1

TB VACCINES PIPELINE Working Group on New TB Vaccines September 2008 According to the Global Plan to Stop TB, 2006-2015, the introduction of new, effective TB vaccines will be an essential component of any strategy to eliminate TB by 2050. New TB vaccines to prevent childhood and adult forms of TB, to prevent progression of latent infection to active disease and to shorten drug treatment regimens or reduce the risk of relapse can fundamentally alter our approach to TB control. It is anticipated that the new generation of TB vaccines will work best using a heterologous prime-boost strategy to strengthen the immune response induced by the current BCG. This “prime-boost” strategy would include administration of BCG or, for example, a new recombinant BCG (rBCG), the “prime”, followed by a “booster” inoculation with a different vaccine to infants and young children before they are exposed to TB, or as a separate booster to young adults, or as an adjunct to chemotherapy. TB vaccines under development could work in several ways: 1) Prevent infection 2) Prevent primary disease 3) Prevent latent infection 4) Prevent reactivation of latent infection 5) Shorten the course and improve the response to chemotherapy The following is a list of TB vaccines under development presented in the following categories, with some candidates falling into more than one category: Priming: Vaccine candidates that would serve as the “prime” in a prime-boost regimen and intended to prevent TB. Boosting: Vaccine candidates that would serve as the “boost” in a prime-boost regimen and intended to prevent TB. Immunotherapy: Vaccines candidates that could be administered after a person has been exposed to M.tb to prevent reactivation or progression to TB disease and/or to shorten or improve the response to chemotherapy. Vaccine candidates are further divided into those that were, are, or will be in Phase I clinical development by the end of 2009, and those that are still in preclinical development with an anticipated entry into clinical development in 2010 or after. Vaccines intended for veterinary use are not included in this document. The information contained here was provided by the vaccine developers, unless otherwise indicated and includes updates for 2008. The asterisk (*) indicates that the information is the same as that presented in the previous Pipeline Report and no update was provided for this report. This TB Vaccines Pipeline document presents those products in development that have been brought to the attention of the working groups. The timelines given are those provided by the sponsor and are dependent upon progress in preclinical and clinical studies. Please note that no standard evaluation criteria have been applied for inclusion in this TB Vaccines Pipeline document. The list will be revised periodically and updated versions will be published annually through the Retooling and working groups’ websites.

2

TABLE OF CONTENTS A. PRIMING..................................................................................................................................... 4

1. Phase I: By end of 2009.......................................................................................................... 4 a. rBCG30 ............................................................................................................................... 4 b. rBCG∆ureC:Hly (VPM1002) ............................................................................................... 4 c. AERAS-407......................................................................................................................... 5 d. rBCG30ARMF..................................................................................................................... 5 e. rBCG(mbtB)30 .................................................................................................................... 6 f. Nas L3/Htk BCG .................................................................................................................. 6 g. mc26220, mc26221, mc26222, mc26231 ............................................................................. 7 *h. HBHA (heparin-binding haemagglutinin)........................................................................... 7 i. mc25059 ............................................................................................................................... 8 j. Attenuated Live Vaccine based on PhoP............................................................................. 8

2. Phase I: 2010 or Later............................................................................................................. 9

a. paBCG (pro-apoptotic BCG)............................................................................................... 9 b. rBCG T+B ........................................................................................................................... 9 c. rM. smegmatis T+B........................................................................................................... 10 d. Streptomyces live vector................................................................................................... 10 e. rBCG TB-Malaria .............................................................................................................. 11

B. BOOSTING............................................................................................................................... 12

1. Phase I: By end of 2009........................................................................................................ 12 a. Mycobacterium vaccae (inactivated) ................................................................................ 12 b. MVA85A............................................................................................................................ 12 c. M72 ................................................................................................................................... 13 d. AERAS-402....................................................................................................................... 13 e. SSI Hybrid-1...................................................................................................................... 14 f. SSI HyVac 4/AERAS-404 .................................................................................................. 14 g. AERAS-405....................................................................................................................... 15 h. r30..................................................................................................................................... 15 i. Nas L3/Htk BCG................................................................................................................. 16 *j. HspC™ TB Vaccine.......................................................................................................... 16 *k. HBHA (heparin-binding haemagglutinin) ......................................................................... 17 l. NasL3/AM85B conjugate ................................................................................................... 17

2. Phase I: 2010 or Later........................................................................................................... 18

a. TBVax ............................................................................................................................... 18 b. PP1, PP2, PP3.................................................................................................................. 18 c. F36, F727.......................................................................................................................... 19 *d. Ac2SGL Diacylated Sulfoglycolipids ............................................................................... 19 e. HVJ-Envelope (liposome)/HSP65 DNA+IL-12 DNA......................................................... 20 *f. R32Kda-BCG.................................................................................................................... 20 g. ID83................................................................................................................................... 21 h. rBCG T+B ......................................................................................................................... 21 i. rM. smegmatis T+B............................................................................................................ 22 j. Streptomyces live vector .................................................................................................... 22 k. rBCG TB-Malaria............................................................................................................... 23

C. IMMUNOTHERAPY.................................................................................................................. 24

1. Phase I: By end of 2009........................................................................................................ 24 a. MVA85A............................................................................................................................ 24 b. RUTI.................................................................................................................................. 24 c. Nas L3/Htk BCG................................................................................................................ 25 d. NasL3/AM85B conjugate .................................................................................................. 25 *e. hspDNA vaccine .............................................................................................................. 26

3

f. HG856A ............................................................................................................................. 26 *g. HBHA (heparin-binding haemagglutinin)......................................................................... 27 h. HG85A/B........................................................................................................................... 27

2. Phase I: 2010 or Later........................................................................................................... 28

a. HG856-BCG...................................................................................................................... 28 b. HG856-SeV....................................................................................................................... 28 c. F36, F727.......................................................................................................................... 29 d. Mycobacterium vaccae Heat-Killed .................................................................................. 29 *e. Ac2SGL Diacylated Sulfoglycolipids ................................................................................ 30

