Mycobacterium bovis BCG Vaccine Strains Lack narK2 and narX Induction and Exhibit Altered Phenotypes during Dormancy

ABSTRACT Mycobacterium tuberculosis is the causative agent of tuberculosis, a disease that affects one-third of the world's population. The sole extant vaccine for tuberculosis is the live attenuated Mycobacterium bovis bacillus Calmette-Guerin (BCG). We examined 13 representative BCG strains from around the world to ascertain their ability to express DosR-regulated dormancy antigens. These are known to be recognized by T cells of M. tuberculosis-infected individuals, especially those harboring latent infections. Differences in the expression of these antigens could be valuable for use as diagnostic markers to distinguish BCG vaccination from latent tuberculosis. We determined that all BCG strains were defective for the induction of two dormancy genes: narK2 (Rv1737c) and narX (Rv1736c). NarK2 is known to be necessary for nitrate respiration during anaerobic dormancy. Analysis of the narK2/X promoter region revealed a base substitution mutation in all tested BCG strains and M. bovis in comparison to the M. tuberculosis sequence. We also show that nitrate reduction by BCG strains during dormancy was greatly reduced compared to M. tuberculosis and varied between tested strains. Several dormancy regulon transcriptional differences were also identified among the strains, as well as variation in their growth and survival. These findings demonstrate defects in DosR regulon expression during dormancy and phenotypic variation between commonly used BCG vaccine strains.

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The double-sided effects of Mycobacterium Bovis bacillus Calmette–Guérin vaccine

npj Vaccines ◽

10.1038/s41541-020-00278-0 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Junli Li ◽

Lingjun Zhan ◽

Chuan Qin

Keyword(s):

Literature Review ◽

Experimental Evidence ◽

Mycobacterium Bovis ◽

Virus Disease ◽

Bcg Vaccine ◽

Bacillus Calmette Guerin ◽

Mycobacterial Infections ◽

Specific Effects ◽

Mycobacterial Diseases ◽

Protection Mechanisms

AbstractBacillus Calmette–Guérin (BCG), the only vaccine proven to be effective against tuberculosis (TB), is the most commonly used vaccine globally. In addition to its effects on mycobacterial diseases, an increasing amount of epidemiological and experimental evidence accumulated since its introduction in 1921 has shown that BCG also exerts non-specific effects against a number of diseases, such as non-mycobacterial infections, allergies and certain malignancies. Recent Corona Virus Disease 2019 (COVID-19) outbreak has put BCG, a classic vaccine with significant non-specific protection, into the spotlight again. This literature review briefly covers the diverse facets of BCG vaccine, providing new perspectives in terms of specific and non-specific protection mechanisms of this old, multifaceted, and controversial vaccine.

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IFN-α Boosting of Mycobacterium bovis Bacillus Calmette Güerin-Vaccine Promoted Th1 Type Cellular Response and Protection against M. tuberculosis Infection

BioMed Research International ◽

10.1155/2017/8796760 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

C. E. Rivas-Santiago ◽

G. G. Guerrero

Keyword(s):

Immune Response ◽

Mycobacterium Bovis ◽

Cellular Immune Response ◽

Cellular Response ◽

Bacterial Load ◽

Bcg Vaccine ◽

Type I ◽

Bacillus Calmette Guerin ◽

Type I Ifns ◽

Cellular Immune

The role of type I IFNs in the pathogenesis and control of mycobacterial infection is still controversial. It has been reported that type I IFNs exacerbated M. tuberculosis infection through hampering Th1 type cellular immune response. However, under certain conditions they can act as natural immune adjuvants for commercial vaccines. At this point, we have reported recently that successive IFN-alpha boosting of Mycobacterium bovis Bacillus Calmette Güerin (BCG) vaccinated mice protected adult mice from intradermal M. lepraemurium infection and a difference in iNOS was observed. In the present work, we have found that intramuscular IFN-α boosting of Mycobacterium bovis Bacillus Calmette Güerin (BCG) vaccine, either in vitro (human cell line or macrophages derived from PBMC) or in vivo (aerosol mouse model of MTb infection), promoted mostly the development of specific anti-antimycobacterial Th1 type cytokines (IFN-γ; IL-12, TNF-alpha, and IL-17; IL1β) while bacterial load reduction (0.9 logs versus PBS or BCG vaccine) was observed. These findings indicate that, under the experimental settings reported here, interferon alpha can drive or affect the TH cellular immune response in favour of BCG-inducing immunity against M. tuberculosis infection.

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Successful Handling of Disseminated BCG Disease in a Child with Severe Combined Immunodeficiency

Case Reports in Medicine ◽

10.1155/2011/527569 ◽

2011 ◽

Vol 2011 ◽

pp. 1-5 ◽

Cited By ~ 9

Author(s):

Sílvia Bacalhau ◽

Cristina Freitas ◽

Rosalina Valente ◽

Deolinda Barata ◽

Conceição Neves ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Primary Immunodeficiency ◽

Mycobacterium Bovis ◽

Severe Combined Immunodeficiency ◽

Vaccination Strategy ◽

Bcg Vaccine ◽

Bacillus Calmette Guerin ◽

Combined Immunodeficiency ◽

High Burden ◽

Life Threatening

In high-burden countries,Mycobacterium bovisBacillus Calmette-Guérin (BCG) vaccine is administered in newborn to prevent severeMycobacterium tuberculosisinfection. Because life-threatening disseminated BCG disease may occur in children with primary immunodeficiency, vaccination strategy against tuberculosis should be redefined in non-high-burden countries. We report the case of a patient with X-linked severe combined immunodeficiency (SCID) who developed disseminated BCG disease, highlighting the specific strategies adopted.

