- Email: [email protected]
Tuberculosis: Vaccine and drug development
ARTICLE IN PRESS Tuberculosis (2007) 87, S10–S13
Available at www.sciencedirect.com
journal homepage: http://intl.elsevierhealth.com/journals/tube
REVIEW
Tuberculosis: Vaccine and drug development Masao Mitsuyamaa, David N. McMurrayb, a
Graduate School of Medicine, Kyoto University, Kyoto, Japan College of Medicine, Texas A&M University System Health Science Center, College Station, TX, USA
b
There were three presentations at the Conference which focused on the development of new tuberculosis (TB) vaccines. Vaccination is expected to make a major contribution to the ultimate goal eliminating global TB in the next 50 years.1 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. Excellent reviews of the types of new TB vaccines which are currently under development in the US, Japan, and elsewhere have been published in the past 2 years.1–6 In addition, several recent articles have highlighted the challenges to the development of a new TB vaccine,7,8 including the issue of safety.9,10 The development of new TB vaccines takes place against the backdrop of current vaccination policy with BCG. Many nations around the world, including Japan and other Asian countries, routinely vaccinate newborns and children with BCG. At the Conference, Dr. Masao Mitsuyama reviewed the current knowledge regarding genetic diversity of BCG vaccine strains used globally in the context of the controversy surrounding the variable efficacy of BCG in protecting adults against pulmonary TB. He discussed the hypotheses which have been proposed to explain the failure of BCG in some countries, including interference by exposure to environmental mycobacteria. Dr. Mitsuyama reviewed TB vaccine coverage and application strategies in Japan and other Asian countries, and presented a consensus understanding of the value of BCG in protecting infants against severe, extrapulmonary TB. He emphasized the need for validated immunological biomarkers of vaccine-induced
Corresponding author. Tel.: +1 979 845 1367; fax: +1 979 845 3479.
E-mail address: [email protected] (D.N. McMurray). 1472-9792/$ - see front matter & 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tube.2007.05.006
protection against TB which would be useful in future clinical trials of novel vaccines. A necessary step in the development of new TB vaccines is the evaluation of their immunogenicity and protective efficacy in standardized animal models of pulmonary TB. The process of testing new TB vaccines in animal models has been reviewed recently.11,12 Several fundamentally different types of TB vaccines have been tested in animal models, representing a wide range of vaccine development strategies, including mycobacterial proteins and peptides in adjuvants,2,13–16 recombinant BCG strains overexpressing specific mycobacterial antigens or engineered to escape from the phagosome,17,18 live, attenuated vectors expressing mycobacterial antigens,19 and rationally attenuated mutants of M. tuberculosis.20–22 Another vaccine development strategy which has been the focus of research is the use of mycobacterial DNA.23 At the Conference, Dr. Masaji Okada reviewed the development and testing of novel DNA vaccines for TB, including the concept of boosting immunity in individuals previously vaccinated with BCG.24,25 DNA vaccines for TB have been studied extensively in Japan and China, as illustrated in recent publications.26–28 The latter study reported the development of a DNA vaccine encapsulated in microspheres, an approach which has also been used successfully to deliver BCG vaccine orally to mice.29 Dr. Okada reported the activities of a network of Asian investigators involved in the development of therapeutic vaccines for use in patients infected with MDR-TB, and described a network of hospitals within Japan which could be linked in the clinical testing of new TB vaccines.
