TY - JOUR
T1 - Licensed Bacille Calmette-Guérin (BCG) formulations differ markedly in bacterial viability, RNA content and innate immune activation
AU - Angelidou, Asimenia
AU - Conti, Maria Giulia
AU - Diray-Arce, Joann
AU - Benn, Christine S.
AU - Shann, Frank
AU - Netea, Mihai G.
AU - Liu, Mark
AU - Potluri, Lakshmi Prasad
AU - Sanchez-Schmitz, Guzman
AU - Husson, Robert
AU - Ozonoff, Al
AU - Kampmann, Beate
AU - van Haren, Simon Daniël
AU - Levy, Ofer
N1 - Publisher Copyright:
© 2020 The Authors
PY - 2020/2/24
Y1 - 2020/2/24
N2 - Background: Bacille Calmette-Guérin (BCG), the live attenuated tuberculosis vaccine, is manufactured under different conditions across the globe generating formulations that may differ in clinical efficacy. Innate immune recognition of live BCG contributes to immunogenicity suggesting that differences in BCG viability may contribute to divergent activity of licensed formulations. Methods: We compared BCG-Denmark (DEN), -Japan (JPN), -India (IND), -Bulgaria (BUL) and -USA in vitro with respect to a) viability as measured by colony-forming units (CFU), mycobacterial membrane integrity, and RNA content, and b) cytokine/chemokine production in newborn cord and adult peripheral blood. Results: Upon culture, relative growth was BCG-USA > JPN ≫ DEN > BUL = IND. BCG-IND and -BUL demonstrated >1000-fold lower growth than BCG-JPN in 7H9 medium and >10-fold lower growth in commercial Middlebrook 7H11 medium. BCG-IND demonstrated significantly decreased membrane integrity, lower RNA content, and weaker IFN-γ inducing activity in whole blood compared to other BCGs. BCG-induced whole blood cytokines differed significantly by age, vaccine formulation and concentration. BCG-induced cytokine production correlated with CFU, suggesting that mycobacterial viability may contribute to BCG-induced immune responses. Conclusions: Licensed BCG vaccines differ markedly in their content of viable mycobacteria possibly contributing to formulation-dependent activation of innate and adaptive immunity and distinct protective effects.
AB - Background: Bacille Calmette-Guérin (BCG), the live attenuated tuberculosis vaccine, is manufactured under different conditions across the globe generating formulations that may differ in clinical efficacy. Innate immune recognition of live BCG contributes to immunogenicity suggesting that differences in BCG viability may contribute to divergent activity of licensed formulations. Methods: We compared BCG-Denmark (DEN), -Japan (JPN), -India (IND), -Bulgaria (BUL) and -USA in vitro with respect to a) viability as measured by colony-forming units (CFU), mycobacterial membrane integrity, and RNA content, and b) cytokine/chemokine production in newborn cord and adult peripheral blood. Results: Upon culture, relative growth was BCG-USA > JPN ≫ DEN > BUL = IND. BCG-IND and -BUL demonstrated >1000-fold lower growth than BCG-JPN in 7H9 medium and >10-fold lower growth in commercial Middlebrook 7H11 medium. BCG-IND demonstrated significantly decreased membrane integrity, lower RNA content, and weaker IFN-γ inducing activity in whole blood compared to other BCGs. BCG-induced whole blood cytokines differed significantly by age, vaccine formulation and concentration. BCG-induced cytokine production correlated with CFU, suggesting that mycobacterial viability may contribute to BCG-induced immune responses. Conclusions: Licensed BCG vaccines differ markedly in their content of viable mycobacteria possibly contributing to formulation-dependent activation of innate and adaptive immunity and distinct protective effects.
KW - BCG vaccine formulation
KW - Chemokine
KW - Colony forming units
KW - Cord blood
KW - Cytokine
KW - Viability
UR - http://www.scopus.com/inward/record.url?scp=85079163992&partnerID=8YFLogxK
U2 - 10.1016/j.vaccine.2019.11.060
DO - 10.1016/j.vaccine.2019.11.060
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C2 - 32005538
AN - SCOPUS:85079163992
SN - 0264-410X
VL - 38
SP - 2229
EP - 2240
JO - Vaccine
JF - Vaccine
IS - 9
ER -
