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Current approches in TB vaccines Research
The document discusses approaches for developing new tuberculosis (TB) vaccines. It describes existing TB vaccines like BCG and aims of new TB vaccines to induce TH1 cytokines and CD4+ or CD8+ T cell responses. New vaccines are being developed to prevent initial infection, boost immunity in BCG-primed individuals, or help treat active TB disease. They utilize various vaccine delivery systems including plasmid DNA, bacterial spores, viral vectors, and recombinant bacteria. Whole cells, recombinant cells, and adjuvanted subunit vaccines featuring TB antigens are also under investigation. New antigen discovery strategies incorporate bioinformatics, proteomics, and identifying antigens expressed during latent TB infection.
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Current approches in TB vaccines Research
- 1. Approaches in NEW TB VaccineDevelopment 1 Existing Vaccine : Mycobacterium bovis bacillus Calmette-Guerin (BCG) vaccine
- 2. 2 New TB VaccineResearch Aims TB vaccine candidates are based on agents that induce classical TH1 cytokines such as • IFN-γ or • TNF-α from either • CD4+ • or CD8+ T cells. 1.Prime/Pre-exposure: Replacement of the existing BCG vaccine to prevent infection or establishment of granuloma 2. Prime-boost/Post-exposure : Administration as a booster in recently- or remotely- BCG primed individuals • prevent disease • Reactivation of latency 3.Immunotherapy/Therapeutic vaccines: used as an adjunct to chemotherapy in active TB disease or latent tuberculosis infection (LTBI). Shorten course of chemotherapy and Decrease relapse or reinfection
- 3. Vaccine Delivery Systems •Plasmid DNA • pVRC8400 • Bacterial spore • B.subtilis • Advuvants • ASO1 • MPL • GLA, • CPG7909 • eiconazoids • aGalcer • Lactoferrin 3 • Recombinant virus • r Adenovirus • r Modified Vaccinia virus Ankara • r Rhesus cytomegalovirus • Recombinant Bacteria • r MTB/rBCG • r M.smegmatis • r M.shottsii • r salmonella
- 4. Whole/recombinant /fragmented cellsApproaches Heat -inactivated environmental non-tuberculous mycobacterium. Whole cell • DAR-901-M.obuense (Dartmouth Uni) • M. Vaccae (longhom) • M. indicus pranii (Gov.of india) therapeutic vaccine that consists of detoxified liposomal fragments of MTB- latent TB Fragmented Cell RUTI1 (Archivel Farma S.L.) recombinant BCG (rBCG) mutant expressing listeriolysin O, a secreted thiol-activated cholesterol-binding hemolysin (Hly) from Listeria monocytogenes. Recombinant Mycobacterial VPM1002 rBCGΔUre-C:Hly (Vakzine Projekt Management GmbH)) Recombinant MTB mutant lacking expression of genes for several virulence factors, including ESAT6 and mutations in genes required for synthesis of bacterial cell wall components that protect MTB from host defences Recombinant Mycobacterial MTBVAC. (University of Zaragoza) 4 Genetically modified BCG such that it overexpresses major secretory proteins, early targets for the host immune response against M.tb (antigen 85A,85B,Rv3407 Recombinant BCG AERAS-422
- 5. Adjuvanted Subunit FusionProtein Vaccines MTB antigens 85B TB10.4 Adjuvant IC31 H4-IC31 (Sanofi Pasteur) virulence- associated Rv2608, Rv3619, Rv3620 latency- associated Rv1813 GLA-SE (Acts as a Toll- like receptor 4) ID93+GLA-SE (Infectious Diseases Research Institute) Antigen 85B (Ag85B) ESAT-6 latency- associated antigen (Rv2660c) H56:IC31 (Statens Serum Institut) Mtb32A and Mtb39A adjuvant AS01E M72+AS01E (GlaxoSmithKline) Antigen 85B (Ag85B Early Secretory Antigenic Target 6 (ESAT-6) adjuvanted with IC31 Hybrid 1-IC31 and Hybrid 1-CAF01 (Statens Serum Institut) Heparin-binding haemaglutinin (HBHA) Antigen 85B antigen85B-HBHA (Aeras, in Institut Pasteur 5 •Enhance the effectiveness of BCG. •Regimens would retain BCG vaccination of neonates •Involve the delivery of immunodominant mycobacterial antigens to the immune system, using: 1. Viral vectored vaccines 2. Protein – adjuvant vaccines
- 6. Virus Vectored Vaccines(delivery system) ChAd-Ag85A( Uni Oxford) Chimpanzee adenovirus (ChAd) vectors (RhCMV) Rhesus cytomegalovirus vectors expressing SIV antigen MVA85A (UOXF/Aeras) Modified Vaccinia virus Ankara serves as a delivery system for the MTB antigen 85A. AdAg85A (MacMaster Uni) A replication deficient serotype 5 adenoviral vector expressing the MTB antigen 85A, an immunodominant surface antigen of MTB Crucell Ad35/Aeras 402 A replication-deficient adenovirus vector containing the MTB antigens 85A, 85B and TB10.4 6
- 7. Route of Immunizationof New TB Vaccines 7 Aerosole Inhalation-by air-jet nebulizers Oral Nasal
- 8. New Antigen DiscoveryStrategies 8 Bioinformatics • Epitope prediction • Antigens preferentially unregulated during latent infection Proteomics • Biochemical fractionation of Mtb antigens (e.g. culture filtrate proteins • Identification of Mtb antigens present in bodily fluids of TB patients e.g. Urine • Identification of Mtb peptides processed in vivo during infection and associated with MHC molecules
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Editor's Notes
- #3 • Pre-exposure TB vaccines(prime ): Intended for use in newborns or young infants to replace or amplify BCG early in life and before exposure to TB, these vaccines and intended to prevent TB in people who have not been infected with M.tb. (MVA85A, Aeras 402. Aeras 404/ Hyvac 4, M72, rBCG30, VPM1002,Aeras rBCG • Post-exposure TB vaccines(Prime Boost): Given post-infancy, typically to school children, adolescents or adults, who have either been vaccinated or latently infected with the TB bacteria or both, these vaccines reduce progression to active disease. (H56, ID93) • Therapeutic(immunotherapy) vaccines: These vaccines are given to individuals with active TB in conjunction with TB drug therapy with the aim of shortening the duration of the drug therapy. (RUTI, M.vaccae).
- #5 Perforation of the phagosomal membrane allows egress of recombinant BCG antigens into the cytosol, facilitating MHC**-mediated CD 8 T-cell priming
- #6 ESAT6-Early secreted antigenic target for mycobacterium CFP-culture filtrate protein RD-regions of difference Dos-hypoxia related transcriptional factor SGL-sulfoglycolipids Heparin-binding haemaglutinin (HBHA) is a protein antigen involved in extrapulmonary dissemination of MTB, and is associated with strong T cell responses in individuals with LTBI, but not in those with active TB
- #7 Chimpanzee adenovirus (ChAd) vectors : they are natural respiratory viruses and can target the lung where Mycobacterium tuberculosis (MTB) Cytomegalovirus as a TB vaccine vector :Rhesus cytomegalovirus (RhCMV) vectors expressing SIV antigen have been shown to control the infection of highly pathogenic SIVMAC239 in rhesus macaques
- #10 tuberculin skin test (TST) and interferon gamma release assays (IGRAs)