TBPhase 1NCT00654316
Study of the Safety and Immunogenicity of Bacille Calmette Guerin (BCG) Vaccine
A Phase 1 study testing BCG in people with TB, run by University of Oxford at 1 site in United Kingdom.
Trial summary
Tuberculosis (TB) kills about three million people annually. It is estimated that one third of the world's population are latently infected with Mycobacterium tuberculosis (M.tb). Multi-drug resistant strains of M.tb, and co-infection with M.tb and HIV present major new challenges. The currently available vaccine, M. Read more about this study
- Who is it for?
- Ages 18 to 55 yearsHealthy volunteers can take part
- Conditions the study is for
- TB
- What is being tested?
- BCG
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 11 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Feb 2004to Nov 2005
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Healthy adult aged 18-55 years.
- Normal medical history and physical examination.
- Normal urine dipstick, blood count, liver enzymes, and creatinine.
Who cannot join
- Exposure to TB at any point. A positive ESAT6/CFP10 Elispot response (defined as greater than 5 spots/well above background and at least double the background response).
- Clinically significant history of skin disorder (eczema, psoriasis, etc.), allergy, immunodeficiency, cardiovascular disease, respiratory disease, endocrine disorder, liver disease, renal disease, gastrointestinal disease, neurological illness, psychiatric disorder, drug or alcohol abuse.
- Oral or systemic steroid medication or the use of immunosuppressive agents.
- Positive HIV antibody test, HCV antibody test or positive HBV serology except post-vaccination.
- Heaf test greater than Grade II
- Confirmed pregnancy
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Centre for Clinical Vaccinology and Tropical Medicine
Oxford, Oxfordshire, OX3 7LJ
About this study
Official title: A Phase I Study of the Safety and Immunogenicity of BCG (Bacille Calmette-Guerin) Vaccine Delivered Intradermally by a Needle Injection in Healthy Volunteers Who Have Previously Received BCG.
Tuberculosis (TB) kills about three million people annually. It is estimated that one third of the world's population are latently infected with Mycobacterium tuberculosis (M.tb). Multi-drug resistant strains of M.tb, and co-infection with M.tb and HIV present major new challenges. The currently available vaccine, M. bovis BCG, is largely ineffective at protecting against adult pulmonary disease in endemic areas and it is widely agreed that a new more effective tuberculosis vaccine is a major global public health priority1. However, it may be unethical and impractical to test and deploy a vaccine strategy that does not include BCG, as BCG does confer worthwhile protection against TB meningitis and leprosy. An immunisation strategy that includes BCG is also attractive because the populations in which this vaccine candidate will need to be tested will already have been immunised with BCG.
M.tb is an intracellular organism. CD4+ Th1-type cellular responses are essential for protection and there is increasing evidence from animal and human studies that CD8+ T cells also play a protective role2. However, it has generally been difficult to induce strong cellular immune responses in humans using subunit vaccines. DNA vaccines induce both CD4+ and CD8+ T cells and thus offer a potential new approach to a TB vaccine. DNA vaccines encoding various antigens from M. tuberculosis have been evaluated in the murine model, and to date no DNA vaccine alone has been shown to be superior to BCG.
A heterologous prime-boost immunisation strategy involves giving two different vaccines, each encoding the same antigen, several weeks apart. Such regimes are extremely effective at inducing a cellular immune response. Using a DNA- prime/MVA-boost immunisation strategy induces high levels of CD8+ T cells in animal models of malaria and HIV5, and high levels of both CD4+ and CD8+ T cells in animal models of TB. BCG immunisation alone induces only CD4+ T cells in mice. A prime-boost strategy using BCG as the prime and a recombinant MVA encoding an antigen from M.tb that is also present in BCG (antigen 85A: 'MVA85A') as the boost, induces much higher levels of CD4+ T cells than BCG or MVA85A alone. In addition, this regime generates specific CD8+ T cells that are undetectable following immunisation with BCG alone.
Read the detailed description
Recombinant viruses as vaccines.
Recombinant viruses used alone have for some years represented a promising vaccine delivery system, particularly for inducing cellular immune responses8. The recombinant virus encodes the immunising protein or peptide. Immunisation by a recombinant virus vaccine occurs when host cells take up and express the inoculated attenuated virus encoding a protective antigen. The expressed protein often has the native conformation, glycosylation, and other post-translational modifications that occur during natural infection. Recombinant viral vaccines may elicit both antibody and cytotoxic T-lymphocyte responses, which persist without further immunisations.
