New initiatives for TB vaccines TBVAC Follow-up to the TB vaccine cluster, led by the Pasteur Institute Goal is to take the best new TB vaccines through phase I and II clinical trials Total grant approx €18 million MUVAPRED New study, led by Chiron Goal is to take promising new vaccines for TB and HIV that can be delivered by the oral route through phase I clinical trials Total grant approx €15 million

The Hybrid1 vaccine NVA Ag85B ESAT Ag85B ESAT The Hybrid1 vaccine has been tested in a variety of animal species and in multiple delivery systems. It has been shown to be immunogenic in all species so far tested Epitope mapping with human cells has shown that peptides from these molecules can bind to a wide variety of HLA types and consistent with this, the two proteins are widely recognised in sensitised humans

Percent survival Days post-infection Naive ESAT-6 Ag85B Hybrid BCG Survival of vaccinated mice

Survival of vaccinated guinea pigs Weeks post infection % survival Naive BCG Ag85B-ESAT-6 Ag85B dESAT-6 Ag85B+dESAT-6

Priming: PBS BCG BCG BCG Hybrid Hybrid Boosting: PBS PBS BCG Hybrid PBS Hybrid IFN-  (ng/ml) Boosting of vaccine immunogenicity after 9 months in mice

Boosting BCG efficacy in guinea pigs

Lung IFN  (pg/ml) Priming: PBS sc oral nasal sc sc Boosting: PBS sc oral nasal oral nasal * * * * Lung response to oral/nasal vaccination

0 Log reduction in CFU Priming: PBS BCG sc oral nasal sc sc Boosting: PBS sc oral nasal oral nasal * * * * * * Reduction of CFU in lung by oral/nasal vaccination

 The Hybrid1 vaccine appears to be safe and well tolerated  It is effective as a primary vaccine in mice, guinea pigs and primates  It appears to be effective as a booster vaccine in mice and guinea pigs  It is effective when delivered percutaneously or via the nasal route Conclusion I

TBVAC timeline Comparative analysis of new vaccine candidates GMP production Tox testing Stability testing Clinical trial design Phase I Phase Ia Phase Ib Clinical trial design Phase II Europe Phase Ib Phase II Africa Clinical trial design Phase I Comparative analysis of new delivery systems Phase I Europe Improved models for memory and lung pathology

MUVAPRED timeline GMP production Tox testing Stability testing Clinical trial design Phase I Phase Ia Phase Ib Clinical trial design Phase II Europe Phase Ib Phase II Africa?

Does BCG offer only short-term protection in humans? Meta-analysis of multiple trials suggests that infant vaccination with BCG protects against childhood manifestations of TB for up to 10 years 1 This is supported by recent work showing deferment of TB meningitis in BCG-vaccinated children 2 and waning protection in adult vaccinees over time 3 1. Pediatrics 1995 Jul;96(1 Pt 1): Colditz GA, et al. 2. Indian J Pediatr 1996 Sep;63(5): Mittal SK, et al. 3. Scand J Respir Dis 1976;57(5): Sjogren I.

BCG is efficient when used in skin test negative donors (Hart and Sutherland 1977) BCG is efficient when used in neonates (Al-Kassimi 1995; Colditz 1995) BCG vaccination results in accelerated skin test conversion but rapid waning in areas with environmental exposure - and more sustained responses in areas with low sensitization (Palmer 1952) BCG efficacy - evidence from human trials

These studies suggest that BCG works in naive donors (such as infants) but fails over time, and is ineffective in adults This means that: 1. Stopping infant vaccination with BCG would be ethically difficult 2. There is a place for a vaccine targetted to adults, which could supplement rather than replace BCG BCG - Replace or Repair?

When do we vaccinate? Gambia Zambia Ethiopia Age of patient at admission % BCG scar 1% 65% 70%

The Paradox of the TB Market Unfortunately, the TB market is not like any other. While the target population is huge (est. 132 million doses per year) the market size is very small (curr. est. 34 million € per year) This is because: BCG is very cheap (0.28 € per dose) Disease - and therefore vaccine use - is highest in the poorest countries Moreover, the chronic nature of the disease means that phase III trials will be very expensive - in the range of million €

Bringing a TB Vaccine to Market Given the cost issue, a TB vaccine will have to be approached differently from a conventional vaccine/pharmaceutical if commercial development is to be successful 1.Public assistance will be essential for development - in this regard, the EC proposes making approximately 300 million € available in its clinical trial platform, in which TB vaccine development is a priority 2.Staggered pricing regimens (for example, 50€ in the developed world and 4€ in the developing world) would swell the world market to approx 600 million €. This is in principle acceptable to regulatory authorities