New Generation BCG Vaccines

Abstract

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 CD4þ and CD8þ 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 been

Recombinant Mycobacterium bovis BCG for immunotherapy in nonmuscle invasive bladder cancer

“…The development of expression vectors for mycobacteria has allowed not only the possibility of introducing exogenous DNA in mycobacteria but also expressing a variety of heterologous genes in BCG Tullius and Horwitz (2011). The first Escherichia colimycobacteria shuttle plasmid was developed in 1987 by Jacobs et al (1987) with a DNA sequence of the mycobacteriophage TM4 ligated to an E. coli cosmid.…”

Inhaled Vaccines for the Prevention of Tuberculosis

“…Over the last decades, several types of vaccines have been evaluated in animal models for protection against TB infection including, recombinant BCG, BCG over-expressing native proteins, attenuated MTB, subunit and DNA vaccines. Except for attenuated MTB, none of these vaccines can provide the same or better level of protection as the universal BCG in animal models [43].…”

“…These vaccines can replicate in vitro, in media containing specific supplements and in cultured macrophages but their replication in animal models is highly restricted; thus avoiding serious disseminated disease in these patients. Other forms of BCG have been developed to express immunomodulatory cytokines (Table 1) or genetically modified to enhance antigen presentation [43]. Two approaches have been used to improve antigen presentation either by enhancing MHC I or MHC II antigen presentation.…”

“…Summary of new vaccine candidates against TB by modification of the whole bacterium (modified from[43,46]). …”