<p>Tuberculosis caused by <italic>Mycobacterium tuberculosis</italic>, remains a major cause of morbidity and mortality throughout the world despite more than a half century of widespread vaccination, claiming millions of lives every year [1]. The extraordinary high prevalence of the latent infection [estimated at one-third of the world's population or 2 billion people] is one of the main factors contributing to the high incidence of active tuberculosis. The other factor is convergence of the TB and HIV epidemics. With HIV/AIDS fueling the TB crisis, the WHO has estimated that more than 1 billion people will be infected with TB bacilli in the next 20 years.</p><p>There are two vaccination strategies against TB –pre exposure –prophylatic and post exposure – therapeutic exposure to the pathogen. Many experts believe that for complete eradication of TB, there is a need for a cheap and effective vaccine for mass immunization [6,7]. BCG is the only vaccine presently available against tuberculosis but it is estimated to prevent only 5% of the all potentially vaccine-preventable deaths due to tuberculosis [8]. However, it has been found to be effective against disseminated and meningeal tuberculosis in young children [9]. In a number of studies from different parts of the world, the protective efficacy of BCG vaccine against adult pulmonary TB has varied dramatically from 80% to 0%, the latter in a trial in Chingleput, India [10, 11].</p><p>Smith <italic>et al.</italic> [12] reported that though BCG is a good vaccine, a number of unknown host as well as environmental factors adversely affect its protective efficacy and impair the ability of certain individuals to respond successfully. Besides the genetic differences among BCG strains, the observed variability in BCG efficacy has also been attributed to methodological differences among the clinical trials, genetic differences within and among host populations, varying levels of malnutrition among host populations, virulence differences among <italic>M.tuberculosis</italic> strains, varying efficacy of BCG against primary infection in children and endogenous reactivation of persistent infection versus exogenous re-infection, and effects of environmental mycobacteria on the host immune response to BCG. However, no single factor fully explains the observed variability in BCG efficacy. In addition to its variable efficacy and its interference with tuberculin skin test screening, BCG's usefulness is limited due to its potential lack of safety in immuno-compromised individuals: a number of cases of disseminated BCG infection attributable to BCG vaccination have been reported in HIV+ and other immuno-compromised individuals [13,14].</p><p>Further complicating the evaluation of BCG is the lack of comparability among the vaccination studies due to the use of 6 different BCG sub-strains [Copenhagen-1331, Pasteur-1173P, Glaxo-1077, Tokyo-172, Russian, Moreau]. The comparative genomic analysis of different BCG strains has shown that there is no uniformity among all presently used vaccines and this genetic variability may contribute to the variation in protective efficacy seen in different geographic regions of the world [15]. Progress in applying the strategy of case detection and supervised chemotherapy [DOTS –directly –observed therapy] to control tuberculosis has been documented in some countries, but the major burden of the disease has not changed because the control programmes have not been implemented effectively world-wide [16]. This, along with the appearance of Multi-Drug Resistant [MDR] clinical isolates of <italic>M.tuberculosis</italic>, leads to the conclusion that current disease control measures like BCG and DOTS are not enough to control tuberculosis globally [6].</p><p>There is an urgent need to have an effective vaccine for the ultimate control of the current TB pandemic [6, 17, 18]. Clearly, the development of more effective vaccines and immunization strategies designed to protect against primary infection and to boost waning BCG-induced protective immune responses are needed to facilitate world-wide control of tuberculosis. The search for new <italic>M.tuberculosis</italic> antigens which can be recognized by the immune system of infected humans or can provide good protection in the different animal models is a challenging task. The sequencing of the <italic>M.tuberculosis</italic> genome has further accelerated the process of antigen discovery including the discovery of M.tb 8.4 [19]. A major international research effort to develop new TB vaccines has been underway for many years and, as a result, over the last 10 years more than 200 TB vaccine candidates have been tested in mouse, guinea pig and on human primate models [20,21].