Licensed Bacille Calmette-Guérin (BCG) formulations differ markedly in bacterial viability, RNA content and innate immune activation.

Adult BCG Vaccine / genetics Bulgaria Denmark Humans Immunity, Innate Immunogenicity, Vaccine India Infant, Newborn Japan Microbial Viability Mycobacterium bovis / immunology RNA, Bacterial / analysis United States

BCG vaccine formulation Chemokine Colony forming units Cord blood Cytokine Viability

Journal

Vaccine

ISSN: 1873-2518

Titre abrégé: Vaccine

Pays: Netherlands

ID NLM: 8406899

Informations de publication

Date de publication:
24 02 2020

Historique:

received: 26 05 2019

revised: 24 10 2019

accepted: 25 11 2019

pubmed: 2 2 2020

medline: 20 3 2021

entrez: 2 2 2020

Statut: ppublish

Résumé

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. 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. 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. 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.

Sections du résumé

BACKGROUND

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.

Identifiants

DOI: 10.1016/j.vaccine.2019.11.060 PMID: 32005538 PMC: PMC7556328

pubmed: 32005538

pii: S0264-410X(19)31614-7

doi: 10.1016/j.vaccine.2019.11.060

pmc: PMC7556328

mid: NIHMS1569299

pii:

doi:

Substances chimiques

BCG Vaccine 0

RNA, Bacterial 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng