Unique Gene Expression Profiles in Infants Vaccinated with Different Strains ofMycobacterium bovisBacille Calmette-Guérin

Abstract

Vaccination with Mycobacterium bovis bacille Calmette-Guérin (BCG) has variable efficacy in preventing tuberculosis. We hypothesized that some of this variation might be due to differences among BCG strains. To test this, neonates in Orizaba, Mexico, were vaccinated with one of three different BCG strains (BCG-Brazil It is estimated that approximately one-third of the world's population is infected with Mycobacterium tuberculosis, with 8 million new cases and nearly 3 million deaths occurring annually (30,38). Mycobacterium bovis bacille Calmete-Guérin (BCG), the most widely used vaccine in the world, is highly effective at reducing the risk of disseminated forms of tuberculosis in early childhood (11). However, studies have shown that its protection against adult tuberculosis is at best variable and often negligible (17). Variable BCG efficacy has been attributed to geographical differences (17), a masking effect due to an environmental mycobacterium (14), host genetic factors, or variations in BCG vaccine strains.Genomic analysis of BCG vaccines demonstrated that there are numerous genetic differences among the strains, including single-nucleotide polymorphisms, duplications, and deletions. The impact of these differences on the protective efficacy of BCG has not been determined. Functional studies comparing BCG immunogenicity and efficacy in laboratory animal models are subject to considerable controversy. In a mouse model, different BCG strains induced various levels of protection, with Japanese BCG (JBCG) unable to provide protection against mycobacterial challenge (7, 32). However, in a guinea pig model, both JBCG and Danish BCG (DBCG) provided good protection (43). In a recent study in Africa, vaccination with JBCG resulted in greater secretion of Th1 cytokines gamma interferon (IFN-␥), tumor necrosis factor alpha (TNF-␣), and interleukin-2 (IL-2) than vaccination with DBCG (12).Central to the development of tuberculosis is the inability of M. tuberculosis-infected macrophages to contain the pathogen and the failure of T cells to confer long-lasting protective immunity. Therefore, the efficacy of BCG is associated with not only innate but also adaptive immune responses. In this study, we evaluated M. tuberculosis-specific recall immune response in infants vaccinated 1 year earlier with one of three BCG strains. After stimulation of peripheral blood mononuclear cells (PBMC) with culture filtrate proteins (CFP), mRNA for a panel of immune-related genes was monitored by quantitative real-time PCR. PBMC from children immunized with Brazilian BCG (BBCG) and DBCG expressed higher levels of IL-12␤, IL-27, and IFN-␥ in response to CFP, while those from children immunized with JBCG expressed higher levels of IL-1␣, IL-1␤, IL-6, and IL-24. MATERIALS AND METHODSParticipants. Healthy neonates were recruited at a community-based, general hospital in Veracruz, Mexico. Exclusion criteria for enrollment were birth weight below 2,500 g, a family history of tuberculosis, and known human immunodeficiency virus infection. In...

Mycobacterium bovisBCG Immunization Induces Protective Immunity against Nine DifferentMycobacterium tuberculosisStrains in Mice

“…By contrast, the impact of immunizing with various live attenuated vaccine strains (including different BCG preparations) is unclear. Although different BCG strains have been shown to induce unique immune responses in animal models and humans, both preclinical study results and data from clinical trials have strongly suggested that different BCG preparations usually yield similar levels of protection when given at equivalent doses by the same route of administration (4,40,42). In fact, we have shown that the BCG Pasteur and SSI BCG strains induce statistically indistinguishable protective responses against the M. tuberculosis HN878 and M. tuberculosis Erdman strains (S. Derrick, unpublished data).…”

Delaying Bacillus Calmette-Guérin Vaccination from Birth to 4 1/2 Months of Age Reduces Postvaccination Th1 and IL-17 Responses but Leads to Comparable Mycobacterial Responses at 9 Months of Age

“…Several theories have been proposed to explain the variation in BCG efficacy throughout the world, including differences in dose (10), strains of BCG vaccine (11)(12)(13), age of vaccination (14), methodological practices (10,15), and genetic factors (16). However, one widely accepted hypothesis is that natural immunity to nontuberculous mycobacteria (NTM) in the environment renders BCG vaccine less effective or masks its protective effect (17)(18)(19)(20).…”

A DNA vaccine expressing CFP21 and MPT64 fusion protein enhances BCG-induced protective immunity against Mycobacterium tuberculosis infection in mice

“…In addition, diVerential immunogenicity of BCG Japan was also reported. Vaccination with BCG Japan resulted in greater secretion of Th1 cytokines such as IFN-, TNF-, and IL-2, when compared with BCG Danish-vaccinated infants [30], while Wu reported that BCG Japan-vaccinated infants had a signiWcantly greater expression of proinXammatory cytokines in PBMC, such as IL-1, IL-1 , IL-6, and IL-24, than BCG Denmark or BCG Brazil did [31]. Taken together, we can conclude that the discrepancy of above results about immunogenicity and Fig.…”