4

A. PRIMING

1. Phase I: By end of 2009

a. rBCG30 Type of product Recombinant BCG expressing high amounts of the 30 kDa Mycobacterium tuberculosis Antigen 85B. Sponsors rBCG30 was developed in Marcus Horwitz’s laboratory at UCLA with funding from the NIAID, NIH. The Phase I study was sponsored by Aeras Global TB Vaccine Foundation. Product description rBCG30 is a recombinant BCG Tice overexpressing the 30 kDa M. tuberculosis Antigen 85B. The vaccine is one order of magnitude more potent than BCG in the guinea pig model of pulmonary tuberculosis. The vaccine is intended primarily for newborns. Stage of development A Phase I trial of rBCG30 has been completed in the USA demonstrating that it is safe and significantly more immunogenic than BCG. A Phase III trial is in planning. Date of entry or expected date of entry into Phase I trials Phase I trial completed. Expected date for completion of Phase III trials 2015

b. rBCG∆ureC:Hly (VPM1002) Type of product Recombinant BCG expressing listeriolysin as well as carrying a urease deletion mutation. Sponsors rBCG∆ureC:Hly (VPM1002) originates from the group of Professor S.H.E Kaufmann from the Max Planck Institute for Infection Biology (Berlin, Germany). rBCG∆ureC:Hly (VPM1002) is being developed in cooperation with Vakzine Projekt Management GmbH (VPM). VPM holds the exclusive worldwide license for VPM1002 (rBCG∆ureC:Hly). Product description rBCG∆ureC:Hly (VPM1002) is a recombinant BCG expressing listeriolysin as a mechanism to induce antigen-specific CD4+ and CD8+ T cells via escape of mycobacterial antigens from the phagosome and/or crosspriming. Urease has been deleted as a means of providing the optimal pH for listeriolysin function. Stage of development A GMP manufacturing process is in place and production has been completed. The effectiveness of the vaccine candidate VPM1002 has already been demonstrated in pre-clinical models at the Berlin-based Max-Planck Institute for Infection Biology. A clinical Phase I trial was approved by the regulatory agency, PEI, in August 2008. First volunteer was vaccinated in September 2008. Date of entry or expected date of entry into Phase I trials Phase I trial started in September 2008. Expected date for completion of Phase III trials 2015

5

A. PRIMING 1. Phase I: By end of 2009

c. AERAS-407 Type of product Recombinant BCG expressing a mutated perfringiolysin in ∆ureC background to allow access of BCG to the eukaryotic cytosol for improved class I presentation. High valency classical, dormancy, and resuscitation/reactivation antigens are overexpressed. Sponsors Aeras Global TB Vaccine Foundation with funding from the Bill & Melinda Gates Foundation and the government of the Netherlands Product description AERAS-407 is a recombinant BCG vaccine derived from Danish 1331 expressing a G137Q pfoA allele which allows approximately 30% of organisms to escape the phago-lysosome 48 hours post infection. Safer than BCG in SCID mouse study. AERAS-407 over-expresses common antigens such as 85A and 85B and antigens involved in latency and reactivation/resuscitation including the DosR regulon and reactivation and resuscitation factors. Stage of development Manufacture complete, product vialed for Phase I trial Date of entry or expected date of entry into Phase I trials 2009 Expected date for completion of Phase III trials 2017

d. rBCG30ARMF Type of product Recombinant BCG expressing very high amounts of the 30 kDa M. tuberculosis Antigen 85B and lacking an antibiotic resistance marker. Sponsors Developed in Marcus Horwitz’s laboratory at UCLA with funding from the NIAID, NIH. Product description Recombinant BCG Tice overexpressing the 30 kDa M. tuberculosis Antigen 85B in amounts even greater than rBCG30 and lacking an antibiotic resistance marker. The vaccine is intended primarily for newborns. Stage of development A Phase I trial is in planning. Date of entry or expected date of entry into Phase I trials 2009 Expected date for completion of Phase III trials 2017

6

A. PRIMING 1. Phase I: By end of 2009

e. rBCG(mbtB)30 Type of product Recombinant BCG engineered for limited replication in the host and expressing high amounts of the 30 kDa Mycobacterium tuberculosis Antigen 85B Sponsors Developed in Marcus Horwitz’s laboratory at UCLA with funding from the NIAID, NIH. Product description Recombinant BCG Tice engineered for limited replication in the host and that overexpresses the 30 kDa M. tuberculosis Antigen 85B. The vaccine is significantly more potent than BCG in the guinea pig model of pulmonary tuberculosis and well-tolerated in SCID mice. The vaccine is intended for HIV-positive infants and adults. Stage of development A Phase I trial is in planning. Date of entry or expected date of entry into Phase I trials 2009 Expected date for completion of Phase III trials 2017

f. Nas L3/Htk BCG Type of product Nasal vaccine/Heat killed whole BCG strain Copenhagen in Eurocine L3™ adjuvant Sponsors The NasL3/Htk BCG vaccine was developed at the Swedish Institute for Infectious Disease Control/Karolinska Institute, Stockholm, Sweden; supported by the Swedish Heart & Lung Foundation, the Swedish Research Council and the European Commission. Product description The NasL3/Htk BCG is a vaccine for intra-nasal immunization and hence avoids possible dangerous handling of needles. It gives excellent local as well as systemic immune responses and is intended both as a boost and a pre-exposure vaccine for all groups, including children and HIV infected patients. Stage of development The Eurocine L3™ adjuvant has been approved by the Swedish FDA for Phase I/II studies and was found safe and well tolerated in an earlier Diphtheria toxoid Phase I/II vaccine trial. The NasL3/Htk BCG vaccine is well tolerated and gives excellent protection (in means of long time survival) in preclinical animal experiments. Date of entry or expected date of entry into Phase I trials 2009-2010 Expected date for completion of Phase III trials TBD

