Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02259608 |
| Other study ID # |
NL45427.091.13 |
| Secondary ID |
2013/319 |
| Status |
Completed |
| Phase |
N/A
|
| First received |
September 26, 2014 |
| Last updated |
October 3, 2014 |
| Start date |
November 2013 |
| Est. completion date |
April 2014 |
Study information
| Verified date |
October 2014 |
| Source |
Radboud University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Netherlands: Medical Ethics Review Committee (METC) |
| Study type |
Interventional
|
Clinical Trial Summary
Rationale: The live attenuated Bacillus Calmette-Guerin (BCG) vaccine protects against
extrapulmonary infection with Mycobacterium tuberculosis and leprosy. It has been shown that
vaccination with BCG also leads to nonspecific protective effects, e.g. reduced infant
mortality as a result of less severe infections, stimulation of the immune system in
patients with bladder cancer and higher cytokine production upon restimulation of
macrophages with non-related infectious pathogens in vitro. However, because the live
attenuated BCG vaccine cannot be used in immune compromised hosts, the investigators would
like to determine whether similar protective non-specific effects can be induced by
γ-irradiated BCG.
Objective: To determine whether vaccination with γ-irradiated BCG results in a higher
cytokine response by monocytes upon restimulation in vitro with infectious pathogens,
compared to monocytes before the vaccination.
Study design: Explorative intervention trial. Study population: Healthy volunteers, 18 - 55
years old. Intervention: Healthy volunteers will be vaccinated with γ-irradiated BCG
vaccine.
Main study parameters/endpoints: Blood will be drawn before and at two different time points
after vaccination with BCG to perform restimulation of isolated cells in vitro and compare
cytokine production.
Nature and extent of the burden and risks associated with participation, benefit and group
relatedness: There is no known direct benefit for the volunteers to participate in the
trial. The risks are negligible. BCG vaccination can cause pain and scarring at the site of
injection, just as fever and headache. Local hematoma formation can occur at the site of the
blood drawing. This will be minimized by the blood collection by experienced persons.
Description:
1. INTRODUCTION AND RATIONALE
The live attenuated Bacillus Calmette-Guerin (BCG) vaccine protects against
extrapulmonary infection with Mycobacterium tuberculosis and against leprosy [1, 2]. It
has been shown that vaccination with BCG also leads to non-specific protective effects:
early administration of BCG vaccination could lead to reduced child mortality, mainly
as a result of reduced neonatal sepsis, respiratory infection, and fever. [3-5]
Furthermore, BCG has also been used in patients with bladder cancer, to induce an
improved reaction of the immune system, which prevents tumor progression and dead. [6]
Recently, it was shown that BCG vaccination can induce epigenetic changes in human
monocytes, which result in higher pro-inflammatory cytokines response upon
restimulation with non-related pathogens in vitro. [7] The observed effects are
proposed to be due to modulation of the human innate immune system, in a process called
'trained immunity'. Upon stimulation with a pathogen, the innate immune system becomes
primed and is able to react faster and more efficient to a secondary (and non-related)
stimulus. [7, 8]
Considering these beneficial effects of BCG on innate host defense, it is reasonable to
hypothesize that it would be helpful to generate a 'trained immunity status' in hosts
defective in T- and B-cell immunity, as they are more vulnerable to infections.
However, because of their immune compromised status, these patients cannot be
vaccinated with live attenuated vaccines (e.g. BCG). [9] Vaccination with y-irradiated
BCG would be possible, but it is not known whether the γ-irradiated vaccine has the
same protective non-specific effects on innate host defense. In recent in-vitro
experiments, the investigators have demonstrated that y-irradiated BCG can train
monocytes in vitro (not published). Therefore, the aim of this study is to determine
whether γ-irradiated BCG is able to train the human innate immune system of healthy
volunteers in-vivo, just as shown before with the live attenuated BCG vaccine [7].
2. OBJECTIVES
Primary Objective: To determine whether γ-irradiated BCG can train the innate immune
system in vivo, by comparing cytokine production upon ex-vivo restimulation with
pathogens before, 2 weeks and 3 months after vaccination with y-irradiated BCG.
3. STUDY DESIGN
An explorative intervention study with a duration of three months will be performed. 15
Healthy volunteers will be recruited to receive a vaccination with γ-irradiated BCG.