</p><p>Vaccination is expected to make a major contribution to the ultimate goal of eliminating global TB in the next 50 years [6]. Several TB vaccine candidates have shown sufficient promise in pre-clinical testing in various animal models to warrant applications for regulatory approval for initial Phase I [safety] testing in human subjects. This is a very important step for any new TB vaccine, and initially requires a small study in healthy, PPD-negative individuals [usually adults] in the country in which the vaccine was developed. Additional Phase I trials may be conducted in PPD+ individuals, children, infants, or other groups for which the vaccine may be indicated ultimately. Often these trials are combined with a Phase IIA trial in which clinical samples are collected for measurement of immunological responses to the vaccine. The demonstration of safety and immunogenicity are prerequisites for any new TB vaccine to go forward into Phase III [efficacy] trials.</p><p><xref ref-type="table" rid="tab001">Table 1</xref> lists several of the vaccines which are currently at some step in the process of being tested in human subjects. As can be appreciated, these vaccines represent a wide range of vaccine development strategies, from mycobacterial proteins and peptides in adjuvants, to DNA preparations, and live, attenuated vectors expressing mycobacterial antigens. Although Ag85 is a frequent antigenic target in the new vaccines, other antigens have been included as well. The critical issues in the clinical trials of these vaccines differ a bit depending upon the vaccine type. For example, for the living vaccines (e.g. recombinant BCG strains, rationally attenuated <italic>M tuberculosis)</italic>, the principal concern is safety. For the subunit vaccines (e.g., proteins or peptides), the principal challenge is the development of a safe and effective adjuvant. For the DNA vaccines, the issue is effective delivery strategies which insure long-lasting immunity [20]. <table-wrap id="tab001"><label>Table 1</label><caption><p>TB Vaccine Candidates in/entering Phase I Clinical Trials</p></caption><table><thead><tr><th>TB Vaccine Candidate</th></tr></thead><tbody><tr><td valign="top"><hr /></td></tr><tr><td valign="top">Modified Vaccinia Ankara - Ag85B</td></tr><tr><td valign="top">Recombinant BCG - Ag85A</td></tr><tr><td valign="top">Recombinant BCG - listeriolysin</td></tr><tr><td valign="top">Rationally attenuated M tuberculosis</td></tr><tr><td valign="top">Mtb72f fusion protein + adjuvant</td></tr><tr><td valign="top">ESAT6/Ag85A + adjuvant</td></tr><tr><td valign="top">DNA multigene cocktail</td></tr><tr><td valign="top">Inactivated M vaccae</td></tr></tbody></table></table-wrap></p><p>The vast majority of the novel TB vaccines which have been tested to date for protective efficacy in animal models were evaluated as prophylactic vaccines, i.e., immunologically naive animals were given the vaccine followed, after some appropriate interval, by virulent challenge with <italic>M tuberculosis</italic>. However, the current widespread use of BCG in the high-burden countries where a new vaccine is most urgently needed complicates the evaluation and use of any new TB vaccine. It is clear that BCG will continue to be used in those countries and that new TB vaccines will be tested in that context. This fact, coupled with the general consensus that few, if any, of the new vaccines appear to induce a level of resistance when given alone which is superior to BCG in experimental animals, has led many in the TB vaccine development community to embrace a prime-boost strategy. The concept is to boost pre-existing BCG-induced immunity with a new protein/peptide or attenuated vector vaccine. Initially, the boosters would be given to individuals who had received the BCG vaccine currently used in their community, however, an attractive alternative would be to prime with a recombinant BCG strain over-expressing the proteins to be used in the boost.</p></sec></body><back><ref-list><title>References

