bcg: what have we learnt in 100 years? · 2021. 4. 30. · summary •100 years on, there is still...
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BCG: What have we learnt in 100 years?
Helen McShane
The Jenner Institute
University of Oxford
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What we thought we knew?
• Safe
• Reliable protection against disseminated disease
• No effect of boosting on protection against disease
• Protection against leprosy
• Association with reduction in all cause mortality
• Intravesical installation for bladder cancer
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Pooled rate ratios for pulmonary tuberculosis, according to trial characteristics.
Mangtani et al, CID 2013
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The magnitude of the BCG-attributable increase in IFNγ correlates with known protective efficacy
Malawi UK
Black et al, The Lancet 2002
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Protection against M.tb infection as determined by QuantiFERON in children vaccinated with BCG.
Roy et al, BMJ 2014~15% protection
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What do we now know?
• Less safe in some populations (Hessling)
• Protection can be durable (Abubakar)
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BCG IFN-g ELISPOT and Ag85A IgG are immune correlates in BCG-vaccinated infants
0
50
100
150
200
300
400
SF
C/m
illio
n P
BM
C
0
1
2
3
4
OD
0
1
2
3
4
OD
Ag85A IgG Day 0 Ag85A IgG Day 28
estimated odds ratio 0.62, p = 0.019
Fletcher HA et al Nature Communications, 2016
BCG-IFN- ELISPOT
OR 0.502, p = 0.013
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BCG revaccination reduces rate of sustained QFT conversion in South African adolescents
Nemes et al, NEJM 2018
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BCG revaccination in school children in Brazil does not enhance protection against TB disease
Rodrigues et al Lancet 2005
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“ No evidence that any of the trial vaccines contributed to protection against tuberculosis”
Lancet 1996
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Why the difference?
•Different endpoint
•Different population
•Difference may be real
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BCG revaccination boosts Th1, Th17 and BCG-reactive
NK cells
Suliman et al, 2016
Rakshit et al, 2019
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Mucosal BCG protects better against low dose M.tb infection than intradermal BCG in NHPs
Dijkman et al NM 2019
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IV BCG profoundly alters the outcome of M.tbinfection in NHPs
Darrah et al, 2020Sharpe et al, 2016
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Infant BCG reduces non tuberculous infections in first 6 weeks
Prentice et al, The Lancet 2021
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What do we still not know
• Immunological mechanisms of protection
• Against infection
• Against disease
• With IV BCG
• Which antigens are protective
• Unbiased identification of novel protective antigens
• How to quantify NTM exposure
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IV BCG in mice expands HSCs and induces epigenetic changes in macrophages that are protective in vivo
Kaufmann et al, Cell 2018
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Next generation BCG vaccines
• VPM1002
• Phase III RCT in infants in Gabon, Kenya, South Africa,
Tanzania and Uganda
• Primary Endpoint: QFT conversion
• Secondary Endpoint: TB disease
• n ~7000
• MTBVAC
• Phase IIa in newborns ongoing
• Phase III to start Q4 2021 / Q1 2022
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Summary
• 100 years on, there is still much we do not understand
about BCG
• Despite > 4.2bn doses administered
• But still a lot we can learn
• Parallel animal and human experimental medicine
studies can be very informative
• BCG replacement vaccines now in late stage
development
• Need to be superior for efficacy and/or safety
• Need also to be non-inferior for non-specific effects
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Acknowledgements
Jenner TB group: • Julia Marshall• Iman Satti• Rachel Tanner• Stephanie Harris• Hazel Morrison• Suzy Jackson• Rachel Wittenberg• Emily Hoogkamer• Marco Polo Peralta
Alvarez• Ingrid Cabrera Puig• Raquel Lopez-Ramon
Alison Lawrie• Sam Vermaak• Elena Stylianou
Oxford Centre for Respiratory Medicine• Henry Bettinson• Tim Hinks
Study participants
Lynda StewartAnne KasmarWillem Hanekom
PHE, Porton• Andrew White• Sally Sharpe• Ann Rawkins