The Inconsistent Efficacy of BCG
Different Sub-strains of BCG, Different Phenotypes
BCG which is currently the only licensed vaccine against TB, was developed between 1908 and 1921 by repeated sub-culture of an M. bovis strain isolated from a cow. A total of 231 passages resulted in attenuation of the strain. This was observed first in calves and subsequently in guinea pigs and other animal models.[10] In 1921, BCG was administered for the first time orally to a newborn and by late 1920s, the original BCG Pasteur was disseminated throughout the world.
Prior to the adoption of freeze-drying in the 1960s, individual laboratories preserved their strain by repeated sub-culture passages, and this resulted in appearance of different BCG sub-strains that became designated by the laboratory. Five main strains are used today in international immunization programs: Pasteur 1173 P2, Danish 1331, Glaxo 107, Tokyo 172-1 and the Russian BCG-I; the Moreau RDJ strain is used mainly in Brazil.[14] Genomic analysis of BCG strains has documented multiple molecular changes.[1,15–17] The main reason for BCG attenuation is the loss of the region of difference 1 (RD1) associated with loss of the immunodominant virulence factor the early secretory antigen of 6 kDa (ESAT-6). Multiple other deletions probably contribute to phenotypic differences between BCG strains and while there are clear reactogenicity differences, it is not clear whether strain differences are a significant factor contributing to the variable efficacy of BCG observed in clinic.[18]
Dosage & Methods of Administration of BCG
Since 1974, intradermal BCG vaccination at birth has been included in the WHO Expanded Programme on Immunization (EPI) resulting in more than 3 billion cumulative vaccinations worldwide and approximately 100 million vaccinations per year.[14] The concentration of live particles in the vaccines ranges from 50,000 to 3 million per dose depending on the BCG strain.[19]
BCG in Developed & Developing Countries
BCG is effective against rare forms of severe childhood TB meningitis and miliary disease, however, the variation in protection against common pulmonary TB that BCG offers has generally been disappointing in trials conducted in the developing world.[20,21] In order to develop new vaccines against TB, we need to understand the possible factors and the mechanisms that could affect the efficacy of BCG in developed versus developing and underdeveloped countries. Such factors should be taken into consideration in design of clinical trials, as well as in preclinical studies, which should optimally mimic as closely as possible the conditions in the clinical setting where the new candidate is aimed for evaluation, taking into account the potential impact of poor socio-economic lifestyle, environmental mycobacteria and co-infection with other pathogens on the immune status of an individual.
Environmental Mycobacteria
Saprophytic environmental species of non-tuberculous mycobacteria (NTM) are known to be common in soil and untreated water. In developing countries most people are skin test positive to many mycobacterial antigens, whereas in developed countries at higher latitudes this is less usual.[22] NTM are thought to affect BCG efficacy in pre-exposed children by masking or blocking ability of BCG to confer protective responses.[23] Continuing NTM exposure of individuals could induce sensitization, as suggested by animal studies in which mice exposed to NTM need higher doses to shift from latent to progressive disease.[24,25]
Socio-economic Conditions, Co-infection With Other Pathogens & Malnutrition
The impact of socio-economic status on TB susceptibility and incidence is considered to be of prodigious significance.[26,27] Recent studies show that crowded, poorly ventilated, moist and dark places, where sunlight is limited are accounted for the high incidence of TB in the poor parts of developing countries, such as India.[28] Latent TB and low-socio-economic status have been shown to be predictors of TB disease in Worcester, a poverty stricken region near Cape Town, South Africa.[29]
In the context of poor socio-economic conditions in developing countries, where BCG presents the greatest variability in protection as compared with developed countries, chronic viral (HIV) and parasitic infections (helminths, malaria) can greatly influence the population's susceptibility to TB and response to BCG.[30,31] Intestinal parasites, such as helminths, cause chronic immune system activation and associated immunosuppression,[32] which can be a risk factor for increased TB susceptibility.[33,34] Infection of mothers with schistosomiasis and filariasis has been shown to influence infant responses to neonatal BCG immunization.[35] In mice, Schistosoma mansoni infection reduces the protective efficacy of BCG vaccination against virulent MTB.[36]
Malnutrition is a child of poverty. Protein energy malnutrition has been shown to affect safety of BCG in mice[37] and impair development of cell-mediated immunity to BCG in mice[38] and in guinea pigs,[39] where BCG has an established safety and efficacy profile, and in clinic it has been directly associated with increased risks of TB disease.[40] Protein deficiency is associated with tuberculin anergy (false-negative TST), which results in poor detection of clinical TB.[41,42] Malnutrition and helminths infection in children cause indeterminate results to the QuantiFERON-TB Gold In-Tube assay (QFT-IT).[43]
There is increasing evidence highlighting the importance of vitamin D as a potent modulator of human immune responses and in the control of MTB infection.[44–46] Vitamin D deficiency is directly linked to TB susceptibility[47] and clinical studies show that vitamin D supplementation accelerates resolution of inflammatory responses and enhances anti-mycobacterial immunity during TB treatment.[48–50] More recently, vitamin C was shown to have potent bactericidal effect on MTB, as high doses of vitamin C killed multi- and totally drug resistant strains, and the bacteria did not develop resistance to the vitamin.[51]
A proposed model that might explain the variable BCG response could involve epigenetic mechanisms known to be modulated by environmental factors (e.g., nutrition, stress, pollution, infections and other environmental factors), which in turn can affect changes in immune system phenotype.[52] In addition to epigenetic modifications, action of microRNA on epigenetic markers has also been suggested to play a role in regulation and development of protective inflammatory immune responses to etiological agents[53] and could possibly affect regulation of immune response development to vaccination against these agents. Recent observations suggesting that vitamin D influences epigenetics provide a new insight for the importance of vitamin D in utero in reducing risk of chronic diseases later in life.[54] Emerging evidence suggests that chronic infections of mothers, stress and malnutrition can affect in utero development through alterations in postnatal gene expression and metabolic pathways central to accurate functioning and maintenance of health.[55] Although evidence exists for other inflammatory diseases, research is still required to understand how epigenetics could play a role in response to vaccination against TB and disease development later on in life. Recent observations show that intestinal microbiota in infants and adults may have implications in the development of immune responses against microbial infections.[56–58] Moreover, prenatal influences including stress, illness, diet and drug intake have been suggested to play a role in development of gut microbiota in neonates.[57] These data make one reason that chronic parasitic and viral infections, such as helminths and HIV in pregnant mothers as well as malnutrition, may have important implications in the development of the immune status of an infant. Epigenetics and gut microbiota could hold a key to the variable responses to BCG vaccination or to new vaccines (BCG-replacements or boosts) in the underdeveloped and developing world as compared with developed countries. It might be interesting to explore the role of poverty-associated factors in epigenetic mechanisms and gut microbiota in the development of immune responses following vaccination.
Expert Rev Vaccines. 2013;12(12):1431-1448. © 2013 Expert Reviews Ltd.