JII

Journal of Immunology and Immunopathology

0972-0561

The Indian Society of Immunology & Immunopathology

jii-8-2-siip005

RESEARCH NOTE

Current Status of TB Vaccines

Gupta

Deputy Director

National JALMA Institute for Leprosy & Other Mycobacterial Diseases, Tajganj, Agra-282 001.

122006

828284

<p>Tuberculosis caused by <italic>Mycobacterium tuberculosis</italic>, remains a major cause of morbidity and mortality throughout the world despite more than a half century of widespread vaccination, claiming millions of lives every year [1]. The extraordinary high prevalence of the latent infection [estimated at one-third of the world's population or 2 billion people] is one of the main factors contributing to the high incidence of active tuberculosis. The other factor is convergence of the TB and HIV epidemics. With HIV/AIDS fueling the TB crisis, the WHO has estimated that more than 1 billion people will be infected with TB bacilli in the next 20 years.</p><p>There are two vaccination strategies against TB –pre exposure –prophylatic and post exposure – therapeutic exposure to the pathogen. Many experts believe that for complete eradication of TB, there is a need for a cheap and effective vaccine for mass immunization [6,7]. BCG is the only vaccine presently available against tuberculosis but it is estimated to prevent only 5% of the all potentially vaccine-preventable deaths due to tuberculosis [8]. However, it has been found to be effective against disseminated and meningeal tuberculosis in young children [9]. In a number of studies from different parts of the world, the protective efficacy of BCG vaccine against adult pulmonary TB has varied dramatically from 80% to 0%, the latter in a trial in Chingleput, India [10, 11].</p><p>Smith <italic>et al.</italic> [12] reported that though BCG is a good vaccine, a number of unknown host as well as environmental factors adversely affect its protective efficacy and impair the ability of certain individuals to respond successfully. Besides the genetic differences among BCG strains, the observed variability in BCG efficacy has also been attributed to methodological differences among the clinical trials, genetic differences within and among host populations, varying levels of malnutrition among host populations, virulence differences among <italic>M.tuberculosis</italic> strains, varying efficacy of BCG against primary infection in children and endogenous reactivation of persistent infection versus exogenous re-infection, and effects of environmental mycobacteria on the host immune response to BCG. However, no single factor fully explains the observed variability in BCG efficacy. In addition to its variable efficacy and its interference with tuberculin skin test screening, BCG's usefulness is limited due to its potential lack of safety in immuno-compromised individuals: a number of cases of disseminated BCG infection attributable to BCG vaccination have been reported in HIV+ and other immuno-compromised individuals [13,14].</p><p>Further complicating the evaluation of BCG is the lack of comparability among the vaccination studies due to the use of 6 different BCG sub-strains [Copenhagen-1331, Pasteur-1173P, Glaxo-1077, Tokyo-172, Russian, Moreau]. The comparative genomic analysis of different BCG strains has shown that there is no uniformity among all presently used vaccines and this genetic variability may contribute to the variation in protective efficacy seen in different geographic regions of the world [15]. Progress in applying the strategy of case detection and supervised chemotherapy [DOTS –directly –observed therapy] to control tuberculosis has been documented in some countries, but the major burden of the disease has not changed because the control programmes have not been implemented effectively world-wide [16]. This, along with the appearance of Multi-Drug Resistant [MDR] clinical isolates of <italic>M.tuberculosis</italic>, leads to the conclusion that current disease control measures like BCG and DOTS are not enough to control tuberculosis globally [6].</p><p>There is an urgent need to have an effective vaccine for the ultimate control of the current TB pandemic [6, 17, 18]. Clearly, the development of more effective vaccines and immunization strategies designed to protect against primary infection and to boost waning BCG-induced protective immune responses are needed to facilitate world-wide control of tuberculosis. The search for new <italic>M.tuberculosis</italic> antigens which can be recognized by the immune system of infected humans or can provide good protection in the different animal models is a challenging task. The sequencing of the <italic>M.tuberculosis</italic> genome has further accelerated the process of antigen discovery including the discovery of M.tb 8.4 [19]. A major international research effort to develop new TB vaccines has been underway for many years and, as a result, over the last 10 years more than 200 TB vaccine candidates have been tested in mouse, guinea pig and on human primate models [20,21].