7

A. PRIMING 1. Phase I: By end of 2009

g. mc26220, mc26221, mc26222, mc26231 Type of product Live attenuated M. tuberculosis strain Sponsors Jacobs Laboratory/Albert Einstein College of Medicine Product description Non-replicating, M. tuberculosis strain (∆lysA ∆panCD) auxotrophic for lysine and pantothenate

Stage of development Pre-clinical Date of entry or expected date of entry into Phase I trials Late 2009 Expected date for completion of Phase III trials TBD

*h. HBHA (heparin-binding haemagglutinin) Type of product Purified protein from Mycobacterium bovis BCG. Sponsors HBHA was discovered in Camille Locht’s laboratory, sponsored by the Institut Pasteur de Lille and Inserm (Institut National de la Santé et de la Recherche Médicale) in Lille, France. The work was partially supported by the European Community grant under FP6: TB-VAC consortium. Product description HBHA is a naturally methylated 21-kDa protein and functions as an adhesin for binding of M. tuberculosis to non-phagocytic cells. As a single antigen it provides protection similar to that of BCG in mouse models. Methylation is essential for protection. Given as a booster after BCG vaccination it significantly enhances protection over BCG alone. Healthy M. tuberculosis-infected human individuals (latent infection) respond to HBHA with a strong IFN-g response as well as with strong CD8+ T cell responses (IFN-g production, perforin production, bactericidal activity and cytotoxicity). Stage of development Preclinical development stage, planning of Phase I trials Date of entry or expected date of entry into Phase I trials 2009 Expected date for completion of Phase III trials 2017

8

A. PRIMING 1. Phase I: By end of 2009

i. mc25059 Type of product Live attenuated M. bovis BCG Danish strain Sponsors Jacobs Laboratory/Albert Einstein College of Medicine Product description Replicating pro-apoptotic M. bovis BCG strain (∆nuoG)

Stage of development Pre-clinical Date of entry or expected date of entry into Phase I trials Late 2009 Expected date for completion of Phase III trials TBD

j. Attenuated Live Vaccine based on PhoP Type of product: Live Vaccine based on rational attenuation of M. tuberculosis with the goal to replace BCG. A new generation vaccine has been constructed based on two independent genetic deletions without antibiotic markers. Sponsors: Candidate vaccines based on M. tuberculosis phoP mutants were developed in Carlos Martin’s laboratory at the University of Zaragoza in collaboration with Brigitte Gicquel’s laboratory at the Pasteur Institute in Paris, with national funds from Spain and France and with funds from the European Commission. Vaccine GMP production is sponsored by Genoma España. Product description: Live vaccine based on rational attenuation of M. tuberculosis by inactivation of phoP, a positive regulator of virulence genes. The vaccine candidate was tested for protection and safety in different animal models. Recently, following the Geneva Consensus for new live vaccines, two non-reverting genetic deletions, without presence of antibiotic markers, were genetically engineered for the final construct of MTBVAC. The deleted genes are involved in biosynthesis regulation of complex lipids implicated in M. tuberculosis virulence. Stage of development: Late pre-clinical testing and GMP production. Date of entry or expected date of entry into Phase I trials Late 2009-2010 Expected date for completion of Phase III trials: TBD

9

A. PRIMING

2. Phase I: 2010 or Later

a. paBCG (pro-apoptotic BCG) Type of product Modified BCG with reduced activity of one or more anti-apoptotic microbial enzymes including iron co-factored superoxide dismutase (SodA), glutamine synthetase (GlnA1), thioredoxin, and thioredoxin reductase Sponsors The paBCG technology was developed in Doug Kernodle’s laboratory at Vanderbilt University Medical Center and the Nashville Veterans Affairs Medical Center with funding from the NIAID, NHLBI, and a 2002 VIP award from Sequella Global TB Foundation (now Aeras). The technology has been licensed by Aeras for further development. Product description Four immune-enhancing modifications have been introduced into BCG, alone and in combination. The modifications include: expression of dominant-negative SodA mutant; allelic inactivation of secA2 (by Miriam Braunstein at the University of North Carolina at Chapel Hill), elimination of diploid sigH, and expression of dominant-negative GlnA1 mutant. We constructed four 1st-generation vaccines with a single modification, six 2nd-generation vaccines with two modifications, four 3rd-generation vaccines with three modifications, and a single 4th-generation paBCG vaccine with all four modifications. Although intended primarily as priming, pre-exposure vaccines, the 3rd- and 4th-generation paBCG vaccines are cleared by the host after adaptive immunity develops and this enables boosting either with paBCG or the parent BCG vaccine to induce secondary responses. Stage of development Pre-clinical Date of entry or expected date of entry into Phase I trials Per Aeras, most likely in combination with other modifications to BCG. Expected date for completion of Phase III trials Per Aeras, most likely in combination with other modifications to BCG.

b. rBCG T+B Type of product Recombinant BCG expressing multiple T and B epitopes of M. tuberculosis Sponsors Universiti Sains Malaysia, Malaysia-Finlay Institute, Cuba Product description rBCG T+B are BCG strains expressing different combinations of T and B epitopes of M. tuberculosis which elicit T cell and antibody responses against the selected epitopes. Stage of development Pre-clinical Date of entry or expected date of entry into Phase I trials TBD Expected date for completion of Phase III trials TBD