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Tuberculosis and BCG in Europe

Eurosurveillance ◽

10.2807/esm.11.03.00603-en ◽

2006 ◽

Vol 11 (3) ◽

pp. 3-4 ◽

Cited By ~ 1

Author(s):

J M Watson

Keyword(s):

Twentieth Century ◽

Mycobacterium Bovis ◽

Bcg Vaccine ◽

Bacillus Calmette Guerin ◽

Sensitivity Testing ◽

Tuberculin Sensitivity ◽

National Programmes ◽

The World ◽

Low Incidence

BCG (Bacillus Calmette-Guerin) vaccine was developed from an attenuated strain of Mycobacterium bovis at the beginning of the twentieth century. Its widespread use as a vaccine against tuberculosis spread in Europe, and subsequently globally, over the next 50 years. It remains one of the most frequently administered vaccines in the world. It has also been one of the most controversial. Widely differing estimates of the effectiveness of BCG at protecting against different forms of tuberculosis in different population subgroups in different settings have been published [1]. Some countries, with a low incidence of tuberculosis, did not adopt the use of BCG vaccine at all and some others abandoned its use at a later stage. In addition, great variation developed in national programmes for the administration of BCG including the age(s) at which it should be given, whether or not its administration should be preceded by tuberculin sensitivity testing, and whether repeat vaccinations with BCG should be given.

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Pharmaceutical Characterization of Mycobacterium bovis Bacillus Calmette-Guérin (BCG) Vaccine Used for the Treatment of Superficial Bladder Cancer

Journal of Pharmaceutical Sciences ◽

10.1002/jps.2600820602 ◽

1993 ◽

Vol 82 (6) ◽

pp. 555-562 ◽

Cited By ~ 13

Author(s):

Michael J. Groves

Keyword(s):

Bladder Cancer ◽

Mycobacterium Bovis ◽

Superficial Bladder Cancer ◽

Bcg Vaccine ◽

Bacillus Calmette Guerin

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Whole genome sequence analysis of Mycobacterium bovis bacillus Calmette–Guérin (BCG) Tokyo 172: A comparative study of BCG vaccine substrains

Vaccine ◽

10.1016/j.vaccine.2009.01.034 ◽

2009 ◽

Vol 27 (11) ◽

pp. 1710-1716 ◽

Cited By ~ 48

Author(s):

Masaaki Seki ◽

Ikuro Honda ◽

Isao Fujita ◽

Ikuya Yano ◽

Saburo Yamamoto ◽

...

Keyword(s):

Sequence Analysis ◽

Comparative Study ◽

Mycobacterium Bovis ◽

Genome Sequence ◽

Bcg Vaccine ◽

Whole Genome Sequence ◽

Whole Genome ◽

Bacillus Calmette Guerin ◽

Genome Sequence Analysis

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Immunobiological Markers in Prophylaxis Post-exposure with Single Dose of Rifampicin and BCG Vaccine in Contacts of Multibacillary Leprosy Cases: Study Protocol (Preprint)

10.2196/preprints.20968 ◽

2020 ◽

Author(s):

Camila Massae Sato ◽

Omar Ariel Espinosa Domínguez ◽

Gutembergue Santos de Sousa ◽

Fabiane Verônica da Silva ◽

Roberta Olmo Pinheiro ◽

...

Keyword(s):

Single Dose ◽

Bcg Vaccine ◽

Reference Laboratory ◽

Serological Response ◽

Bacillus Calmette Guerin ◽

Prophylactic Measure ◽

Mato Grosso ◽

Household Contacts ◽

Ifn Γ ◽

Multibacillary Leprosy

BACKGROUND Leprosy contacts are sensitive indicator of the magnitude of severity, and a high risk for infection and disease, especially if the individuals are exposed to the bacillus with multibacillary cases, which reinforces the need for chemoprophylactic measures, such as the use single-dose rifampicin (SDR) combined with BCG vaccine. OBJECTIVE Our study will analyze the serological response of anti-NDO-LID, HO-1/HMOX and serum IFN-γ concentration as a prophylactic measure after the use of single-dose rifampicin (SDR) combined with the Bacillus Calmette-Guérin vaccine (BCG) among multibacillary leprosy household contacts. METHODS Intervention study based on a prospective cohort of household contacts of new cases of multibacillary leprosy diagnosed and registered in the Information System on Diseases of Compulsory Declaration (SINAN – Sistema de Informação de Agravos de Notificação) and residents in the municipalities of Cuiabá and Cáceres, Mato Grosso, in the years 2019 and 2020. Contacts with no signs and symptoms compatible with the disease of the intervention group will receive single-dose rifampicin (SDR) combined with BCG vaccine and will be compared to the control group. The follow-up of the cohort will last 12 months. The analyses of the anti-NDO-LID, HO-1/HMOX and serum concentration of IFN-γ tests as immunological markers before, 6 and 12 months after the intervention will be conducted in a reference laboratory (FIOCRUZ). RESULTS The study is still recruiting participants and is expected to be completed in September 2020. CONCLUSIONS Our study seeks to analyze the response of anti-NDO-LID, HO-1/HMOX tests and serum IFN-γ concentration as a prophylactic measure after the use of single-dose rifampicin (SDR) combined with the Bacillus Calmette-Guérin vaccine (BCG) in home contacts of multibacillary leprosy cases. CLINICALTRIAL Brazilian Registry of Clinical Trials (ReBEC), RBR-6yg2z9. Retrospectively registered on 3 de Out. de 2019.

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