A Study to Quantify Bacille Calmette Guerin (BCG) and Characterise the Immune Response After BCG Vaccination
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|ClinicalTrials.gov Identifier: NCT00653627|
Recruitment Status : Completed
First Posted : April 7, 2008
Last Update Posted : July 1, 2010
|First Submitted Date ICMJE||April 2, 2008|
|First Posted Date ICMJE||April 7, 2008|
|Last Update Posted Date||July 1, 2010|
|Study Start Date ICMJE||August 2007|
|Actual Primary Completion Date||April 2010 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Quantification of BCG after BCG vaccination [ Time Frame: 2 or 4 weeks ]|
|Original Primary Outcome Measures ICMJE||Same as current|
|Current Secondary Outcome Measures ICMJE
||Immunogenicity of BCG vaccination [ Time Frame: 2 or 4 weeks ]|
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||A Study to Quantify Bacille Calmette Guerin (BCG) and Characterise the Immune Response After BCG Vaccination|
|Official Title ICMJE||A Human Pilot Study to Quantify BCG From the BCG Vaccination Site, and to More Fully Characterise the Immune Response to BCG|
|Brief Summary||This is a human pilot study of 16 healthy BCG-naïve volunteers to quantify BCG from the BCG vaccination site. Volunteers will be vaccinated with BCG. The first 8 will go on to have a punch biopsy and suction blister of the vaccination sites at 2 weeks post vaccination (arm A) the second 8 will have a biopsy and blister at 1 or 4 weeks post-vaccination (arm B). Methods of mycobacterial quantification on these tissue samples will then be compared|
Over the last 3 years, the McShane group in Oxford have established a clinical trial programme to evaluate the safety and immunogenicity of this BCG prime-MVA85A boost vaccination strategy in a series of Phase I studies in the UK.
To date, in Oxford, the safety and immunogenicity of MVA85A (dose 5x10^7 pfu) has been assessed in 14 mycobacterially and BCG naïve individuals, 27 individuals previously vaccinated with BCG and 12 individuals latently infected with M.tb. In all 53 individuals there have been no serious or severe adverse events, and a single vaccination with MVA85A has been highly immunogenic in BCG naïve volunteers, and significantly moreso in BCG primed volunteers. (23) Following the success of the UK studies, 21 healthy individuals (11 BCG naïve, 10 BCG primed) in the Gambia and 24 healthy adults in Cape Town, South Africa (ongoing age de-escalation phase II trial), have now been vaccinated with MVA85A, with no serious or severe adverse events, and a safety and immunogenicity profile comparable to the UK. A study in infants in the Gambia is now underway and the adolescent arm of the age de-escalation studies in Cape Town is now also underway.
Interferon-gamma as a protective correlate and the need to identify other immunological correlates of protection:
In all of the studies to date, (both preclinical and clinical), the main immunological readout has been the ex-vivo interferon-gamma (IFN- ) Elispot assay, used to assess specific T cell responses to tuberculin PPD, purified antigen 85 complex and pools of overlapping 15mer peptides spanning the length of antigen 85A. The secretion of IFN-y from antigen-specific T cells is the best available immunological correlate of protective immunity. The rationale and evidence supporting the use of assays for determining IFN- production as a correlate of protection are substantial, but alone, it may not be sufficient. There is increasing evidence that CD4(+) T cells possess IFN-gamma-independent mechanisms that can limit the growth of an intracellular pathogen and are dominant in secondary responses to M. tuberculosis.
It is clear that new immunological correlates of protection need to be identified, and given the considerable time and cost involved in any Phase III efficacy trial of a new TB vaccine, there is therefore an urgent need to identify protective correlates which will help distinguish between candidates demonstrated to be safe and immunogenic in phase I trials.
Whilst we cannot infect human volunteers with TB to address this issue, we can use another replicating mycobacteria, BCG, as a surrogate. A good vaccine for TB should also reduce BCG replication and increase BCG clearance. The objective of this proposal is to perform the preliminary work necessary to develop such a BCG 'challenge' model in which bacterial (BCG) load in the skin is assessed following vaccination with MVA85A.
