Chronic pulmonary infection with Pseudomonas aeruginosa
remains the most important cause of lung disease in patients with Cystic
Fibrosis. This infection leads to an acceleration of lung disease, coupled
with a deterioration of the function of the lungs. During the last ten
years, early and aggressive interventions with antibiotics, given orally,
intravenously and or by inhalation, have improved lung function, reduced
local lung inflammation and sometimes have eliminated the presence of
Pseudomonas aeruginosa from the lungs of patients with CF, at least
for some time.
Despite this clear therapeutic success, and in spite of important changes
in preventive hygiene and new guidelines designed to avoid contamination
in CF Centers, during CF camps and meetings among patients with and without
Pseudomonas aeruginosa infection, there is intense interest in the development
of vaccines for the prevention of infections of the lungs with P. aeruginosa.
In order to provide a good immunological response, such as is available
with other vaccines against bacterial infections, such as diphtheria and
tetanus, several parts of the Pseudomonas aeruginosa cell body have been
identified as potential candidates for producing an efficient vaccine.
The elements of the outer membrane proteins, OMP, the so-called hairs,
pili, the proteic part of the locomotion apparatus, the flagellum, and,
more recently, translocation proteins related to the secretive activity
of P. aeruginosa are of particular interest.
All the above proteins, that are potentially efficient in an antibody
stimulating vaccination, are still the objects of preliminary studies.
Another possible vaccine starting point is an element of the P. aeruginosa
surface which is called lipo-poly-saccharide (lipo = fat, poly = multiple,
saccharide = sugar), LPS. This element of P. aeruginosa is known to stimulate
high affinity antibodies which protect the lung against this part of the
P. aeruginosa surface. High affinity means that there is a strong attraction
between the above-mentioned LPS and the newly stimulated antibodies which
will possibly destroy the bacteria (see figure 1).
To achieve induction of these high affinity antibodies (highly efficient
antibodies) a team from the company Berna Biotech Ltd. Berne, and the
CF Center, Department of Pediatrics, University of Berne initiated a clinical
trial in cystic fibrosis patients in 1989. The evaluations of results
after 1, 3 and 4 years showed safety and the capacity of the vaccine to
stimulate a good antibody-response, that is, the vaccine tested in the
trial produced a good immune response in CF patients who received the
vaccine.
“a
real effect of the vaccine in preventing and/or delaying a chronic
infection with Pseudomonas” |
After ten years of follow-up studies the team succeeded in showing complete
safety for long term use, and also a real effect of the vaccine in preventing and/or delaying a chronic infection with Pseudomonas
aeruginosa in a group of 25 CF-patients in comparison to control patients
with CF matched for age, sex and genetic mutations who did not receive the
vaccine (figure 2). In 2001, a multicenter, double-blind, placebo controlled
(so-called phase III) clinical trial was started. It is still in progress
and we are expecting the final results in about 2 years.
As the first vaccine against P. aeruginosa lung-infections in the world,
this development may well signify a great advance in the anti-infection
therapy of CF. Unfortunately it will not mean that we will definitely
be free from this resistant and devastating bacterial infection as a result
of using this vaccine. In the best case scenario it may complement the
strategy of classical CF lung-therapy, represented by inhalation of bronchodilators,
followed by chest-physiotherapy and expectoration (2 -3 times a day) and
if necessary coupled with inhalations of DNASE and/or antibiotics (tobramycin).
Without these pre-requisites the vaccine approach alone, cannot achieve
the best possible outcomes for individuals with CF.
How to use the vaccine in CF patients without P. aeruginosa infection
and the timing of the application of booster vaccinations are questions
that still remain to be answered. They will not be settled before the
end of the ongoing multicenter study, hopefully to be reported in 2006.