ARTICLE IN PRESS Tuberculosis: Vaccine and drug development 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 M. tuberculosis. 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, DNA, or attenuated vector vaccine. Several vaccines have been tested as boosters in BCG-primed mice or guinea pigs.19,30–33 There is a great need to devise strategies to deal with the enormous burden of persistently infected individuals globally, estimated to comprise fully one-third of the world’s population. The concept of modulating the immune responses of such chronically infected individuals in a way which would reduce or eliminate the risk of reactivation TB has been discussed widely. There are many impediments to the development of a so-called ‘‘latency vaccine’’, not the least of which is the lack of a reliable animal model of latency. These issues have been discussed recently.34 The critical issues in 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 M. tuberculosis), 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 longlasting immunity.9 Dr. David McMurray reported at the conference that several new TB vaccines were currently in Phase I human testing. This 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 critical issues which impact upon the design of TB vaccine field trials have been reviewed recently.35 The determination of safety and immunogenicity are prerequisites for any new TB vaccine to go forward into Phase III (efficacy) trials. Phase I and II vaccine trials are relatively small and inexpensive, however, Phase III trials of new TB vaccines will be large, complicated, costly endeavors requiring international private/public partnerships and a long planning process. The complexities of evaluating new TB vaccines during the product development phase have been analyzed recently.36 Dr. McMurray discussed the role of the Aeras Global TB Vaccine Foundation in the movement of TB vaccines from the bench through clinical testing to the bedside. Aeras, funded principally by the Bill and Melinda
S11 Gates Foundation, is the most visible non-profit organization currently working to take new TB vaccines from the preclinical stage through Phase III testing in humans. Aeras has developed a pilot plant for batch production of TB vaccines and a laboratory division in which immunological assays are being developed and validated for use in human trials. More importantly, Aeras has built a consortium of academic institutions, public foundations, US and European government organizations, and vaccine industrial partners, which will be necessary to carry new TB vaccines forward. Field trial sites for new TB vaccines are currently being developed by Aeras in South Africa and India, two of the countries which will benefit most from an improved TB vaccine. Two presentations at the Conference focused on recent advances in the development of new TB drugs. Dr. Gail Cassell emphasized the global crisis presented by MDR-TB and directed many of her comments to the challenges of developing and providing the so-called ‘‘second line’’ antibiotics which are necessary to treat MDR-TB patients. Second line drugs are more expensive, take longer to act, induce more side effects, and must be given in complicated regimens. Only five second-line drugs are currently available, and their availability is restricted due to high cost and the limited manufacturing capacity which currently exists for these drugs. A serious concern is the lack of data on the resistance of MDR-TB strains to second line drugs. Treatment failure is reported in about 10% of such patients, but little information exists regarding resistance to specific second line drugs. In addition, it is estimated that only a small fraction (o5%) of global MDR-TB cases are currently being treated. Dr. Cassell discussed the functions of the Green Light Committee (GLC), which has improved access to second line therapies by negotiating price reductions for high burden countries while assuring drug quality. South Africa, India and Russia are currently participating in the program. Although the involvement of the GLC has driven the costs of second line drugs down, they are still beyond the reach of some of the most resource-poor countries. Dr. Cassell concluded her presentation by stating that the long-term solution to the MDR-TB crisis will be the development of new antibiotics, novel immunotherapeutic approaches, and better vaccines. With the involvement of not-for-profit organizations, such as the Global Alliance for TB Drug Development and MEND, the NIH, and the private sector, she expects that 6–7 new drugs may be available in the next 5 years. Dr. Makoto Matsumoto summarized the current status of TB drug development in Japan. He pointed out that the desirable characteristics of new anti-TB drugs should include: (1) shortened treatment regimens; (2) effectiveness against MDR strains; (3) lack of interactions with antiretroviral drugs; and (4) activity against persistent bacilli in patients with latent TB. He reported on a drug discovery program at his company which focused on mycolic acid inhibitors, and presented data on a very promising new compound (OPC-67683) which has a very low minimal inhibitory concentration (MIC) against clinical isolates and was active against intracellular mycobacteria. Mice infected with virulent M. tuberculosis intravenously were treated for 4 weeks with OPC and standard first line anti-TB drugs. OPC reduced bacterial loads in the lungs more effectively than
ARTICLE IN PRESS S12 the other drugs and showed no interactions when given in various combinations. When combined with rifampicin and pyrazinamide, OPC reduced treatment duration significantly (6 to 4 months) in the mouse model. While these presenters highlighted the encouraging progress which has been made in recent years in the development of novel TB vaccines and therapeutic agents, they also emphasized the challenges which must be overcome to make these new tools available in high-burden countries with scant resources.
M. Mitsuyama, D.N. McMurray
16.
17.
18. 19.
Funding: None Competing interests: None declared
20.