</p><p>Vaccination is expected to make a major contribution to the ultimate goal of eliminating global TB in the next 50 years [6]. Several TB vaccine candidates have shown sufficient promise in pre-clinical testing in various animal models to warrant applications for regulatory approval for initial Phase I [safety] testing in human subjects. This is a very important step for any new TB vaccine, and initially requires a small study in healthy, PPD-negative individuals [usually adults] in the country in which the vaccine was developed. Additional Phase I trials may be conducted in PPD+ individuals, children, infants, or other groups for which the vaccine may be indicated ultimately. Often these trials are combined with a Phase IIA trial in which clinical samples are collected for measurement of immunological responses to the vaccine. The demonstration of safety and immunogenicity are prerequisites for any new TB vaccine to go forward into Phase III [efficacy] trials.</p><p><xref ref-type="table" rid="tab001">Table 1</xref> lists several of the vaccines which are currently at some step in the process of being tested in human subjects. As can be appreciated, these vaccines represent a wide range of vaccine development strategies, from mycobacterial proteins and peptides in adjuvants, to DNA preparations, and live, attenuated vectors expressing mycobacterial antigens. Although Ag85 is a frequent antigenic target in the new vaccines, other antigens have been included as well. The critical issues in the clinical trials of these vaccines differ a bit depending upon the vaccine type. For example, for the living vaccines (e.g. recombinant BCG strains, rationally attenuated <italic>M tuberculosis)</italic>, the principal concern is safety. For the subunit vaccines (e.g., proteins or peptides), the principal challenge is the development of a safe and effective adjuvant. For the DNA vaccines, the issue is effective delivery strategies which insure long-lasting immunity [20]. <table-wrap id="tab001"><label>Table 1</label><caption><p>TB Vaccine Candidates in/entering Phase I Clinical Trials</p></caption><table><thead><tr><th>TB Vaccine Candidate</th></tr></thead><tbody><tr><td valign="top"><hr /></td></tr><tr><td valign="top">Modified Vaccinia Ankara - Ag85B</td></tr><tr><td valign="top">Recombinant BCG - Ag85A</td></tr><tr><td valign="top">Recombinant BCG - listeriolysin</td></tr><tr><td valign="top">Rationally attenuated M tuberculosis</td></tr><tr><td valign="top">Mtb72f fusion protein + adjuvant</td></tr><tr><td valign="top">ESAT6/Ag85A + adjuvant</td></tr><tr><td valign="top">DNA multigene cocktail</td></tr><tr><td valign="top">Inactivated M vaccae</td></tr></tbody></table></table-wrap></p><p>The vast majority of the novel TB vaccines which have been tested to date for protective efficacy in animal models were evaluated as prophylactic vaccines, i.e., immunologically naive animals were given the vaccine followed, after some appropriate interval, by virulent challenge with <italic>M tuberculosis</italic>. However, the current widespread use of BCG in the high-burden countries where a new vaccine is most urgently needed complicates the evaluation and use of any new TB vaccine. It is clear that BCG will continue to be used in those countries and that new TB vaccines will be tested in that context. This fact, coupled with the general consensus that few, if any, of the new vaccines appear to induce a level of resistance when given alone which is superior to BCG in experimental animals, has led many in the TB vaccine development community to embrace a prime-boost strategy. The concept is to boost pre-existing BCG-induced immunity with a new protein/peptide or attenuated vector vaccine. Initially, the boosters would be given to individuals who had received the BCG vaccine currently used in their community, however, an attractive alternative would be to prime with a recombinant BCG strain over-expressing the proteins to be used in the boost.</p></sec></body><back><ref-list><title>ReferencesAnon. Global tuberculosis Control. WHO Report. 2002. World Health Organization, Geneva, Switzerland, 2002, p 181.Corbett

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