10

A. PRIMING 2. Phase I: 2010 or Later

c. rM. smegmatis T+B Type of product Recombinant M. smegmatis expressing multiple T and B epitopes of M. tuberculosis Sponsors Universiti Sains Malaysia, Malaysia-Finlay Institute, Cuba Product description rM. smegmatis T+B are M. smegmatis strains expressing different combinations of T and B epitopes of M. tuberculosis. Stage of development Pre-clinical Date of entry or expected date of entry into Phase I trials TBD Expected date for completion of Phase III trials TBD

d. Streptomyces live vector Type of product Recombinant Streptomyces expressing multiple T and B epitopes of M. tuberculosis Sponsors Finlay Institute, Cuba-Center of Pharmaceutical Chemistry, Cuba Product description Non recombinant and recombinant Streptomyces expressing T and B epitopes of M. tuberculosis. Immunization with Streptomyces strains elicits recognition of proteins of mycobacteria. Stage of development Pre-clinical Date of entry or expected date of entry into Phase I trials TBD Expected date for completion of Phase III trials TBD

11

A. PRIMING 2. Phase I: 2010 or Later

e. rBCG TB-Malaria Type of product Recombinant BCG expressing multiple epitopes of M. tuberculosis fused to Malarial epitopes and antigens Sponsors Universiti Sains Malaysia, Malaysia Product description rBCG TB-Malaria are BCG strains expressing different combinations of T epitopes of M. tuberculosis and Malarial antigens and epitopes which elicit T cell responses against the M. tuberculosis epitopes and T and B responses against the Malarial antigens and epitopes. Stage of development Pre-clinical Date of entry or expected date of entry into Phase I trials TBD Expected date for completion of Phase III trials TBD

12

B. BOOSTING

1. Phase I: By end of 2009

a. Mycobacterium vaccae (inactivated) Type of product Inactivated whole cell bacterial vaccine derived from a non-tuberculous mycobacterium. Sponsors Developed by SR Pharma (SRP), London. Phase I and II trials sponsored by the Elizabeth Glaser Pediatric AIDS Foundation, Sigrid Juselius Foundation, Hitchcock Foundation, SRP, and Dartmouth Medical School. Current Phase III trial in Tanzania, the DARDAR Trial, sponsored by the Division of AIDS, National Institutes of Health (USA). Product description Heat-inactivated bacterial suspension of M. vaccae (MV) given via the intradermal route in a 3 or 5 dose schedule (BCG prime-MV boost). Objective is expeditious development of a safe and immunogenic new TB vaccine for HIV-positives. Stage of development Phase I trials initiated 1994 (US), Phase II trials demonstrated boosting in BCG-primed, HIV-positives (Zambia, Finland). Phase III RCT initiated in BCG-primed, HIV-positives in 2001 (DarDar trial, Tanzania). Date of entry or expected date of entry into Phase I trials 1994 Expected date for completion of Phase III trials DarDar Trial completed in 2008

b. MVA85A Type of product BCG boosting vaccine Sponsors Oxford University Product description MVA85A – recombinant MVA expressing antigen 85A

Stage of development Phase IIa ongoing in Cape Town and The Gambia Date of entry or expected date of entry into Phase I trials 2002 Expected date for completion of Phase III trials Phase IIb scheduled to start in Q1 2009, expected date of completion of Phase III is 2014.

13

B. BOOSTING 1. Phase I: By end of 2009

c. M72 Type of product Recombinant protein composed of a fusion of M. tuberculosis antigens Rv1196 and Rv0125 Sponsors M72-based vaccine is developed by GlaxoSmithKline Biologicals. Clinical Development to date has been carried out in partnership with TB-VAC consortium funded by the European Commission (contract No LSHP-CT-2003-503367) and Aeras Global TB Vaccine Foundation, with funding from the Bill & Melinda Gates Foundation. Product description M72 is a purified recombinant protein formulated with GSK proprietary Adjuvant Systems

Stage of development M72 has been evaluated in multiple Phase I/II trials in the United States, Belgium and Switzerland, in BCG naïve and BCG-vaccinated healthy adults as well as in previously TB-infected adults. M72 is currently in Phase II in TB endemic countries. Date of entry or expected date of entry into Phase I trials 2004 Expected date for completion of Phase III trials 2014

d. AERAS-402 Type of product Replication-deficient adenovirus 35 vector expressing M. tuberculosis antigens Ag85A, Ag85B, and TB10.4. Sponsors AERAS-402 is being developed by Crucell Holland B.V. and the Aeras Global TB Vaccine Foundation, with funding from the Bill & Melinda Gates Foundation and the government of the Netherlands. Product description Adenovirus 35 is an advanced adenoviral vector system for the induction of antigen-specific CD4+ and CD8+ T-cell responses Stage of development AERAS-402 has successfully completed Phase I trials in the United States and is now in Phase I trials in South Africa Date of entry or expected date of entry into Phase I trials 2006 Expected date for completion of Phase III trials 2015

14

B. BOOSTING 1. Phase I: By end of 2009

e. SSI Hybrid-1 Type of product Adjuvanted recombinant protein composed of M. tuberculosis antigens Ag85B and ESAT-6. Sponsors Hybrid-1 is being developed by the Statens Serum Institute and the European TB vaccine project (TBVAC), with funding from the European Commission. Product description Hybrid-1 is a fusion of separate M. tuberculosis protein antigens delivered in Intercell’s proprietary adjuvant IC31. Both the protein and adjuvant components have been optimized for large-scale, low-cost production and the complete vaccine has been tested in both liquid and freeze-dried formulations with long shelf lives, making it the vaccine currently most advanced towards an actual product. Stage of development Hybrid-1 has successfully completed Phase I clinical trials in Europe and is in Phase I trials in Ethiopia, with Phase II trials following in 2009. Date of entry or expected date of entry into Phase I trials 2006 Expected date for completion of Phase III trials 2015

f. SSI HyVac 4/AERAS-404 Type of product Adjuvanted recombinant protein composed of a fusion of M. tuberculosis antigens Ag85B and TB10.4. Sponsors HyVac 4 is being developed by the Statens Serum Institute, Intercell, Sanofi Pasteur, and Aeras, with funding from the Bill & Melinda Gates Foundation and the European Commission. Product description HyVac 4 is a fusion of separate M. tuberculosis protein antigens delivered in Intercell’s proprietary adjuvant IC31. Both the protein and adjuvant components are GMP products capable of large-scale, low-cost production. Stage of development A Phase I trial of HyVac 4/AERAS-404 was initiated in Sweden and Finland in 2007 and 2008. Date of entry or expected date of entry into Phase I trials 2007 Expected date for completion of Phase III trials 2017