Ethical approval: Not required 21.
References 1. Young D, Dye C. The development and impact of tuberculosis vaccines. Cell 2006;124:683–7. 2. Reed S, Lobet Y. Tuberculosis vaccine development; from mouse to man. Microbes Infect 2005;7:922–31. 3. Kaufmann SH, McMichael AJ. Annuling a dangerous liaison: vaccination strategies against AIDS and tuberculosis. Nat Med 2005;11(Suppl. 4):33–44. 4. Skeiky YAW, Sadoff JC. Advances in tuberculosis vaccine strategies. Nat Rev Microbiol 2006;4:469–76. 5. Kaufmann SHE, Baumann S, Nassar Edine A. Exploiting immunology and molecular genetics for rational vaccine design against tuberculosis. Int J Tuberc Lung Dis 2006;10:1068–79. 6. Sander C, McShane H. Translational mini-review series on vaccines: development and evaluation of improved vaccines against tuberculosis. Clin Exp Immunol 2007;147:401–11. 7. Rook GAW, Dheda K, Zumla A. Immune responses to tuberculosis in developing countries: implications for new vaccines. Nat Rev Immunol 2005;5:661–7. 8. Nagelkerke NJD, de Vlas SJ, Mahendradhata Y, Ottenhoff THM, Borgdorff M. The search for a tuberculosis vaccine: an elusive quest? Tuberculosis 2006;86:41–6. 9. Brennan MJ. The tuberculosis vaccine challenge. Tuberculosis 2005;85:7–12. 10. Orme IM. Safety issues regarding new vaccines for tuberculosis, with an emphasis on post-exposure vaccination. Tuberculosis 2006;86:68–73. 11. Orme IM. Mouse and guinea pig models for testing new tuberculosis vaccines. Tuberculosis 2005;85:13–7. 12. Izzo A, Brandt L, Lasco T, Kipnis AP, Orme IM. NIH pre-clinical screening program: overview and current status. Tuberculosis 2005;85:25–8. 13. Langermans JAM, Doherty TM, Vervenne RAW, van der Laan T, Lyashchenko K, Greenwald R, et al. Protection of macaques against Mycobacterium tuberculosis infection by a subunit vaccine based on a fusion protein of antigen 85B and ESAT-6. Vaccine 2005;23:4935–43. 14. Dietrich G, Aagaard C, Leah R, Olsen AW, Stryhn A, Doherty TM, et al. Exchanging ESAT6 with TB10.4 in an Tg85B fusion molecule-based tuberculosis subunit vaccine: efficient protection and ESAT6-based sensitive monitoring of vaccine efficiency. J Immunol 2005;174:6332–9. 15. Andersen CS, Dietrich J, Agger EM, Lycke NY, Lovgren K, Andersen P. The combined CTA1-DD/ISCOMs vector is an effective intranasal adjuvant for boosting prior Mycobacterium
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
bovis BCG immunity to Mycobacterium tuberculosis. Infect Immun 2007;75:408–16. Dietrich J, Billeskov R, Doherty M, Andersen P. Synergistic effect of bacillus Calmette Guerin and a tuberculosis subunit vaccine in cationic liposomes: increased immunogenicity and protection. J Immunol 2007;178:3721–30. Horwitz MA. Recombinant BCG expressing Mycobacterium tuberculosis major extracellular proteins. Microbes Infect 2005;7:947–54. Eddine AN, Kaufmann SHE. Improved protection by recombinant BCG. Microbes Infect 2005;7:939–46. McShane H, Pathan AA, Sander CR, Goonetilleke NP, Fletcher HA, Hill AVS. Boosting BCG with MVA85A: the first candidate subunit vaccine for tuberculosis in clinical trials. Tuberculosis 2005;85:47–52. Martin C, Williams A, Hernandez-Pando R, Cardona PJ, Gormly E, Bordat Y, et al. The live Mycobacterium tuberculosis phoP mutant strain is more attenuated than BCG and confers protective immunity against tuberculosis in mice and guinea pigs. Vaccine 2006;24:3408–19. Aguillar