BCG and Other Candidate Vaccines for Tuberculosis

1. BCGand Other Candidate Vaccines for Tuberculosis RajKumar Kayal Guwahati

2. Tuberculosis: Global Burden • One third of world’s population infected with M. tuberculosis • Every year, 8 million cases of infective disease • 2 million die of tuberculosis every year • Ranks among 10 top causes of death • MDR tuberculosis • XDR tuberculosis • Declared as global emergency by WHO

3. BCG Vaccine: Attenuated M. bovis • Albert Calmette & Camille Guerin • 1921: 13 years & 231 generations of subcultures: launched in 1924 • Pasteur, Tokyo, Danish, Russian, GSK, Tice etc. strains • Freeze dried, reconstituted in N/S, 0.1 mg in 0.1ml, I/D over L shoulder

4. BCG Vaccine • Over 100 m children vaccinated / year • In India, Danish strain 1331 at Guindy • Store with diluent in ‘Fridge, avoid exposure to sunlight • Reconstituted vaccine to be used within 3 hours

5. Worldwide BCG coverage

6. BCG: Side Effects • Local Abscess • Regional Adenopathy +- Suppuration • Osteitis • Disseminated BCG Disease • Hypersensitivity reactions • Others: Otitis, cutaneous lesions, metastatic abscesses, renal lesions etc.

7. BCG Side Effects: Management • Local Abscess: No treatment • Lymphadenitis: ?Drugs, ?Surgery • Disseminated : ATT- pyrazinamide • Osteitis: Drugs + surgery • Anaphylaxis: Standard treatment

8. BCG: Efficacy • 80% protection against TBM & mTB • Overall 0-80% protection • Effect wanes over 10-20 years • Protection only in naïve subjects • No booster effect • Risk of Disease in Immunocompromised Subjects

9. Development of New Vaccines • Preclinical: Lab studies, animal models • Phase I: Small field study: Safety • Phase II: Slightly larger study: Does it induce the “right” immune response • Phase III: Does it protect against TB • License, Launch & Distribute • Phase IV: Post-marketing surveillance

10. Possible types of new vaccines • Pre-exposure • Post-exposure • Boost : early or late • Therapeutic

11. M. Tuberculosis Genome

12. Possible Candidate Vaccines • Improved BCG • Attenuated M. tuberculosis • Adjuvanated Protein, Peptide. Or DNA subunit Vaccine • Virus vectored Vaccine • Other Approaches

13. Improved BCG • Expression of cytokine genes • Over expression of protective antigens e.g., AG85B • Reconstitution of deleted gene segments To be used as pre-exposure vaccine rBCG30, BCG:RD1, rBCG:D ure C-llo+

14. Attenuated M. tuberculosis • Targeted inactivation of metabolic genes/ virulence genes To be used as post-exposure vaccine

15. Adjuvanated Protein, Peptide, or DNA subunit Vaccine • Hypothesis driven selection: secreted AG, O2 starving • Empirical selection: T cell recognition, MHC binding, Combination of Antigens Early or late boost

16. Virus Vectored Vaccine • Modified Vaccinia Ankara Adenovirus Early or late boost

17. Other Approaches • Nucleocapsids • Killed mycobacteria e.g., M. vaccae or RUTI: as therapeutic vaccine • Bacteria vectored AG : Salmonella • Non-protein AG • Conjugate vaccine

18. Vaccines currently under trial

19. THANK YOU