bcg and other candidate vaccines for tuberculosis rajkumar kayal guwahati
TRANSCRIPT
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BCG and Other Candidate Vaccines
for Tuberculosis
RajKumar KayalGuwahati
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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
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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
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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
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Worldwide BCG coverage
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BCG: Side Effects
Local Abscess Regional Adenopathy +- Suppuration Osteitis Disseminated BCG Disease Hypersensitivity reactions Others: Otitis, cutaneous lesions,
metastatic abscesses, renal lesions etc.
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BCG Side Effects: Management
Local Abscess: No treatment Lymphadenitis: ?Drugs, ?Surgery Disseminated : ATT- pyrazinamide Osteitis: Drugs + surgery Anaphylaxis: Standard treatment
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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
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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
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Possible types of new vaccines
Pre-exposure Post-exposure Boost : early or late Therapeutic
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M. Tuberculosis Genome
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Possible Candidate Vaccines
Improved BCG Attenuated M. tuberculosis Adjuvanated Protein, Peptide. Or DNA
subunit Vaccine Virus vectored Vaccine Other Approaches
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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+
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Attenuated M. tuberculosis
Targeted inactivation of metabolic genes/ virulence genes
To be used as post-exposure vaccine
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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
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Virus Vectored Vaccine
Modified Vaccinia Ankara Adenovirus
Early or late boost
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Other Approaches
Nucleocapsids Killed mycobacteria e.g., M. vaccae or
RUTI: as therapeutic vaccine Bacteria vectored AG : Salmonella Non-protein AG Conjugate vaccine
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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
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