LD, Infante E, Bianco MV, Cataldi A, Bigi F, HernandezPando R. Immunogenicity and protection induced by Mycobacterium tuberculosis mce2 and mce-3 mutants in a BALB/c mouse model of progressive pulmonary tuberculosis. Vaccine 2006;24:2333–42. Sambandamurthy VK, Jacobs Jr WR. Live attenuated mutants of Mycobacterium tuberculosis as candidate vaccines against tuberculosis. Microbes Infect 2005;7:955–61. Khera A, Singh R, Shakila H, Rao V, Dhar N, Narayanan PR, et al. Elicitation of efficient, protective immune responses by using DNA vaccines against tuberculosis. Vaccine 2005;23:5655–65. Kita Y, Tanaka T, Yoshida S, Ohara N, Kaneda Y, Kuwayama S, et al. Novel recombinant BCG and DNA—vaccination against tuberculosis in a cynomologus monkey model. Vaccine 2005; 23:2132–5. Yoshida S, Tanaka T, Kita Y, Kuwayama S, Kanamaru N, Muraki Y, et al. DNA vaccine using hemagglutinating virus of Japanliposome encapsulating combination encoding mycobacterial heat shock protein 65 and interleukin-12 confers protection against Mycobacterium tuberculosis by T cell activation. Vaccine 2006;24:1191–204. Matsumoto M, Umemori K, Ozeki Y, Furugen M, Tatsuo T, Hirayama Y, et al. DNA augments antigenicity of mycobacterial DNA-binding protein-1 and confers protection against Mycobacterium tuberculosis infection in mice. J Immunol 2005;175:441–9. Li H, Li R, Ren H, Zou Y, Chen X, Shi X, et al. The immunogenicity and protective efficacy of Mtb8.4/hIL-12 chimeric gene vaccine. Vaccine 2006;24:1315–23. Cai H, Hu XD, Yu DH, Li SX, Tian X, Zhu YX. Combined DNA vaccine encapsulated in microspheres enhanced protection efficacy against Mycobacterium tuberculosis infection of mice. Vaccine 2005;23:4167–74. Aldwell FE, Brandt L, Fitzpatrick C, Orme IM. Mice fed lipidencapsulated Mycobacterium bovis BCG are protected against aerosol challenge with Mycobacterium tuberculosis. Infect Immun 2005;73:1903–5. Mc Shane H, Pathan AA, Sander CR, Keating SM, Gilbert SC, Huygen K, et al. Recombinant modified vaccinia virus Ankara expressing antigen 85A boost BCG primed and naturally acquired anti-mycobacterial immunity in humans. Nat Med 2004;10:1240–4. Williams A, Goonetilleke NP, McShane H, Clark SO, Hatch G, Gilbert SG, et al. Boosting with poxviruses enhances Mycobacterium bovis BCG efficacy against tuberculosis in guinea pigs. Infect Immun 2005;73:3814–6. Romano M, D’Souza S, Adnet PY, Laali R, Jurion J, Palfiet K, et al. Priming but not boosting with plasmid DNA encoding
ARTICLE IN PRESS Tuberculosis: Vaccine and drug development mycolyl-transferase Ag85A from Mycobacterium tuberculosis increases the survival time of Mycobacterium bovis BCG vaccinated mice against low dose intravenous challenge with M. tuberculosis H37Rv. Vaccine 2006;24:3353–64. 33. Gilbert SC, Moorthy VS, Andrews L, Pathan AA, McConkey SJ, Vuola JM, et al. Synergistic DNA-MVA prime-boost vaccination regimes for malaria and tuberculosis. Vaccine 2006;24: 4554–61.
S13 34. Andersen P. Vaccine strategies against latent tuberculosis. Trends Microbiol 2007;15:7–13. 35. Ibanga HB, Brookes RH, Hill PC, Owaife PK, Fletcher HA, Leinhardt C, et al. Early clinical trials with a new tuberculosis vaccine, MVA85A, in tuberculosis-endemic countries: issues in study design. Lancet Infect Dis 2006;6:522–8. 36. Sadoff JC, Hone D. The role of ‘‘go no-go’’ decisions in TB vaccine development. Microbes Infect 2005;7:899–904.