Many viruses have been investigated as potential recombinant vaccines. The successful worldwide eradication of smallpox via vaccination with live vaccinia virus highlighted vaccinia as a candidate for recombinant use. The recognition in recent years that non-replicating strains of poxvirus such as MVA and avipox vectors can be more immunogenic than traditional replicating vaccinia strains has enhanced the attractiveness of this approach. MVA (modified vaccinia virus Ankara) is a strain of vaccinia virus which has been passaged more than 570 times though avian cells, is replication incompetent in human cell lines and has a good safety record. It has been administered to more than 120,000 vaccinees as part of the smallpox eradication programme, with no adverse effects, despite the deliberate vaccination of high risk groups. This safety in man is consistent with the avirulence of MVA in animal models. MVA has six major genomic deletions compared to the parental genome severely compromising its ability to replicate in mammalian cells. Viral replication is blocked late during infection of cells but importantly viral and recombinant protein synthesis is unimpaired even during this abortive infection. Replication-deficient recombinant MVA has been seen as an exceptionally safe viral vector. When tested in animal model studies recombinant MVAs have been shown to be avirulent, yet protectively immunogenic as vaccines against viral diseases and cancer. The most useful data on the safety and efficacy of various doses of a recombinant MVA vaccine comes from clinical trial data with a recombinant MVA expressing a number of CTL epitopes from Plasmodium falciparum pre-erythrocytic antigens fused to a complete pre-erythrocytic stage antigen, Thrombospondin Related Adhesion Protein (TRAP). These trials have given a total of 169 immunisations with this recombinant MVA, to 49 UK vaccinees 38 Gambian vaccines (20 of whom were children aged 1-5). 6 doses of 1 x 10^7 pfu, 139 doses of 5 x 10^7 pfu, 6 doses of 1 x 10^8 pfu and 18 doses of 2.5 x 10^8 pfu have been administered, all without serious adverse effects.
Recombinant MVA encoding antigen 85A
Secreted antigens from M. tuberculosis are released from actively metabolising bacteria, and are important targets in protective immunity. Antigen 85A is a major secreted antigen from M. tuberculosis which forms part of the antigen 85 complex (A, B and C). This complex constitutes a major portion of the secreted proteins of both M.tb and BCG. It is involved in fibronectin binding within the cell wall and has mycolyltransferase activity.
MVA85A induces both a CD4+ and a CD8+ epitope when used to immunise mice. When mice are primed with BCG and then given MVA85A as a boost, the levels of CD4+ and CD8+ T cells induced are higher than with either BCG or MVA85A alone.
We are evaluating the safety and immunogenicity of the following 3 groups:
- BCG alone
- MVA85A alone
- BCG prime-MVA85A boost
BCG-BCG provides a control group for BCG-MVA85A. Many countries have a tradition of repeated BCG vaccination and the criteria for revaccination differ between countries.
- Conditions
- TB
- Being tested
- BCG
- Keywords
- TB, Tuberculosis, MVA85A, Vaccine, BCG
- Medical subject headings
- Tuberculosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BCGBiological
Also called Bacille Calmette-Guerin
intradermal injection of 0.1ml BCG over the deltoid muscle
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | BCG delivered intradermally into the deltoid region in volunteers who have received BCG 10 - 20 years previously. Receives: Biological: BCG |
What is being measured
The primary outcome is the main question the study is designed to answer.
The occurence and severity of local side-effects The occurence and severity of systemic side-effects
Measured: 1 year
Secondary outcomes (1)
The induction of T cell responses (as measured by an interferon-gamma Elispot assay). Other exploratory cellular immunology assays will be performed as such assays are developed.
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Apr 2008 (estimated)
- Study startFeb 2004
- Primary completionNov 2005
- Study completionNov 2005
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for TBStudies of the same condition, open and under way.
- More trials run by University of OxfordThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Prevention
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 11 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Oxford
- Sponsor type
- University, hospital or other
- Investigators
- Helen McShane, Principal investigator, University of Oxford
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00654316
- Sponsor's protocol ID
- TB006
- Status last verified
- Mar 2008
- First submitted
- 2 Apr 2008
- Last updated
- 7 Apr 2008
- Results posted
- No
- Data monitoring committee
- Yes
Publications
McShane H, Brookes R, Gilbert SC, Hill AV. Enhanced immunogenicity of CD4(+) t-cell responses and protective efficacy of a DNA-modified vaccinia virus Ankara prime-boost vaccination regimen for murine tuberculosis. Infect Immun. 2001 Feb;69(2):681-6. doi: 10.1128/IAI.69.2.681-686.2001.
PubMed 11159955McShane H, Behboudi S, Goonetilleke N, Brookes R, Hill AV. Protective immunity against Mycobacterium tuberculosis induced by dendritic cells pulsed with both CD8(+)- and CD4(+)-T-cell epitopes from antigen 85A. Infect Immun. 2002 Mar;70(3):1623-6. doi: 10.1128/IAI.70.3.1623-1626.2002.
