposal in CF.
Taken together, I believe that in the light of increasing antibiotic resistance rates of clinical P. aeruginosa strains and the inborn tolerance to antibiotics for P. aeruginosa biofilms, and despite significant improvements in the treatment of P. aeruginosa lung infection in patients with CF, particularly administering antibiotics early after first colonization by P. aeruginosa, vaccination is mandatory for patients with CF. Although designing vaccine trials in patients with CF is difficult, the opinion raised by the Cochrane review provides a negative signal for the industry and ethics committees to develop further P. aeruginosa vaccines and appears to focus on the negative results that have been obtained in the large flagella vaccine trial.
Financial & competing interests disclosure
G Döring acted as consultant for the company IMMUNO, which produced the flagella vaccine for the Phase III study. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Related Research Data
References
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