Available at www.sciencedirect.com
journal homepage: http://intl.elsevierhealth.com/journals/tube
REVIEW
Tuberculosis: Vaccine and drug development Masao Mitsuyamaa, David N. McMurrayb, a
Graduate School of Medicine, Kyoto University, Kyoto, Japan College of Medicine, Texas A&M University System Health Science Center, College Station, TX, USA
b
There were three presentations at the Conference which focused on the development of new tuberculosis (TB) vaccines. Vaccination is expected to make a major contribution to the ultimate goal eliminating global TB in the next 50 years.1 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. Excellent reviews of the types of new TB vaccines which are currently under development in the US, Japan, and elsewhere have been published in the past 2 years.1–6 In addition, several recent articles have highlighted the challenges to the development of a new TB vaccine,7,8 including the issue of safety.9,10 The development of new TB vaccines takes place against the backdrop of current vaccination policy with BCG. Many nations around the world, including Japan and other Asian countries, routinely vaccinate newborns and children with BCG. At the Conference, Dr. Masao Mitsuyama reviewed the current knowledge regarding genetic diversity of BCG vaccine strains used globally in the context of the controversy surrounding the variable efficacy of BCG in protecting adults against pulmonary TB. He discussed the hypotheses which have been proposed to explain the failure of BCG in some countries, including interference by exposure to environmental mycobacteria. Dr. Mitsuyama reviewed TB vaccine coverage and application strategies in Japan and other Asian countries, and presented a consensus understanding of the value of BCG in protecting infants against severe, extrapulmonary TB. He emphasized the need for validated immunological biomarkers of vaccine-induced
Corresponding author. Tel.: +1 979 845 1367; fax: +1 979 845 3479.
E-mail address: [email protected] (D.N. McMurray). 1472-9792/$ - see front matter & 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tube.2007.05.006
protection against TB which would be useful in future clinical trials of novel vaccines. A necessary step in the development of new TB vaccines is the evaluation of their immunogenicity and protective efficacy in standardized animal models of pulmonary TB. The process of testing new TB vaccines in animal models has been reviewed recently.11,12 Several fundamentally different types of TB vaccines have been tested in animal models, representing a wide range of vaccine development strategies, including mycobacterial proteins and peptides in adjuvants,2,13–16 recombinant BCG strains overexpressing specific mycobacterial antigens or engineered to escape from the phagosome,17,18 live, attenuated vectors expressing mycobacterial antigens,19 and rationally attenuated mutants of M. tuberculosis.20–22 Another vaccine development strategy which has been the focus of research is the use of mycobacterial DNA.23 At the Conference, Dr. Masaji Okada reviewed the development and testing of novel DNA vaccines for TB, including the concept of boosting immunity in individuals previously vaccinated with BCG.24,25 DNA vaccines for TB have been studied extensively in Japan and China, as illustrated in recent publications.26–28 The latter study reported the development of a DNA vaccine encapsulated in microspheres, an approach which has also been used successfully to deliver BCG vaccine orally to mice.29 Dr. Okada reported the activities of a network of Asian investigators involved in the development of therapeutic vaccines for use in patients infected with MDR-TB, and described a network of hospitals within Japan which could be linked in the clinical testing of new TB vaccines.