PubMed 11854254Whelan KT, Pathan AA, Sander CR, Fletcher HA, Poulton I, Alder NC, Hill AV, McShane H. Safety and immunogenicity of boosting BCG vaccinated subjects with BCG: comparison with boosting with a new TB vaccine, MVA85A. PLoS One. 2009 Jun 16;4(6):e5934. doi: 10.1371/journal.pone.0005934.
PubMed 19529780
Study at a glance
From the registry record, last updated by the sponsor on 7 Apr 2008. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I Study of the Safety and Immunogenicity of BCG (Bacille Calmette-Guerin) Vaccine Delivered Intradermally by a Needle Injection in Healthy Volunteers Who Have Previously Received BCG.
- ClinicalTrials.gov ID
- NCT00654316
- Acronym / sponsor ID
- TB006
- Conditions
- TB
- Keywords
- TB, Tuberculosis, MVA85A, Vaccine, BCG
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 11 participants (actual)
- Lead sponsor
- University of OxfordUniversity, hospital or other
- Study start
- Feb 2004
- Primary completion
- Nov 2005 (actual)
- Study completion
- Nov 2005 (actual)
- First posted
- 7 Apr 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Tuberculosis (TB) kills about three million people annually. It is estimated that one third of the world's population are latently infected with Mycobacterium tuberculosis (M.tb). Multi-drug resistant strains of M.tb, and co-infection with M.tb and HIV present major new challenges. The currently available vaccine, M. bovis BCG, is largely ineffective at protecting against adult pulmonary disease in endemic areas and it is widely agreed that a new more effective tuberculosis vaccine is a major global public health priority1. However, it may be unethical and impractical to test and deploy a vaccine strategy that does not include BCG, as BCG does confer worthwhile protection against TB meningitis and leprosy. An immunisation strategy that includes BCG is also attractive because the populations in which this vaccine candidate will need to be tested will already have been immunised with BCG.
M.tb is an intracellular organism. CD4+ Th1-type cellular responses are essential for protection and there is increasing evidence from animal and human studies that CD8+ T cells also play a protective role2. However, it has generally been difficult to induce strong cellular immune responses in humans using subunit vaccines. DNA vaccines induce both CD4+ and CD8+ T cells and thus offer a potential new approach to a TB vaccine. DNA vaccines encoding various antigens from M. tuberculosis have been evaluated in the murine model, and to date no DNA vaccine alone has been shown to be superior to BCG.
A heterologous prime-boost immunisation strategy involves giving two different vaccines, each encoding the same antigen, several weeks apart. Such regimes are extremely effective at inducing a cellular immune response. Using a DNA- prime/MVA-boost immunisation strategy induces high levels of CD8+ T cells in animal models of malaria and HIV5, and high levels of both CD4+ and CD8+ T cells in animal models of TB. BCG immunisation alone induces only CD4+ T cells in mice. A prime-boost strategy using BCG as the prime and a recombinant MVA encoding an antigen from M.tb that is also present in BCG (antigen 85A: 'MVA85A') as the boost, induces much higher levels of CD4+ T cells than BCG or MVA85A alone. In addition, this regime generates specific CD8+ T cells that are undetectable following immunisation with BCG alone.
Detailed description
Recombinant viruses as vaccines.
Recombinant viruses used alone have for some years represented a promising vaccine delivery system, particularly for inducing cellular immune responses8. The recombinant virus encodes the immunising protein or peptide. Immunisation by a recombinant virus vaccine occurs when host cells take up and express the inoculated attenuated virus encoding a protective antigen. The expressed protein often has the native conformation, glycosylation, and other post-translational modifications that occur during natural infection. Recombinant viral vaccines may elicit both antibody and cytotoxic T-lymphocyte responses, which persist without further immunisations.
Many viruses have been investigated as potential recombinant vaccines. The successful worldwide eradication of smallpox via vaccination with live vaccinia virus highlighted vaccinia as a candidate for recombinant use. The recognition in recent years that non-replicating strains of poxvirus such as MVA and avipox vectors can be more immunogenic than traditional replicating vaccinia strains has enhanced the attractiveness of this approach. MVA (modified vaccinia virus Ankara) is a strain of vaccinia virus which has been passaged more than 570 times though avian cells, is replication incompetent in human cell lines and has a good safety record. It has been administered to more than 120,000 vaccinees as part of the smallpox eradication programme, with no adverse effects, despite the deliberate vaccination of high risk groups. This safety in man is consistent with the avirulence of MVA in animal models. MVA has six major genomic deletions compared to the parental genome severely compromising its ability to replicate in mammalian cells. Viral replication is blocked late during infection of cells but importantly viral and recombinant protein synthesis is unimpaired even during this abortive infection. Replication-deficient recombinant MVA has been seen as an exceptionally safe viral vector. When tested in animal model studies recombinant MVAs have been shown to be avirulent, yet protectively immunogenic as vaccines against viral diseases and cancer. The most useful data on the safety and efficacy of various doses of a recombinant MVA vaccine comes from clinical trial data with a recombinant MVA expressing a number of CTL epitopes from Plasmodium falciparum pre-erythrocytic antigens fused to a complete pre-erythrocytic stage antigen, Thrombospondin Related Adhesion Protein (TRAP). These trials have given a total of 169 immunisations with this recombinant MVA, to 49 UK vaccinees 38 Gambian vaccines (20 of whom were children aged 1-5). 6 doses of 1 x 10^7 pfu, 139 doses of 5 x 10^7 pfu, 6 doses of 1 x 10^8 pfu and 18 doses of 2.5 x 10^8 pfu have been administered, all without serious adverse effects.
