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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