ARTICLE IN PRESS Tuberculosis: Vaccine and drug development 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 M. tuberculosis. 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, DNA, or attenuated vector vaccine. Several vaccines have been tested as boosters in BCG-primed mice or guinea pigs.19,30–33 There is a great need to devise strategies to deal with the enormous burden of persistently infected individuals globally, estimated to comprise fully one-third of the world’s population. The concept of modulating the immune responses of such chronically infected individuals in a way which would reduce or eliminate the risk of reactivation TB has been discussed widely. There are many impediments to the development of a so-called ‘‘latency vaccine’’, not the least of which is the lack of a reliable animal model of latency. These issues have been discussed recently.34 The critical issues in 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 M. tuberculosis), 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 longlasting immunity.9 Dr. David McMurray reported at the conference that several new TB vaccines were currently in Phase I human testing. This 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 critical issues which impact upon the design of TB vaccine field trials have been reviewed recently.35 The determination of safety and immunogenicity are prerequisites for any new TB vaccine to go forward into Phase III (efficacy) trials. Phase I and II vaccine trials are relatively small and inexpensive, however, Phase III trials of new TB vaccines will be large, complicated, costly endeavors requiring international private/public partnerships and a long planning process. The complexities of evaluating new TB vaccines during the product development phase have been analyzed recently.36 Dr. McMurray discussed the role of the Aeras Global TB Vaccine Foundation in the movement of TB vaccines from the bench through clinical testing to the bedside. Aeras, funded principally by the Bill and Melinda
S11 Gates Foundation, is the most visible non-profit organization currently working to take new TB vaccines from the preclinical stage through Phase III testing in humans. Aeras has developed a pilot plant for batch production of TB vaccines and a laboratory division in which immunological assays are being developed and validated for use in human trials. More importantly, Aeras has built a consortium of academic institutions, public foundations, US and European government organizations, and vaccine industrial partners, which will be necessary to carry new TB vaccines forward. Field trial sites for new TB vaccines are currently being developed by Aeras in South Africa and India, two of the countries which will benefit most from an improved TB vaccine. Two presentations at the Conference focused on recent advances in the development of new TB drugs. Dr. Gail Cassell emphasized the global crisis presented by MDR-TB and directed many of her comments to the challenges of developing and providing the so-called ‘‘second line’’ antibiotics which are necessary to treat MDR-TB patients. Second line drugs are more expensive, take longer to act, induce more side effects, and must be given in complicated regimens. Only five second-line drugs are currently available, and their availability is restricted due to high cost and the limited manufacturing capacity which currently exists for these drugs. A serious concern is the lack of data on the resistance of MDR-TB strains to second line drugs. Treatment failure is reported in about 10% of such patients, but little information exists regarding resistance to specific second line drugs. In addition, it is estimated that only a small fraction (o5%) of global MDR-TB cases are currently being treated. Dr. Cassell discussed the functions of the Green Light Committee (GLC), which has improved access to second line therapies by negotiating price reductions for high burden countries while assuring drug quality. South Africa, India and Russia are currently participating in the program. Although the involvement of the GLC has driven the costs of second line drugs down, they are still beyond the reach of some of the most resource-poor countries. Dr. Cassell concluded her presentation by stating that the long-term solution to the MDR-TB crisis will be the development of new antibiotics, novel immunotherapeutic approaches, and better vaccines. With the involvement of not-for-profit organizations, such as the Global Alliance for TB Drug Development and MEND, the NIH, and the private sector, she expects that 6–7 new drugs may be available in the next 5 years. Dr. Makoto Matsumoto summarized the current status of TB drug development in Japan. He pointed out that the desirable characteristics of new anti-TB drugs should include: (1) shortened treatment regimens; (2) effectiveness against MDR strains; (3) lack of interactions with antiretroviral drugs; and (4) activity against persistent bacilli in patients with latent TB. He reported on a drug discovery program at his company which focused on mycolic acid inhibitors, and presented data on a very promising new compound (OPC-67683) which has a very low minimal inhibitory concentration (MIC) against clinical isolates and was active against intracellular mycobacteria. Mice infected with virulent M. tuberculosis intravenously were treated for 4 weeks with OPC and standard first line anti-TB drugs. OPC reduced bacterial loads in the lungs more effectively than
ARTICLE IN PRESS S12 the other drugs and showed no interactions when given in various combinations. When combined with rifampicin and pyrazinamide, OPC reduced treatment duration significantly (6 to 4 months) in the mouse model. While these presenters highlighted the encouraging progress which has been made in recent years in the development of novel TB vaccines and therapeutic agents, they also emphasized the challenges which must be overcome to make these new tools available in high-burden countries with scant resources.
M. Mitsuyama, D.N. McMurray
16.
17.
18. 19.
Funding: None Competing interests: None declared
20.
Ethical approval: Not required 21.