Recombinant MVA encoding antigen 85A
Secreted antigens from M. tuberculosis are released from actively metabolising bacteria, and are important targets in protective immunity. Antigen 85A is a major secreted antigen from M. tuberculosis which forms part of the antigen 85 complex (A, B and C). This complex constitutes a major portion of the secreted proteins of both M.tb and BCG. It is involved in fibronectin binding within the cell wall and has mycolyltransferase activity.
MVA85A induces both a CD4+ and a CD8+ epitope when used to immunise mice. When mice are primed with BCG and then given MVA85A as a boost, the levels of CD4+ and CD8+ T cells induced are higher than with either BCG or MVA85A alone.
We are evaluating the safety and immunogenicity of the following 3 groups:
- BCG alone
- MVA85A alone
- BCG prime-MVA85A boost
BCG-BCG provides a control group for BCG-MVA85A. Many countries have a tradition of repeated BCG vaccination and the criteria for revaccination differ between countries.
Study design
- Primary purpose
- Prevention
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 1 | Experimental | Biological: BCGBCG delivered intradermally into the deltoid region in volunteers who have received BCG 10 - 20 years previously. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- Healthy adult aged 18-55 years.
- Normal medical history and physical examination.
- Normal urine dipstick, blood count, liver enzymes, and creatinine.
Key exclusion criteria (6 listed)
- Exposure to TB at any point. A positive ESAT6/CFP10 Elispot response (defined as greater than 5 spots/well above background and at least double the background response).
- Clinically significant history of skin disorder (eczema, psoriasis, etc.), allergy, immunodeficiency, cardiovascular disease, respiratory disease, endocrine disorder, liver disease, renal disease, gastrointestinal disease, neurological illness, psychiatric disorder, drug or alcohol abuse.
- Oral or systemic steroid medication or the use of immunosuppressive agents.
- Positive HIV antibody test, HCV antibody test or positive HBV serology except post-vaccination.
- Heaf test greater than Grade II
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BCGAlso: Bacille Calmette-Guerinintradermal injection of 0.1ml BCG over the deltoid muscle | Biological | 1 |
Primary outcome
The occurence and severity of local side-effects The occurence and severity of systemic side-effects
Time frame: 1 year
1 secondary outcome
The induction of T cell responses (as measured by an interferon-gamma Elispot assay). Other exploratory cellular immunology assays will be performed as such assays are developed.
Time frame: 1 year
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Apr 2008.
- Background: PubMed 11159955McShane H, Brookes R, Gilbert SC, Hill AV. Enhanced immunogenicity of CD4(+) t-cell responses and protective efficacy of a DNA-modified vaccinia virus Ankara prime-boost vaccination regimen for murine tuberculosis. Infect Immun. 2001 Feb;69(2):681-6. doi: 10.1128/IAI.69.2.681-686.2001.
- Background: PubMed 11854254McShane H, Behboudi S, Goonetilleke N, Brookes R, Hill AV. Protective immunity against Mycobacterium tuberculosis induced by dendritic cells pulsed with both CD8(+)- and CD4(+)-T-cell epitopes from antigen 85A. Infect Immun. 2002 Mar;70(3):1623-6. doi: 10.1128/IAI.70.3.1623-1626.2002.
- Derived from this study: PubMed 19529780Whelan KT, Pathan AA, Sander CR, Fletcher HA, Poulton I, Alder NC, Hill AV, McShane H. Safety and immunogenicity of boosting BCG vaccinated subjects with BCG: comparison with boosting with a new TB vaccine, MVA85A. PLoS One. 2009 Jun 16;4(6):e5934. doi: 10.1371/journal.pone.0005934.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Helen McShane principal investigator
University of Oxford
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing BCG in people with TB, run by University of Oxford at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 Apr 2008. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The occurence and severity of local side-effects The occurence and severity of systemic side-effects (time frame: 1 year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00654316, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Apr 2008.