15

B. BOOSTING 1. Phase I: By end of 2009

g. AERAS-405 Type of product AERAS-405 is a Shigella-delivered recombinant double-stranded RNA nucleocapsid encoding M. tuberculosis antigens covering all stages of disease, including Ag85A, Ag85B, Rv3407, latency antigens and resuscitation promoting factors. Sponsors Developed by Aeras Global TB Vaccine Foundation with funding from the Bill & Melinda Gates Foundation Product description Shigella-delivered nucleocapsids represent an inexpensive means of manufacturing oral delivery vaccines capable of expressing multiple TB antigens and inducing high levels of CD8+ T-cell responses to antigens from all stages of infection and disease.

Stage of development Late preclinical development. Date of entry or expected date of entry into Phase I trials 2009 Expected date for completion of Phase III trials 2018

h. r30 Type of product Purified recombinant 30 kDa Mycobacterium tuberculosis Antigen 85B. Sponsors r30 was developed in Marcus Horwitz’s laboratory at UCLA with funding from the NIAID, NIH. Product description r30 is recombinant 30 kDa Mycobacterium tuberculosis Antigen 85B in native conformation purified from recombinant Mycobacterium smegmatis expressing high amounts of the protein. The vaccine significantly enhances the level of protective immunity conferred by BCG in the guinea pig model of pulmonary tuberculosis. The vaccine is intended as a booster vaccine for persons previously vaccinated with BCG or recombinant BCG. Stage of development A Phase I trial is in planning. Date of entry or expected date of entry into Phase I trials 2009 Expected date for completion of Phase III trials 2017

16

B. BOOSTING 1. Phase I: By end of 2009

i. Nas L3/Htk BCG Type of product Nasal vaccine/Heat killed whole BCG strain Copenhagen in Eurocine L3™ adjuvant Sponsors The NasL3/Htk BCG vaccine was developed at the Swedish Institute for Infectious Disease Control/Karolinska Institute, Stockholm, Sweden supported by the Swedish Heart & Lung Foundation, the Swedish Research Council and the European Commission. Product description The NasL3/Htk BCG is a vaccine for intra-nasal immunisation and hence avoids possible dangerous handling of needles. It gives excellent local as well as systemic immune responses and is intended both as a boost and a pre-exposure vaccine for all groups, including children and HIV infected patients. Stage of development The Eurocine L3™ adjuvant has been approved by the Swedish FDA for Phase I/II studies and was found safe and well tolerated in an earlier Diphtheria toxoid Phase I/II vaccine trial. The NasL3/Htk BCG vaccine is well tolerated and gives excellent protection (in means of long time survival) in preclinical animal experiments. Date of entry or expected date of entry into Phase I trials 2009-2010 Expected date for completion of Phase III trials TBD

*j. HspC™ TB Vaccine Type of product Heat shock protein antigen complexes (HspCs) Sponsors ImmunoBiology Ltd and Aeras Global TB Vaccine Foundation, with funding from the Bill & Melinda Gates Foundation Product description HspC vaccines contain a broad array of TB antigens complexed to endogenous heat shock proteins that ensures efficient antigen presentation. Process for the preparation of HspC vaccines containing the major heat shock proteins from BCG has been developed. These HspC vaccines induce strong protective immunity in animal TB challenge models, including as booster vaccine to BCG. Stage of development Pre-clinical: further process development prior to GMP manufacture Date of entry or expected date of entry into Phase I trials 2009 Expected date for completion of Phase III trials Estimated at 2016

17

B. BOOSTING 1. Phase I: By end of 2009

*k. HBHA (heparin-binding haemagglutinin) Type of product Purified protein from Mycobacterium bovis BCG. Sponsors HBHA was discovered in Camille Locht’s laboratory, sponsored by the Institut Pasteur de Lille and Inserm (Institut National de la Santé et de la Recherche Médicale) in Lille, France. The work was partially supported by the European Community grant under FP6: TB-VAC consortium. Product description HBHA is a naturally methylated 21-kDa protein and functions as an adhesin for binding of M. tuberculosis to non-phagocytic cells. As a single antigen it provides protection similar to that of BCG in mouse models. Methylation is essential for protection. Given as a booster after BCG vaccination it significantly enhances protection over BCG alone. Healthy M. tuberculosis-infected human individuals (latent infection) respond to HBHA with a strong IFN-g response as well as with strong CD8+ T cell responses (IFN-g production, perforin production, bactericidal activity and cytotoxicity). Stage of development Preclinical development stage, planning of Phase I trials Date of entry or expected date of entry into Phase I trials 2009 Expected date for completion of Phase III trials 2017

l. NasL3/AM85B conjugate Type of product Nasal vaccine/Man capped Arabinomannan oligosaccharide (derived from H37Rv) conjugated to Ag 85B in Eurocine L3™ adjuvant Sponsors The NasL3/AM85B conjugate vaccine was developed at the Swedish Institute for Infectious Disease Control/Karolinska Institute, Stockholm, Sweden supported by the Swedish Heart & Lung Foundation, the Swedish Research Council and the European Commission. Product description The NasL3/AM85B is a vaccine for intra-nasal immunisation and hence avoids possible dangerous handling of needles. It gives excellent local as well as systemic immune responses and is intended as a boost vaccine in the young teenager including HIV infected patients. Stage of development The Eurocine L3™ adjuvant has been approved by the Swedish FDA for Phase I/II studies and was found safe and well tolerated in an earlier Diphtheria toxoid Phase I/II vaccine trial. The NasL3/AM85B vaccine is well tolerated and gives excellent protection (in means of long time survival) in preclinical animal experiments. A GMP manufacturing process is in place. Date of entry or expected date of entry into Phase I trials 2008/2009 Expected date for completion of Phase III trials 2017