References 1. Young D, Dye C. The development and impact of tuberculosis vaccines. Cell 2006;124:683–7. 2. Reed S, Lobet Y. Tuberculosis vaccine development; from mouse to man. Microbes Infect 2005;7:922–31. 3. Kaufmann SH, McMichael AJ. Annuling a dangerous liaison: vaccination strategies against AIDS and tuberculosis. Nat Med 2005;11(Suppl. 4):33–44. 4. Skeiky YAW, Sadoff JC. Advances in tuberculosis vaccine strategies. Nat Rev Microbiol 2006;4:469–76. 5. Kaufmann SHE, Baumann S, Nassar Edine A. Exploiting immunology and molecular genetics for rational vaccine design against tuberculosis. Int J Tuberc Lung Dis 2006;10:1068–79. 6. Sander C, McShane H. Translational mini-review series on vaccines: development and evaluation of improved vaccines against tuberculosis. Clin Exp Immunol 2007;147:401–11. 7. Rook GAW, Dheda K, Zumla A. Immune responses to tuberculosis in developing countries: implications for new vaccines. Nat Rev Immunol 2005;5:661–7. 8. Nagelkerke NJD, de Vlas SJ, Mahendradhata Y, Ottenhoff THM, Borgdorff M. The search for a tuberculosis vaccine: an elusive quest? Tuberculosis 2006;86:41–6. 9. Brennan MJ. The tuberculosis vaccine challenge. Tuberculosis 2005;85:7–12. 10. Orme IM. Safety issues regarding new vaccines for tuberculosis, with an emphasis on post-exposure vaccination. Tuberculosis 2006;86:68–73. 11. Orme IM. Mouse and guinea pig models for testing new tuberculosis vaccines. Tuberculosis 2005;85:13–7. 12. Izzo A, Brandt L, Lasco T, Kipnis AP, Orme IM. NIH pre-clinical screening program: overview and current status. Tuberculosis 2005;85:25–8. 13. Langermans JAM, Doherty TM, Vervenne RAW, van der Laan T, Lyashchenko K, Greenwald R, et al. Protection of macaques against Mycobacterium tuberculosis infection by a subunit vaccine based on a fusion protein of antigen 85B and ESAT-6. Vaccine 2005;23:4935–43. 14. Dietrich G, Aagaard C, Leah R, Olsen AW, Stryhn A, Doherty TM, et al. Exchanging ESAT6 with TB10.4 in an Tg85B fusion molecule-based tuberculosis subunit vaccine: efficient protection and ESAT6-based sensitive monitoring of vaccine efficiency. J Immunol 2005;174:6332–9. 15. Andersen CS, Dietrich J, Agger EM, Lycke NY, Lovgren K, Andersen P. The combined CTA1-DD/ISCOMs vector is an effective intranasal adjuvant for boosting prior Mycobacterium
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
bovis BCG immunity to Mycobacterium tuberculosis. Infect Immun 2007;75:408–16. Dietrich J, Billeskov R, Doherty M, Andersen P. Synergistic effect of bacillus Calmette Guerin and a tuberculosis subunit vaccine in cationic liposomes: increased immunogenicity and protection. J Immunol 2007;178:3721–30. Horwitz MA. Recombinant BCG expressing Mycobacterium tuberculosis major extracellular proteins. Microbes Infect 2005;7:947–54. Eddine AN, Kaufmann SHE. Improved protection by recombinant BCG. Microbes Infect 2005;7:939–46. McShane H, Pathan AA, Sander CR, Goonetilleke NP, Fletcher HA, Hill AVS. Boosting BCG with MVA85A: the first candidate subunit vaccine for tuberculosis in clinical trials. Tuberculosis 2005;85:47–52. Martin C, Williams A, Hernandez-Pando R, Cardona PJ, Gormly E, Bordat Y, et al. The live Mycobacterium tuberculosis phoP mutant strain is more attenuated than BCG and confers protective immunity against tuberculosis in mice and guinea pigs. Vaccine 2006;24:3408–19. Aguillar LD, Infante