Such a challenge model is based on evidence that animals given subunit vaccination against TB have attenuated T cell responses to replicating mycobacteria administered as challenge agents. The hypothesis for this model is that replication of BCG and hence the induction of a BCG induced immune response will be abrogated by pre-existing immunity induced by a subunit vaccine, MVA85A. In addition, replication of intradermal BCG administered as a challenge agent can be assessed by biopsies of volunteers' skin. So, these methods would allow correlation of immune responses elicited by MVA85A vaccination with direct or indirect measures of diminished intradermal mycobacterial (BCG) replication in humans.
There are three parts to this model:
2 groups of BCG naïve subjects will be randomised to receive either a single immunization with MVA85A or saline. The numbers per group will be decided on the basis of the results from the murine work and BCG pilot study, accounting for the level of variability in BCG replication, such that the number per group should be able to reliably detect a significant difference in BCG replication between the 2 groups (should it exist). The vaccine-induced immune response will be fully characterised. At 4 weeks, all volunteers will then be "challenged" (intradermally) with BCG. BCG-induced immune responses will be monitored for a further 6 months. In addition, a punch biopsy (+/- suction blister) will be taken from the BCG vaccination site and the amount of bacteria present quantified. The correlation between any reduction in BCG replication and MVA85A-induced immune response will then be assessed, in order to identify a potential correlate of protection.
Future candidate vaccines can then be assessed against their capacity to induce such an immune response.
Potential risks to human subjects:
The general risks to participants in this human pilot study are associated with phlebotomy, vaccination, punch biopsy and suction blister techniques. Mild tenderness, bruising, or fainting may result from venepuncture. The volume of blood drawn over the study period (504.5ml +/- 20ml) should not compromise these otherwise healthy subjects.
BCG is a licensed vaccine which has been in use for the last 100 years, given to 4 billion people, and has an excellent safety profile.
Potential vaccination risks include the following:
(Local reactions: An inflammatory reaction as manifested by redness and swelling, that can form a small ulcer, may occur at the site of vaccine injection. This usually heals and leaves a small flat scar. It is also possible to develop some swelling of glands in the armpit, but less than one centimetre across. These are natural reactions to the vaccine.
Uncommonly (less than 1 in 100 people) swelling of glands in the armpit to more than 1cm across or an ulcer that discharges fluid at the injection site may occur.
Rare side effects (less than 1 in 1000 people) include inflammation of glands, sometimes with abscesses and discharge of fluid from the swellings.
Systemic Reactions: Systemic reactions to immunization with BCG that could potentially occur are rare (less than 1 in 1000 people) and include low-grade fever and headache, and allergic reactions. Disseminated complications of BCG such as osteitis or osteomyelitis have also been reported but are extremely rare and have usually been reported in immunocompromised, not immunocompetent individuals.
Punch biopsy and suction blister risks:
There is a small risk that the punch biopsy site or blister site may become infected. If this did occur, treatment with antibiotics may be required. The punch biopsy site will heal to form a small scar. A small scar might develop at the blister site but often this is barely visible after several months.
Allergic Reactions and Anaphylaxis: As with any vaccine, allergic reactions are possible. Very rarely allergic reactions to local anaesthetic (administered prior to the punch biopsy) may occur.
Known Potential Benefits:
Volunteers will benefit from partial protection against TB, by vaccination with BCG. Volunteers will gain some information about their general health status at the pre-study screening assessment. It is also hoped that the information gained from this study will contribute to the development of a safe and effective TB vaccine for HIV negative and positive individuals.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 1|
|Study Design ICMJE||Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
|Intervention ICMJE||Biological: BCG
Mycobacterium bovis Bacille Calmette-Guerin
|Study Arms ICMJE||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Actual Study Completion Date ICMJE||April 2010|
|Actual Primary Completion Date||April 2010 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years to 50 Years (Adult)|
|Accepts Healthy Volunteers ICMJE||Yes|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United Kingdom|
|Removed Location Countries|
|NCT Number ICMJE||NCT00653627|
|Other Study ID Numbers ICMJE||TB015
COREC Number: 07/Q1604/3
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement ICMJE||Not Provided|
|Responsible Party||Dr Helen McShane, University of Oxford|
|Study Sponsor ICMJE||University of Oxford|
|Collaborators ICMJE||Not Provided|
|PRS Account||University of Oxford|
|Verification Date||June 2010|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP