BCG vaccination was developed by attenuation in vitro over 13 years from a virulent sample of Mycobacterium bovis by Albert Calmette and Camille Guérin at the Pasteur Institute, Lille. The attenuated strain named BCG (Bacillus of Calmette-Guérin) is now known as Mycobacterium bovis BCG. BCG was given to humans for the first time in 1921, since when it has become the most used vaccine in the world [6]. It has been given to 3 billion people with low incidence of serious adverse events [18]; more than 100 million people currently receive the vaccine in order to prevent tuberculosis [23]. More than 90% of global production is made of the Russian BCG-I, Tokyo 172-1, Danish 1331, Moreau RDJ and Pasteur 1173-P2 sub strains [19].
Despite use of the vaccine for more than 80 years, several controversies remain concerning efficacy, with studies reporting protection rates varying between 0 and 80% [12, 13, 4, 11].
Oral administration was the route initially used by Calmette and Guérin, but was replaced by intradermal administration in virtually all countries after the Lubeck accident, in which 67 of 249 babies given the vaccine died due to contamination of the BCG with virulent Mycobacterium tuberculosis [2]. However, Arlindo de Assis continued to administer oral BCG, which was maintained in Brazil until the mid-1970s when it was substituted by the intradermal route. Even after this change in route, the Fundação Ataulpho de Paiva continued to produce the oral vaccine [7].
Studies by Assis and Carvalho [3] showed that none of 167 children developed a response to skin testing one week after oral immunisation; skin-test positivity only appeared from 6 weeks after oral immunisation with BCG Moreau.
It is known that induction of the mucosal immune response is vital for protection against infectious agents whose route of entry is via the mucosa, as is the case for tuberculosis. Oral administration was shown capable of inducing a more substantial mucosal and systemic immune response compared to the intradermal route [16].
Brown et al (2003) [9] showed that BCG could induce mycobacteria-specific antibodies and Williams et al (2004) [26] confirmed that oral vaccination with BCG induced significant increases in IgA isotype anti-LAM antibodies that had important functions in systemic responses as well as offering mucosal protection.
Host resistance to mycobacterial invasion is associated principally with generation of cellular immune responses [15].
CD4+ T cells become activated after presentation of mycobacterial antigens in association with class II MHC molecules, producing cytokines, principally IFN-γ, the principal activator of macrophages [25] that acts in conjunction with TNF-α to recruit macrophages, augmenting the effectiveness of host immune responses [22].
CD8+ T cells are also capable of secreting cytokines including IFN-γ, TNF-α, IL-2 and IL-4 and are important in controlling the equilibrium between Th1 and Th2 responses [25]. Deficiency of these cells provokes poorly organised cellular infiltrates suggesting their importance in the formation of protective granulomas [1]. In addition, these cells appear to have an important role in protection against reactivation of latent infection [21].
Once mycobacteria become intracellular pathogens, serum components cannot gain access and lose their protective function [25]. B-cells have been described as an important source of chemokines involved in granuloma development and consequently inhibit mycobacterial dissemination, resulting in recruitment of appropriate cells to the locality for the first few weeks after infection [8].
The concept of a common mucosal-associated system regulating and coordinating immune responses at mucosal surfaces has been an important advance in our understanding of protection against mucosal pathogens. This system is based on primed T and B lymphocytes that migrate from the site of antigen presentation via lymphatics and blood to selectively "home" to lymphoid tissue at distant sites in gastrointestinal, respiratory, genitourinary and other mucosa-associated regions [17].
In this context, the objective of this study was to analyse humoral and cellular immune responses to mycobacterial antigens and correlate them to the PPD skin tests in healthy adult volunteers in Rio de Janeiro (Brazil) after oral vaccination with M. bovis BCG Moreau RDJ.