BCG and Other Candidate Vaccines

for Tuberculosis

RajKumar KayalGuwahati

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

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

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

Worldwide BCG coverage

BCG: Side Effects

Local Abscess Regional Adenopathy +- Suppuration Osteitis Disseminated BCG Disease Hypersensitivity reactions Others: Otitis, cutaneous lesions,

metastatic abscesses, renal lesions etc.

BCG Side Effects: Management

Local Abscess: No treatment Lymphadenitis: ?Drugs, ?Surgery Disseminated : ATT- pyrazinamide Osteitis: Drugs + surgery Anaphylaxis: Standard treatment

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

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

Possible types of new vaccines

Pre-exposure Post-exposure Boost : early or late Therapeutic

M. Tuberculosis Genome

Possible Candidate Vaccines

Improved BCG Attenuated M. tuberculosis Adjuvanated Protein, Peptide. Or DNA

subunit Vaccine Virus vectored Vaccine Other Approaches

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+

Attenuated M. tuberculosis

Targeted inactivation of metabolic genes/ virulence genes

To be used as post-exposure vaccine

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

Virus Vectored Vaccine

Modified Vaccinia Ankara Adenovirus

Early or late boost

Other Approaches

Nucleocapsids Killed mycobacteria e.g., M. vaccae or

RUTI: as therapeutic vaccine Bacteria vectored AG : Salmonella Non-protein AG Conjugate vaccine

Vaccines currently under trial

Candidate Vaccine type Stage Developed by

MVA Ag85A Virus vectored Phase II ‘05 Oxford Univ.

BCG Ag85A rBCG Phase I ‘03 UCLA/ AERAS

72f fusion protein

SU+ Adj. Phase I ’03 Crixa / GSK/ AERAS

ESAT 6/85B SU + Adj. Phase I ‘05 SSI/ TBVAC

Adenovirus 85A

Virus vectored Phase I ’06 Crucell / AERAS