E, Bianco MV, Cataldi A, Bigi F, HernandezPando R. Immunogenicity and protection induced by Mycobacterium tuberculosis mce2 and mce-3 mutants in a BALB/c mouse model of progressive pulmonary tuberculosis. Vaccine 2006;24:2333–42. Sambandamurthy VK, Jacobs Jr WR. Live attenuated mutants of Mycobacterium tuberculosis as candidate vaccines against tuberculosis. Microbes Infect 2005;7:955–61. Khera A, Singh R, Shakila H, Rao V, Dhar N, Narayanan PR, et al. Elicitation of efficient, protective immune responses by using DNA vaccines against tuberculosis. Vaccine 2005;23:5655–65. Kita Y, Tanaka T, Yoshida S, Ohara N, Kaneda Y, Kuwayama S, et al. Novel recombinant BCG and DNA—vaccination against tuberculosis in a cynomologus monkey model. Vaccine 2005; 23:2132–5. Yoshida S, Tanaka T, Kita Y, Kuwayama S, Kanamaru N, Muraki Y, et al. DNA vaccine using hemagglutinating virus of Japanliposome encapsulating combination encoding mycobacterial heat shock protein 65 and interleukin-12 confers protection against Mycobacterium tuberculosis by T cell activation. Vaccine 2006;24:1191–204. Matsumoto M, Umemori K, Ozeki Y, Furugen M, Tatsuo T, Hirayama Y, et al. DNA augments antigenicity of mycobacterial DNA-binding protein-1 and confers protection against Mycobacterium tuberculosis infection in mice. J Immunol 2005;175:441–9. Li H, Li R, Ren H, Zou Y, Chen X, Shi X, et al. The immunogenicity and protective efficacy of Mtb8.4/hIL-12 chimeric gene vaccine. Vaccine 2006;24:1315–23. Cai H, Hu XD, Yu DH, Li SX, Tian X, Zhu YX. Combined DNA vaccine encapsulated in microspheres enhanced protection efficacy against Mycobacterium tuberculosis infection of mice. Vaccine 2005;23:4167–74. Aldwell FE, Brandt L, Fitzpatrick C, Orme IM. Mice fed lipidencapsulated Mycobacterium bovis BCG are protected against aerosol challenge with Mycobacterium tuberculosis. Infect Immun 2005;73:1903–5. Mc Shane H, Pathan AA, Sander CR, Keating SM, Gilbert SC, Huygen K, et al. Recombinant modified vaccinia virus Ankara expressing antigen 85A boost BCG primed and naturally acquired anti-mycobacterial immunity in humans. Nat Med 2004;10:1240–4. Williams A, Goonetilleke NP, McShane H, Clark SO, Hatch G, Gilbert SG, et al. Boosting with poxviruses enhances Mycobacterium bovis BCG efficacy against tuberculosis in guinea pigs. Infect Immun 2005;73:3814–6. Romano M, D’Souza S, Adnet PY, Laali R, Jurion J, Palfiet K, et al. Priming but not boosting with plasmid DNA encoding
ARTICLE IN PRESS Tuberculosis: Vaccine and drug development mycolyl-transferase Ag85A from Mycobacterium tuberculosis increases the survival time of Mycobacterium bovis BCG vaccinated mice against low dose intravenous challenge with M. tuberculosis H37Rv. Vaccine 2006;24:3353–64. 33. Gilbert SC, Moorthy VS, Andrews L, Pathan AA, McConkey SJ, Vuola JM, et al. Synergistic DNA-MVA prime-boost vaccination regimes for malaria and tuberculosis. Vaccine 2006;24: 4554–61.
S13 34. Andersen P. Vaccine strategies against latent tuberculosis. Trends Microbiol 2007;15:7–13. 35. Ibanga HB, Brookes RH, Hill PC, Owaife PK, Fletcher HA, Leinhardt C, et al. Early clinical trials with a new tuberculosis vaccine, MVA85A, in tuberculosis-endemic countries: issues in study design. Lancet Infect Dis 2006;6:522–8. 36. Sadoff JC, Hone D. The role of ‘‘go no-go’’ decisions in TB vaccine development. Microbes Infect 2005;7:899–904.