γ-irradiated BCG to Train Innate Immunity

May 21, 2016 updated by: Radboud University Medical Center

Training of Innate Immunity by Vaccination With γ-irradiated BCG

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed 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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
15

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 55 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • The subjects must be healthy adults, aged 18 - 55 years old

Exclusion Criteria:

  • Subjects are excluded when they are from tuberculosis endemic countries, if they have been in contact with tuberculosis patients or if they have been earlier 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: BCG vaccine SSI
Healthy volunteers are vaccinated with yBCG. Blood will be drawn before and at several timepoints after vaccination. Cytokine production before vaccination will be used as reference to compare later timepoints with.
Biological: BCG vaccine SSI
BCG vaccination
Other Names:
  • J07AN01

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Cytokine Production Measured by ELISA Compared to Baseline
Time Frame: 0 weeks and 3 months

Comparing tnfa production of PBMCs after 24h stimulation with candida before and 3 months after yBCG vaccination.

Baseline is set as 1.
0 weeks and 3 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Cytokine Production Measured by ELISA Compared to Baseline
Time Frame: 0 weeks and 2 weeks
Ex-vivo cytokine production by PBMCs upon stimulation with several pathogens
0 weeks and 2 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Radboud University Medical Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
November 1, 2013

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
March 1, 2014

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
April 1, 2014

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
September 26, 2014

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 3, 2014

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 8, 2014

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 29, 2016

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 21, 2016

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
January 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • NL45427.091.13
  • 2013/319 (Other Identifier: CMO Arnhem Nijmegen)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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