18

B. BOOSTING

2. Phase I: 2010 or Later

a. TBVax Type of product Epitope-based DNA-prime/peptide-boost vaccine Sponsors TBVax is being developed by EpiVax, Inc. with funding from NIH/NIAID. Product description TBVax is composed of T-cell epitopes for induction of CD4+ and CD8+ T cell responses. It is formulated as a multi-epitope gene delivered in a plasmid vector to prime immune responses and as a pool of peptides delivered in liposomes together with CpG oligodeoxynucleotide adjuvant to boost immune responses. Stage of development TBVax is in early stage pre-clinical development. Date of entry or expected date of entry into Phase I trials 2014 Expected date for completion of Phase III trials 2021

b. PP1, PP2, PP3 Type of product BCG boosting Sponsors Colorado State University/ Mycos Research/CSU Infectious Disease Supercluster Product description A pool of proteins specifically selected for their ability to boost immunity to tuberculosis in BCG-boosted guinea pigs, resulting in doubling of survival. Stage of development Preclinical stage Date of entry or expected date of entry into Phase I trials TBD Expected date for completion of Phase III trials TBD

19

B. BOOSTING 2. Phase I: 2010 or Later

c. F36, F727 Type of product Pre and Post Exposure Sponsors Colorado State University/ Mycos Research/CSU Infectious Disease Supercluster Product description A vaccine consisting of a fusion of correctly acylated Rv1411 and [as an example of an immunogenic protein] ESAT-6. This fusion protects in a mouse model of tuberculosis as a pre-exposure vaccine, and has post-exposure activity in a guinea pig model. Stage of development Preclinical Date of entry or expected date of entry into Phase I trials TBD Expected date for completion of Phase III trials TBD

*d. Ac2SGL Diacylated Sulfoglycolipids** Type of product Subunit Sponsors Invented by Puzo, Gilleron, Stenger and De Libero, Institut de Pharmacologie et de Biologie Structurale, Toulouse, CNRS Product description Ac2SGL Mycobacterial lipids capable of inducing human T cell responses - Ac2SGL is a novel glycolipid antigen with strong immunogenicity during infection with M.tb and with the capacity to prime protective T cells. Stage of development Preclinical Date of entry or expected date of entry into Phase I trials TBD Expected date for completion of Phase III trials TBD **Source: PH Lambert, TB-VAC

20

B. BOOSTING

2. Phase I: 2010 or Later

e. HVJ-Envelope (liposome)/HSP65 DNA+IL-12 DNA Type of product Subunit, viral vectored Sponsors M. Okada et al, Osaka University Product description Combination of DNA vaccines expressing mycobacterial heat shock protein 65 and interleukin 12 delivered by hemagglutinating virus of Japan-liposome. This vaccine gives excellent protection (survival time) of a monkey model of tuberculosis as well as murine TB model. This vaccine also has post-exposure activity in a murine model and monkey model. Stage of development Preclinical Date of entry or expected date of entry into Phase I trials TBD Expected date for completion of Phase III trials TBD

*f. R32Kda-BCG Type of product BCG boosting vaccine Sponsors Bhagawan Mahavir Medical Research Center; LEPRA Society – Blue Peter Research Center, Hyderabad, India Product description r32Kda-BCG – recombinant 85A of M. bovis BCG capable of inducing T cell responses, in vitro and release of significantly high levels of IFN-g in healthy BCG-vaccinated children. Stage of development Preclinical Date of entry or expected date of entry into Phase I trials TBD Expected date for completion of Phase III trials TBD

21

B. BOOSTING 2. Phase I: 2010 or Later

g. ID83 Type of product Adjuvanted subunit, fusion protein Sponsors Infectious Disease Research Institute, Seattle, WA Product description Subunit protein vaccine composed of three different M. tuberculosis antigens. This vaccine induced protection in murine (decreased CFU), guinea pig and non-human primate (survival) models of tuberculosis (TB). This vaccine has also demonstrated post-exposure activity in a murine model of TB. Stage of development Preclinical Date of entry or expected date of entry into Phase I trials TBD Expected date for completion of Phase III trials TBD

h. rBCG T+B Type of product Recombinant BCG expressing multiple T and B epitopes of M. tuberculosis Sponsors Universiti Sains Malaysia, Malaysa-Finlay Institute, Cuba Product description rBCG T+B are BCG strains expressing different combinations of T and B epitopes of M. tuberculosis which elicit T cell and antibody responses against the selected epitopes. Stage of development Pre-clinical Date of entry or expected date of entry into Phase I trials TBD Expected date for completion of Phase III trials TBD

22

B. BOOSTING 2. Phase I: 2010 or Later

i. rM. smegmatis T+B Type of product Recombinant M. smegmatis expressing multiple T and B epitopes of M. tuberculosis Sponsors Universiti Sains Malaysia, Malaysia-Finlay Institute, Cuba Product description r M. smegmatis T+B are M. smegmatis strains expressing different combinations of T and B epitopes of M. tuberculosis. Stage of development Pre-clinical Date of entry or expected date of entry into Phase I trials TBD Expected date for completion of Phase III trials TBD

j. Streptomyces live vector Type of product Recombinant Streptomyces expressing multiple T and B epitopes of M. tuberculosis Sponsors Finlay Institute, Cuba-Center of Pharmaceutical Chemistry, Cuba Product description Non recombinant and recombinant Streptomyces expressing T and B epitopes of M. tuberculosis. Immunization with Streptomyces strains elicits recognition of proteins of mycobacteria. Stage of development Pre-clinical Date of entry or expected date of entry into Phase I trials TBD Expected date for completion of Phase III trials TBD

