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Vaccine. 2020 Feb 24;38(9):2229-2240. doi: 10.1016/j.vaccine.2019.11.060. Epub 2020 Jan 28.

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

Author information

1
Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Precision Vaccines Program, Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: Asimenia.Angelidou@childrens.harvard.edu.
2
Precision Vaccines Program, Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatrics, Sapienza University of Rome, Rome 00185, Italy. Electronic address: MariaGiulia.Conti@childrens.harvard.edu.
3
Precision Vaccines Program, Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: Joann.Arce@childrens.harvard.edu.
4
OPEN, Odense Patient Data Explorative Network, Odense University Hospital/Institute of Clinical Research, University of Southern Denmark, 5000 Odense C, Denmark. Electronic address: CB@ssi.dk.
5
Department of Pediatrics, Royal Children's Hospital, University of Melbourne, Victoria 3052 Australia. Electronic address: shannf@netspace.net.au.
6
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands; Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany. Electronic address: Mihai.Netea@radboudumc.nl.
7
Precision Vaccines Program, Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
8
Precision Vaccines Program, Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: LakshmiPrasad.Potluri@childrens.harvard.edu.
9
Precision Vaccines Program, Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: Guzman.Sanchez-Schmitz@childrens.harvard.edu.
10
Precision Vaccines Program, Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: Robert.Husson@childrens.harvard.edu.
11
Precision Vaccines Program, Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: Al.Ozonoff@childrens.harvard.edu.
12
Vaccine Centre, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK; Vaccines & Immunity Theme, Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, Fajara, PO Box 273, Banjul, Gambia. Electronic address: bkampmann@mrc.gm.
13
Precision Vaccines Program, Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: Simon.VanHaren@childrens.harvard.edu.
14
Precision Vaccines Program, Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT & Harvard, Cambridge, MA 02142, USA. Electronic address: Ofer.Levy@childrens.harvard.edu.

Abstract

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.

KEYWORDS:

BCG vaccine formulation; Chemokine; Colony forming units; Cord blood; Cytokine; Viability

PMID:
32005538
DOI:
10.1016/j.vaccine.2019.11.060
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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: OL is a named inventor on several vaccine adjuvant formulation patent applications. The other authors do not have a commercial or other association that might pose a conflict of interest.

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