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

Ag85B1-285 ESAT-61-95

Ag85B241-260 ESAT-61-20

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

20

40

60

Per

cent

sur

viva

l

100

0

80

Days post-infection

50 100 150 200

Naive

ESAT-6Ag85B

Hybrid

BCG

Survival of vaccinated mice

Survival of vaccinated guinea pigs

Weeks post infection

0 5 10 15 20 25 30

% su

rvival

0

20

40

60

80

100

120

NaiveBCGAg85B-ESAT-6Ag85BdESAT-6Ag85B+dESAT-6

Priming: PBS BCG BCG BCG Hybrid Hybrid

Boosting: PBS PBS BCG Hybrid PBS Hybrid

IFN

- (

ng/m

l)

2

4

6

8

10

0

Boosting of vaccine immunogenicity after 9 months in mice

Boosting BCG efficacy in guinea pigs

0

1000

2000

3000

Lung

IF

N

(pg

/ml)

Priming: PBS sc oral nasal sc sc

Boosting: PBS sc oral nasal oral nasal

*

*

*

*

Lung response to oral/nasal vaccination

0

Log

redu

ctio

n in

CF

U

Priming: PBS BCG sc oral nasal sc sc

Boosting: PBS sc oral nasal oral nasal

0.5

1.0

1.5

*

*

* *

*

*

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 timeline20092005 2006 2007 20082004

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

PhaseIb

Phase II

Africa

Clinical trial design Phase I

Comparative analysis of new delivery systems

Phase I

EuropeImproved models for memory and lung pathology

MUVAPRED timeline20092005 2006 2007 20082004

GMP production

Tox testing

Stability testing

Clinical trial design Phase I

Phase Ia

Phase Ib

Clinical trial design Phase II

Europe

PhaseIb

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 years1

• This is supported by recent work showing deferment of TB

meningitis in BCG-vaccinated children2 and waning

protection in adult vaccinees over time3

1. Pediatrics 1995 Jul;96(1 Pt 1):29-35 . Colditz GA, et al.2. Indian J Pediatr 1996 Sep;63(5):659-664. Mittal SK, et al.3. Scand J Respir Dis 1976;57(5):208-222. 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

difficult2. 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?

10 20 30 40 50 60 70

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 50 - 80 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