23

B. BOOSTING 2. Phase I: 2010 or Later

k. rBCG TB-Malaria Type of product Recombinant BCG expressing multiple epitopes of M. tuberculosis fused to Malarial epitopes and antigens Sponsors Universiti Sains Malaysia, Malaysia Product description rBCG TB-Malaria are BCG strains expressing different combinations of T epitopes of M. tuberculosis and Malarial antigens and epitopes which elicit T cell responses against the M. tuberculosis epitopes and T and B responses against the Malarial antigens and epitopes. Stage of development Pre-clinical Date of entry or expected date of entry into Phase I trials TBD Expected date for completion of Phase III trials TBD

24

C. IMMUNOTHERAPY

1. Phase I: By end of 2009

a. MVA85A Type of product BCG boosting vaccine Sponsors Oxford University Product description MVA85A – recombinant MVA expressing antigen 85A

Stage of development Phase IIa ongoing in Cape Town and The Gambia Date of entry or expected date of entry into Phase I trials 2002 Expected date for completion of Phase III trials Phase IIb scheduled to start in Q1 2009, expected date of completion of Phase III is 2014.

b. RUTI Type of product Fragmented Mycobacterium tuberculosis cells Sponsors RUTI was designed by the Unitat de Tuberculosi Experimental from the Biomedical Research Institute “Germans Trias i Pujol” in Badalona. Catalonia. Spain. RUTI is made under GMP by Archivel Farma,s.l. a spin off Pharmaceutical devoted to the development of RUTI. Product description Mycobacterium tuberculosis cells cultured under stressed conditions, fragmented, detoxified with Triton and liposomed. It generates a strong cellular and humoral polyantigenic response against growing and latent bacilli. It has been designed to shorten the treatment of latent tuberculosis infection to 1 month of chemotherapy. Two inoculations of RUTI are then administered. Stage of development A Phase I trial started on April 2007 in Badalona, Catalonia, Spain. Date of entry or expected date of entry into Phase I trials The Phase I trial has effectively finished in May 2008 giving a good safety and immunogenicity profile. Expected date for completion of Phase III trials A Phase II trial in PPD+ HIV+ and PPD+ HIV- persons is planned to start in May 2009 to search for safety and immunogenicity as well and to determine the better dose. The pivotal study Phase III is planned to start in 2010 and to finish in 2013.

25

C. IMMUNOTHERAPY 1. Phase I: By end of 2009

c. Nas L3/Htk BCG Type of product Nasal vaccine/Heat killed whole BCG strain Copenhagen in Eurocine L3™ adjuvant Sponsors The NasL3/Htk BCG vaccine was developed at the Swedish Institute for Infectious Disease Control/Karolinska Institute, Stockholm, Sweden supported by the Swedish Heart-Lung Foundation, the Swedish Research Council and the European Commission. Product description The NasL3/Htk BCG is a vaccine for intra-nasal immunisation and hence avoids possible dangerous handling of needles. It gives excellent local as well as systemic immune responses and is intended both as a boost and a pre-exposure vaccine for all groups, including children and HIV infected patients. Stage of development The Eurocine L3™ adjuvant has been approved by the Swedish FDA for Phase I/II studies and was found safe and well tolerated in an earlier Diphtheria toxoid Phase I/II vaccine trial. The NasL3/Htk BCG vaccine is well tolerated and gives excellent protection (in means of long time survival) in preclinical animal experiments. Date of entry or expected date of entry into Phase I trials 2009-2010 Expected date for completion of Phase III trials TBD

d. NasL3/AM85B conjugate Type of product Nasal vaccine/Man capped Arabinomannan oligosaccharide (derived from H37Rv) conjugated to Ag 85B in Eurocine L3™ adjuvant Sponsors The NasL3/AM85B conjugate vaccine was developed at the Swedish Institute for Infectious Disease Control/Karolinska Institute, Stockholm, Sweden supported by the Swedish Heart & Lung Foundation, the Swedish Research Council and the European Commission. Product description The NasL3/AM85B is a vaccine for intra-nasal immunisation and hence avoids possible dangerous handling of needles. It gives excellent local as well as systemic immune responses and is intended as a boost vaccine in the young teenager including HIV infected patients. Stage of development The Eurocine L3™ adjuvant has been approved by the Swedish FDA for Phase I/II studies and was found safe and well tolerated in an earlier Diphtheria toxoid Phase I/II vaccine trial. The NasL3/AM85B vaccine is well tolerated and gives excellent protection (in means of long time survival) in preclinical animal experiments. A GMP manufacturing process is in place. Date of entry or expected date of entry into Phase I trials 2008/2009 Expected date for completion of Phase III trials 2017

26

C. IMMUNOTHERAPY 1. Phase I: By end of 2009

*e. hspDNA vaccine Type of product Naked DNA vaccine. Therapeutic vaccine used to augment drug therapy to reduce relapse and prevent drug resistance. Sponsors The hsp65DNA vaccine was discovered by Dr. Doug Lowrie, currently at Cardiff University, Wales, UK, and licensed by Sequella, Inc. Product description The hsp65DNA vaccine consists of a codon-optimized heat shock protein from M. leprae, a CpG island, a promotor to drive expression in mammalian hosts, and multiple lac operon repressor binding sites (proprietary pORT system in lieu of antibiotic resistance gene). Intramuscular injection of vaccine into drug-treated mice increased T-cell immune function and reduced bacterial load. Stage of development An efficient GMP manufacturing method is established. Pre-clinical toxicity studies are being planned. Date of entry or expected date of entry into Phase I trials 2009 Expected date for completion of Phase III trials

f. HG856A Type of product Chimeric ESAT6/Ag85a DNA vaccine Sponsors Shanghai H&G Biotechnology Co., LTD Product description Two copies of esat6 genes were inserted into the Acc I site of ag85a gene and then this chimeric gene was linked with pVAX1 vector Stage of development This DNA vaccine has been evaluated for the protection against TB on monkey model and for the immunotherapy of MDR TB on mouse model. The preclinical experiment using plasmid DNA associated with conventional chemotherapy for the treatment of MDR-TB infected monkeys will be finished by the end of 2008. Date of entry or expected date of entry into Phase I trials DNA vaccine immunotherapy of MDR in 2009 Expected date for completion of Phase III trials 2011

