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Approaches in
NEW TB Vaccine Development
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Existing Vaccine : Mycobacterium bovis bacillus Calmette-Guerin (BCG) vaccine
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New TB Vaccine Research 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
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Vaccine Delivery Systems
• Plasmid DNA• pVRC8400
• Bacterial spore• B.subtilis
• Advuvants • ASO1• MPL• GLA,• CPG7909• eiconazoids• aGalcer• Lactoferrin
• 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
Whole/recombinant /fragmented cells Approaches
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 CellRUTI1 (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 MycobacterialMTBVAC. (University of Zaragoza)
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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 BCGAERAS-422
Adjuvanted Subunit Fusion Protein 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 Mtb39Aadjuvant 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)
Antigen85B
antigen85B-HBHA (Aeras, in Institut Pasteur
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•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 vaccines2. Protein – adjuvant vaccines
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
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Route of Immunization of New TB Vaccines
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Aerosole
Inhalation-by air-jet nebulizers
Oral
Nasal
New Antigen Discovery Strategies
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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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Summary
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Electroporated DNA vaccination
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