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). Thus, although many strains produce both toxins, antibodies to only toxin A can mediate protection. Animals vaccinated with recombinant spores were fully able to survive reinfection, a property that is particularly important for a disease with which patients are prone to relapse. We show that mucosal immunization, not parenteral delivery, is required to generate secretory IgA and that production of these neutralizing polymeric antibodies correlates with protection. This work demonstrates that an effective vaccine against C. difficile can be designed around two attributes, mucosal delivery and the repeat domain of toxin A.

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Bacillus species, typically Bacillus subtilis, are being used as probiotics and mounting evidence indicates that Bacillus species are important for development of a robust gut-associated lymphoid system (GALT). We used a number of gut isolates of Bacillus incorporating three species, B. subtilis, Bacillus licheniformis and Bacillus flexus to evaluate the nature of interaction between spores and the GALT. In mice orally administered with spores, evidence of cell proliferation was determined in the germinal centers of Peyer's patches. Stimulation of antigen-presenting cells and T lymphocytes was also markedly enhanced. Cytokines were shown to be induced in spleens and mesenteric lymph nodes of mice including the proinflammatory cytokines, tumour necrosis factor-alpha and IL-6. We also demonstrated that vegetative cells of B. subtilis can stimulate expression of the toll-like receptor (TLR) genes for TLR2 and TLR4. However, we were able to show that spores could not stimulate either and must, by default, interact with another TLR and by this mechanism help activate innate immunity.

c Needle-free, mucosal immunization is a highly desirable strategy for vaccination against many pathogens, especially those entering through the respiratory mucosa, such as Mycobacterium tuberculosis. Unfortunately, mucosal vaccination against tuberculosis (TB) is impeded by a lack of suitable adjuvants and/or delivery platforms that could induce a protective immune response in humans. Here, we report on a novel biotechnological approach for mucosal vaccination against TB that overcomes some of the current limitations. This is achieved by coating protective TB antigens onto the surface of inert bacterial spores, which are then delivered to the respiratory tract. Our data showed that mice immunized nasally with coated spores developed humoral and cellular immune responses and multifunctional T cells and, most importantly, presented significantly reduced bacterial loads in their lungs and spleens following pathogenic challenge. We conclude that this new vaccine delivery platform merits further development as a mucosal vaccine for TB and possibly also other respiratory pathogens. Athird of the world's population is estimated to be infected with Mycobacterium tuberculosis, the causative pathogen of tuberculosis (TB). Although the incidence of TB has been slowly decreasing from year to year, this disease still accounts for over a million deaths per annum, mostly in the developing world. TB, however, is also beginning to have an impact on the more developed nations, for example, because of the increased levels of people movement and international travel, which only serve to disseminate TB. Controlling TB relies on a number of strategies, including vaccination, drug therapy, and improved living standards. However, only improved living standards have been shown to have any real impact, and both the current TB drugs and vaccination strategies carry a number of inherent flaws. With drug therapy, multiresistant strains of M. tuberculosis and, more recently, extensively drug-resistant (XDR) M. tuberculosis variants have emerged, showing that drug development may, at most, produce only a short-term impact. The current vaccine against TB, M. bovis BCG, is generally considered unsatisfactory because of its variable efficacy (in different parts of the world) and the shortlived protection that it confers, especially against the reactivated pulmonary form of the disease. For these reasons, BCG is no longer routinely used in some countries.Bearing in mind these concerns, a better vaccine is now a priority. It should be noted that the results of the first-ever efficacy trial (phase 2b) of a new TB vaccine (MVA85A) that could boost the efficacy of BCG was concluded in early 2013 but with disappointing results (1). Although other trials are planned or are in progress for at least nine other TB vaccines, it is clear that the tasks ahead will be challenging. There are some important issues regarding the design of TB vaccines that might now be reconsidered, for example, the general assumption that cellular responses are of paramount imp...