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.

1. Approaches
in
NEW TB Vaccine Development
1
Existing Vaccine : Mycobacterium bovis bacillus
Calmette-Guerin (BCG) vaccine

2. 2
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

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 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 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 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 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 Immunization of New TB Vaccines
7
Aerosole
Inhalation-by air-jet nebulizers
Oral
Nasal

8. New Antigen Discovery Strategies
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

9. 9

10. Summary
10

11. 11

12. 12

13. Electroporated DNA vaccination
1
3

14. 14