After informed consent, 40ml of blood will be drawn before vaccination and at 2 weeks
and 3 months post-vaccination.
4. STUDY POPULATION 4.1 Population Healthy volunteers, 18 - 55 yr old. 4.2 Inclusion
criteria The subjects must be healthy adults, aged 18 - 55 years old. 4.3 Exclusion
criteria Subjects are excluded when they are from tuberculosis endemic countries, if
they have been in contact with tuberculosis patients or if they already have been
vaccinated with BCG. The subjects are excluded from the study if they suffer for any
disease, including intercurrent infections. Subjects are not allowed to use any
medication except oral anticonceptive agents.
4.4 Sample size calculation This is an explorative trial, for which sample size
calculation is not possible.
5. TREATMENT OF SUBJECTS 5.1 Investigational product/treatment Subjects will be vaccinated
with a y-irradiated BCG vaccine (BCG-Vaccin SSI [Nederlands Vaccin Instituut]), which
is purchased from Radboud Apotheek B.V.
γ-Irradiation of the BCG vaccine will be performed by Synergy Health Ede B.V., Ede, The
Netherlands (registered by the Dutch Ministry of Economic Affairs). The BCG vaccine was
radiated in the original packaging with an average dose of 32.2kGy in a JS6500 Tote Box
Irradiator. This dose is based on an in the literature accepted minimal dose of 25kGy,
which has been proven to be sufficient to kill M. tuberculosis [10, 11] . After
irradiation the vaccine will be returned unopened in the original packaging. During the
irradiation a dosimeter is included, so each irradiated batch will come along with a
certificate with the exact irradiation dose used.
5.2 Use of co-intervention Subjects are not allowed to use any medication, except for
oral anticonception.
6. INVESTIGATIONAL PRODUCT 6.1 Name and description of investigational product(s)
y-Irradiated BCG vaccine (BCG-Vaccin SSI [Nederlands Vaccin Instituut]) Danish strain
1331.
6.2 Summary of findings from non-clinical studies The efficacy of killing by
γ-irradiating of the BCG vaccine was verified by culturing the y-irradiated BCG in
special tuberculosis culture medium. No growth was detected after six weeks.
6.3 Summary of findings from clinical studies A related study with a comparable study
setup, in which 20 healthy volunteers were vaccinated with live attenuated BCG vaccine
has already been accomplished. [7] The investigators study will use the same study
protocol. The only difference is that instead of the live attenuated BCG vaccine a
y-irradiated BCG vaccine will be used.
6.4 Summary of known and potential risks and benefits There are no clear benefits for
the volunteers. Potential risks are very small, as BCG is considered a safe vaccine.
BCG vaccination can cause pain and scarring at the site of injection just as fever and
headache, and very sporadic occurring side effects as syncope, convulsions and allergic
reaction. Local hematoma formation can occur at the site of the blood drawing.
6.5 Description and justification of route of administration and dosage Administer at
the upper arm slowly, in about 10 seconds, intracutaneous 0.1ml of the suspended
vaccine, which accounts for 0.075mg of Mycobacterium bovis.
7. METHODS 7.1 Study parameters/endpoints Before the vaccination and at two different time
points after vaccination with γ-irradiated BCG (2 weeks and 3 months) blood will be
drawn, from which PBMCs will be isolated by density centrifugation over Ficoll-Paque.
Monocytes will be restimulated ex-vivo with different pathogens (M. tuberculosis
(1µg/ml), S. aureus, C. albicans (both 1 x 10^6 microorganisms/ml), and E. coli LPS
(10ng/ml). Cytokine production will be assessed after 24h (TNFa, IL 1b and IL-6), 48h
(IFN, IL-10) and 7 days (IL-17, IL-22) stimulation, and compared with cytokine
production before vaccination.
7.2 Study procedures Subjects will be vaccinated with y-irradiated BCG vaccine. Before and
twice after vaccination, 40ml of blood will be drawn.
7.3 Withdrawal of individual subjects Subjects can leave the study at any time for any
reason if they wish to do so without any consequences.
7.4 Replacement of individual subjects after withdrawal Each withdrawn subject will be
replaced, in order that in total 15 subjects will complete the follow-up.