27

C. IMMUNOTHERAPY 1. Phase I: By end of 2009

*g. HBHA (heparin-binding haemagglutinin) Type of product Purified protein from Mycobacterium bovis BCG. Sponsors HBHA was discovered in Camille Locht’s laboratory, sponsored by the Institut Pasteur de Lille and Inserm (Institut National de la Santé et de la Recherche Médicale) in Lille, France. The work was partially supported by the European Community grant under FP6: TB-VAC consortium. Product description HBHA is a naturally methylated 21-kDa protein and functions as an adhesin for binding of M. tuberculosis to non-phagocytic cells. As a single antigen it provides protection similar to that of BCG in mouse models. Methylation is essential for protection. Given as a booster after BCG vaccination it significantly enhances protection over BCG alone. Healthy M. tuberculosis-infected human individuals (latent infection) respond to HBHA with a strong IFN-g response as well as with strong CD8+ T cell responses (IFN-g production, perforin production, bactericidal activity and cytotoxicity). Stage of development Preclinical development stage, planning of Phase I trials Date of entry or expected date of entry into Phase I trials 2009 Expected date for completion of Phase III trials 2017

h. HG85A/B Type of product Chimeric Ag85a/Ag85b DNA vaccine Sponsors Shanghai H&G Biotechnology Co., LTD Product description Truncated ag85b gene was inserted into the Acc I site of ag85a gene and then this chimeric gene was linked with pVAX1 vector Stage of development This DNA vaccine has been evaluated for the immunotherapy of MDR-TB on mouse model. The preclinical experiment using plasmid DNA associated with conventional chemotherapy for the treatment of MDR-TB infected monkeys will be finished by the end of 2008. Date of entry or expected date of entry into Phase I trials DNA vaccine immunotherapy of MDR-TB in 2009 Expected date for completion of Phase III trials 2011

28

C. IMMUNOTHERAPY

2. Phase I: 2010 or Later

a. HG856-BCG Type of product Recombinant BCG overexpressing chimeric ESAT6/Ag85a fusion protein Sponsors Shanghai H&G Biotechnology Co., LTD Product description Recombinant BCG overexpressing chimeric ESAT6/Ag85a fusion protein by using PfurA promoter series. HG856A DNA vaccine prime and boosted with HG856-BCG for the prevention of pulmonary TB in young adults. Stage of development This DNA prime and recombinant BCG boost strategy has been tested on mouse model for the protection against TB infection. This combined vaccine will be evaluated on monkey model in 2008. Date of entry or expected date of entry into Phase I trials 2010 Expected date for completion of Phase III trials 2017

b. HG856-SeV Type of product Recombinant Sendai virus overexpressing chimeric ESAT6/Ag85a fusion protein Sponsors Shanghai H&G Biotechnology Co., LTD Product description Recombinant Sendai virus overexpressing chimeric ESAT6/Ag85a fusion protein HG856A DNA vaccine prime and boosted with HG856-SeV for the prevention of pulmonary TB in young adults.

Stage of development This DNA prime and recombinant SeV boost strategy will be evaluated on monkey model for the protection against TB infection in 2008. Date of entry or expected date of entry into Phase I trials 2010 Expected date for completion of Phase III trials 2017

29

C. IMMUNOTHERAPY 2. Phase I: 2010 or Later

c. F36, F727 Type of product Fusion Sponsors Colorado State University/ Mycos Research/CSU Infectious Disease Supercluster, NIAID, NIH Product description A vaccine consisting of a fusion of correctly acylated Rv1411 and [as an example of an immunogenic protein] ESAT-6. This fusion protects in a mouse model of tuberculosis as a pre-exposure vaccine, and has post-exposure activity in a guinea pig model. Stage of development Preclinical stage Date of entry or expected date of entry into Phase I trials TBD Expected date for completion of Phase III trials TBD

d. Mycobacterium vaccae Heat-Killed Type of product Heat-killed whole cell Mycobacterium vaccae suspension administered by intradermal injections in multiple dose schedule. Sponsors Developed by Stanford Rook Ltd, a subsidiary of SRPharma, now Silence Therapeutics Product description M. vaccae is believed to act as an immunomodulator that promotes bacillary clearance and reduces immunopathology. Treatment is intended as an adjunct to chemotherapy particularly for the management of drug resistant tuberculosis. Stage of development A revision of the GMP manufacturing process has now been completed with several improvements implemented. GMP product could become available when required. Date of entry or expected date of entry into Phase I trials Regulatory advice hints that a Phase 1 trial would not be necessary based on the extensive safety data available on previous M. vaccae preparations used in a number of clinical trials including a Phase III trial in HIV +ve patients. Expected date for completion of Phase III trials TBD

30

C. IMMUNOTHERAPY

2. Phase I: 2010 or Later

*e. Ac2SGL Diacylated Sulfoglycolipids** Type of product Subunit Sponsors Invented by Puzo, Gilleron, Stenger and De Libero, Institut de Pharmacologie et de Biologie Structurale, Toulouse, CNRS Product description Ac2SGL Mycobacterial lipids capable of inducing human T cell responses - Ac2SGL is a novel glycolipid antigen with strong immunogenicity during infection with M.tb and with the capacity to prime protective T cells. Stage of development Preclinical Date of entry or expected date of entry into Phase I trials TBD Expected date for completion of Phase III trials TBD **Source: PH Lambert, TB-VAC