Ignite Creation Date:
2024-05-05 @ 7:22 PM
Last Modification Date:
2024-10-26 @ 9:47 AM
Study NCT ID:
NCT00654316
Status:
COMPLETED
Last Update Posted:
2008-04-07
First Post:
2008-04-02
Brief Title:
Study of the Safety and Immunogenicity of Bacille Calmette Guerin BCG Vaccine
Sponsor:
University of Oxford
Organization:
University of Oxford
Study Overview
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
Status:
COMPLETED
Status Verified Date:
2008-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Tuberculosis TB kills about three million people annually It is estimated that one third of the worlds population are latently infected with Mycobacterium tuberculosis Mtb Multi-drug resistant strains of Mtb and co-infection with Mtb 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
Mtb 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- primeMVA-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 Mtb 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
Mtb 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- primeMVA-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 Mtb 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 120000 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 107 pfu 139 doses of 5 x 107 pfu 6 doses of 1 x 108 pfu and 18 doses of 25 x 108 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 Mtb 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
1 BCG alone
2 MVA85A alone
3 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
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 120000 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 107 pfu 139 doses of 5 x 107 pfu 6 doses of 1 x 108 pfu and 18 doses of 25 x 108 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 Mtb 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
1 BCG alone
2 MVA85A alone
3 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None