Development of the Mycobacterium bovis BCG vaccine: review of the historical and biochemical evidence for a genealogical tree

Oettinger, T; Jørgensen, Morten; Ladefoged, A.; Hasløv, K; Andersen, Peter

doi:10.1054/tuld.1999.0206

Cited by 157 publications

(123 citation statements)

References 43 publications

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“…BCG is the most widely used vaccine in the world and has remained relatively unchanged since 1921 [1,2]. The World Health Organization (WHO) estimates that roughly one third of the world's population is currently infected with MTB, and the incidence rate for new infections is approximately 0.6% per year [3].…”

Section: Introductionmentioning

confidence: 99%

Lactoferrin enhanced efficacy of the BCG vaccine to generate host protective responses against challenge with virulent Mycobacterium tuberculosis

Hwang

Wilk

Budnicka

et al. 2007

Vaccine

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is a disease with world wide consequences, affecting nearly a third of the world's population. The established vaccine for TB, an attenuated strain of Mycobacterium bovis Calmette Guerin (BCG), has existed since 1921. Lactoferrin, an iron binding protein found in mucosal secretions and granules of neutrophils was hypothesized to be an ideal adjuvant to enhance the efficacy of the BCG vaccine, specifically because of previous reports of lactoferrin enhancement of IL-12 production from macrophages infected with BCG. Different vaccination protocols were investigated for generation of host protective responses against MTB infection using lactoferrin admixed to the BCG vaccine. Resulting effects demonstrate that BCG/lactoferrin increased host protection against MTB infection by decreasing organ bacterial load and reducing lung histopathology; significant reduction in tissue CFUs and pathology were observed post challenge compared to those seen with BCG alone. Addition of lactoferrin to the vaccine led to reduced pathological damage upon subsequent infection with virulent MTB, with positive results demonstrated when admixed in oil-based vehicle (incomplete Freund's adjuvant; IFA) or when given with BCG in saline. The observed post-challenge results paralleled increasing production of IFN-γ and IL-6, but only limited changes to proinflammatory mediators TNF-α or IL-1β from BCG stimulated splenocytes. Overall, these studies indicate that lactoferrin is a useful and effective adjuvant to improve efficacy of the BCG vaccine, with potential to reduce related tissue damage and pulmonary histopathology.

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Section: Introductionmentioning

confidence: 99%

Lactoferrin enhanced efficacy of the BCG vaccine to generate host protective responses against challenge with virulent Mycobacterium tuberculosis

Hwang

Wilk

Budnicka

et al. 2007

Vaccine

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“…The history of BCG has been described previously in several excellent reviews 12,[22][23][24][25][26] and is only briefly summarized here. BCG originated with "lait Nocard," a virulent strain of M. bovis isolated from the milk of a cow suffering from tuberculous mastitis.…”

Section: Bcg: a Brief Historymentioning

confidence: 99%

“…27 As early as 1924, cultures of BCG were distributed by the Institute Pasteur to laboratories around the world. 25 The implementation of BCG varied from country to country, and several fascinating histories have been written about specific strains (e.g., BCG-Japan 28 and BCG-Moreau 29 ). Because BCG is a live vaccine, it was necessary…”

Section: Bcg: a Brief Historymentioning

confidence: 99%

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BCG Vaccines: Their mechanisms of attenuation and impact on safety and protective efficacy

Liu

Tran²,

Leung³

et al. 2009

Human Vaccines

126

117

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by MDR strains that are also resistant to a fluoroquinolone and at least one second-line injectable agent (amikacin, kanamycin and/or capreomycin), caught the world's attention after an outbreak in KwaZulu-Natal, South Africa, where 52 of 53 infected patients died. 2 HIV co-infection was a contributing factor in most of these deaths, and indeed, a deadly association between HIV and TB has been known almost since the start of the HIV-epidemic. Of the 1.7 million people who died from TB in 2006, an estimated 200,000 were co-infected with HIV. 1 Because of these situations, effective approaches alternative to antibiotics are urgently needed for the control of TB.Bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis (M. bovis), is currently the only available vaccine against TB. Since 1974, BCG vaccination has been included in the WHO Expanded Program on Immunization. 3 It is estimated that more than 3 billion individuals have been immunized with BCG and over 100 million doses of BCG are administered annually, making it the most widely used vaccine in humans. 3 Meta-analysis studies have confirmed that BCG protects children, providing >80% efficacy against severe forms of TB, including tuberculous meningitis and miliary TB. 4,5 In contrast, evidence for protection against pulmonary TB in adolescents and adults remains contentious as efficacy estimates from clinical trials, observational case control studies and contact studies range from 0 to 80%. 6,7 The reasons for the variable protective efficacy are unknown but several hypotheses have been proposed, including differences among the vaccine strains used in clinical studies, exposure of trial populations to environmental mycobacteria, nutritional or genetic differences in human populations, differences in trial methods, and variations among clinical M. tb strains. 8-13 These explanations are not mutually exclusive and all may contribute to the heterogeneity in vaccine efficacy.A key aspect of this issue may concern the nature of BCG attenuation. Although it is generally considered safe and has been used as a human vaccine since the 1920s, the mechanisms of BCG attenuation remain largely unknown. This is further complicated by the fact that BCG is not a single strain, but instead comprises a number of substrains that exhibit phenotypic and biochemical differences. 14 BCG strains also exhibit differences in residual virulence level. [15][16][17] However, side effects were often attributed to variations in the viability of vaccines during preparation procedures (e.g., freezedrying). 14 In other words, the observed differential virulence among Mycobacterium bovis Bacille Calmette-Guérin (BCG) was developed as an attenuated live vaccine for tuberculosis control nearly a century ago. Despite being the most widely used vaccine in human history, the mechanisms of attenuation of BCG remain poorly understood. BCG is not a single organism, but comprises a number of substrains that differ in genotypes and phenotypes. The impacts of these differences on BCG...

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“…At present, the only available vaccine is the BCG (M. bovis bacillus Calmette-Guérin), which is a deletional mutant of M. bovis that arose spontaneously during subculture on beef-bile-potato medium [135]. In their review, Rook et al [155] expose the limits of BCG and demonstrate that while it helps to protect against childhood forms of TB, it provides variable protection in adults and it has a minimal impact on disease control in developing countries where the vaccine is most needed.…”

Section: Vaccination Vaccines Are Desperately Neededmentioning

confidence: 99%

Pulmonary Tuberculosis and Mycobacterium Tuberculosis: Modern Molecular Epidemiology and Perspectives

Godreuil

Tazi

Bañuls³

2006

Encyclopedia of Infectious Diseases

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Development of the Mycobacterium bovis BCG vaccine: review of the historical and biochemical evidence for a genealogical tree

Cited by 157 publications

References 43 publications

Lactoferrin enhanced efficacy of the BCG vaccine to generate host protective responses against challenge with virulent Mycobacterium tuberculosis

Lactoferrin enhanced efficacy of the BCG vaccine to generate host protective responses against challenge with virulent Mycobacterium tuberculosis

BCG Vaccines: Their mechanisms of attenuation and impact on safety and protective efficacy

Pulmonary Tuberculosis and Mycobacterium Tuberculosis: Modern Molecular Epidemiology and Perspectives

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