UCLA

Bacille de Calmette et Guérin (BCG) was attenuated from a virulent strain of Mycobacterium bovis a century ago and has since been administered as an anti-tuberculosis (TB) vaccine to more than four billion people, making it the most widely used vaccine of all time. Although BCG provides significant protection against disease and death due to childhood and disseminated forms of TB, the efficacy of BCG against adult, pulmonary disease is inconsistent. Thus, despite near universal vaccination with BCG in TB endemic areas, TB remains a heavy burden worldwide, especially in developing nations. In recent years, BCG has been utilized in two major vaccine development strategies. First, BCG has been used as a vector to express foreign antigens in studies aimed at developing new vaccines against a variety of viral, parasitic, and bacterial pathogens, and against cancer and allergic diseases. More recently, in a new vaccine paradigm, BCG has been used as a homologous vector to overexpress native mycobacterial antigens in studies aimed at developing improved vaccines against TB. As a vaccine vector, BCG has several major advantages including a very well-established safety profile, high immunogenicity (excellent CD4{thorn} and CD8{thorn} T-cell responses and strong TH1-Type immune responses), and low manufacturing cost. As a vector for recombinant TB vaccines, BCG has the additional advantages of providing a broad array of relevant mycobacterial antigens in addition to the recombinant antigens, moderate efficacy to begin with, high acceptability as a replacement vaccine for BCG in TB endemic countries, and the capacity to express M. tuberculosis proteins in native form and release them in a way that results in their being processed similarly to M. tuberculosis proteins. In addition to the overexpression of native proteins to improve their immunogenicity and protective efficacy against TB, recombinant BCG vaccines have been developed that express immunomodulatory cytokines or have beenengineered for enhanced antigen presentation. Several new recombinant BCG vaccines against TB have demonstrated improved protective efficacy against M. tuberculosis, M. bovis, and M. leprae in small animal models. Against non-TB targets, results have been variable, but several recombinant BCG vaccines have demonstrated excellent immunogenicity and protective efficacy; stable and highlevel expression of foreign antigens in recombinant BCG, in a way that will make them available for proper processing and presentation, have been recurrent challenges. © Springer Basel AG 2011.