A vaccine that is safe in a naive recipient may have negative eff

A vaccine that is safe in a naive recipient may have negative effects in one with pre-existing immunologic memory (Doherty, 2005). Table 1

shows several tuberculosis vaccine candidates that are currently in advanced stages of clinical trials. Of these, subunit tuberculosis vaccines have received special attention because, in spite of their poor immunogenicity, XL765 they exhibit a high degree of safety and their production can be standardized. Currently, such tuberculosis subunit vaccines are prepared from recombinant proteins, purified from bacterial expression vectors or formulated as naked DNA, consisting of recombinant plasmids encoding Mtb antigens under the control of eukaryotic promoters (Doherty & Andersen, 2005; Hoft, 2008; Carstens, 2009). They can stimulate T-cell responses against key subunit antigens and are

safe even in immunosuppressed individuals. Their main drawback is the limited availability of adjuvants approved for human use to boost their immunogenicity (Hogarth et al., 2003; Mills, 2009). Box 1 provides a short description of adjuvants GDC-0068 clinical trial for human use that have been the result of many years of research and development, including oils and aluminium adjuvants, synthetic adjuvants, second-generation delivery-depot systems and receptor-associated adjuvants (Ott & Van Nest, 2007). Many of these adjuvants have been tested for their efficacy in tuberculosis vaccines, mostly in mouse models in combination with different antigens or fusion proteins. When used alone or in conjunction with BCG in a ‘prime-boost’ strategy or coadjuvanted with cytokines or other molecules, many of these vaccines have been shown to confer L-NAME HCl protective immunity (Lindblad et al., 1997). Secreted proteins, HSP, lipoproteins and putative phosphate transport receptors (PstS)

have all been evaluated for subcutaneous, oral or intranasal priming vaccination, followed by intradermal or oral BCG vaccination (Doherty et al., 2002; Hogarth et al., 2003; Hoft, 2008). Likewise, emulsions (Haile et al., 2004, 2005), microspheres (Ajdary et al., 2007), toxin derivatives (Takahashi et al., 2006; Badell et al., 2009), cationic lipids (D’Souza et al., 2002) and oligodeoxynucleotides (Kamath et al., 2008) have demonstrated efficacy in inducing strong T-cell responses with high titres of IFN-γ and specific antibodies. Table 2 summarizes several studies evaluating the efficacy of different antigen/adjuvant combinations for tuberculosis vaccination.

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