Heparin-binding hemagglutinin as a vaccine candidate against tuberculosis

1. Heparin-binding hemagglutinin as a vaccine candidate against tuberculosis Camille Locht camille.locht@pasteur-lille.fr Cape Town March 25-27, 2013

3. 1908 - 1921 Bacillus Calmette et Guérin (BCG)

5. Tuberculosis Active TB Potential reactivation Latent TB Stable latency Cure

6. TB or not TB

7. Neyrolles et al., PLoS One, 06 Hernandez-Pando et al., Lancet, 2000

8. 100 pN 100 pN 0 pN 0 pN Atomic Force Microscopy Dupres et al., Nat. Meth., 2005

9. Delogu et al., Infect. Immun., 2006

10. P < 0.0001 IFN-g production in response to HBHA 35000 30000 25000 20000 15000 10000 5000 2000 IFN-g (pg/ml) 1800 1600 1400 1200 1000 800 600 400 200 0 Controls LTBI TB n = 11 n = 42 n = 40 Temmerman, Pethe et al., Nat.Med., 2004

11. Corbière et al., PLoS One, 2012

12. A 46 year old man from Morocco, presenting with end-stage renal disease secondary to type 2 diabetes Chills, fever, 4 kg weight loss in a few weeks Dialysis 2007 2009 2011 IGRA screening: PPD : 18972 pg/mL HBHA : 7287 pg/mL QFT : 13.58 U/ml IGRA control: HBHA 0 pg/mL QFT : 14.36 U/ml Esat6 : 3855 pg/ml Anti-TB treatment Culture + 32 days later Corbière et al., PLoS One, 2012

13. IFN- secretion • Cytotoxic activity • Microbicidal activity Potential correlates of protection of the HBHA-induced immune responses in HUMANS Temmerman et al., J. Infect. Dis., 2006

14. Dose-response effect 6.5 * 6 * * CFUs (log10) in the spleen 5,5 5 4.5 DDA-MPL 1xHBHA 2xHBHA 3xHBHA BCG Locht et al., Tuberculosis, 2006

15. Long-term prime/boost Rouanet et al., Microbes Infect., 2010

16. * * * * 6.5 6 CFU (log10) 5.5 5 4.5 Adj. BCG nHBHA rHBHA Temmerman, Pethe et al., Nat.Med., 2004

17. M A E N S N I D D I K A P L L A A L G A A D L A L A T V N E L I T N L R E R A EE T R T D T R S R V E E S R A R L T K LQ E D L P E Q L T E L R E K F T A E E LR K A A E G Y L E A A T S R Y N E L V E R G E A A L E R L R S Q Q S F E E V S A R A E G Y V D Q A V E L T Q E A L G T V A S Q T R A V G E R A A K L V G I E L PK KA A P A K KA A P AK KA A P AK KA A AK KA P A K K A A A K KV T Q K CH3 CH3 2(CH3) CH3 2(CH3) CH3 2(CH3) CH3 2(CH3) CH3 CH3 CH3 2(CH3) 2(CH3) 2(CH3) CH3 Pethe et al., PNAS, 2002

18. * * * * * * * * 1 0 5 1 0 4 3 1 0 (pg/ml) g IFN- 1 0 2 1 0 1 1 0 0 nHBHA rHBHA E. coli rHBHA M. smegmatis

19. Patient number HBHA IPL* HBHA Aeras* 1 5.21 13.53 0.02 2 0.09 3 0.02 0.11 4 0.24 0.27 5 0.07 0.12 6 < 0.01 < 0.01 7 < 0.01 < 0.01 8 1.43 0.73 9 1.62 1.28 Non-infected; LTBI; TB * ng/ml IFN-; Aeras 445

20. First step Second step D2 rHBHA nHBHA

21. HBHA Purify HBHA Use HBHA for diagnostics Use HBHA as a vaccine

22. HBHA

23. Université Libre de Bruxelles S. Temmerman V. Corbière V. Dirix F. Mascart Institut Pasteur de Lille Past F. D. Menozzi K. Pethe Present A.-S. Debrie C. Rouanet H. Drobecq D. Raze M. Loyens S. Lecher N. Mielcarek C. Locht AERAS K. Velmurugan B. Kalampanayil M. J. Brennan Product Development Team/TB-VI G. Thiry M. Roumiantzeff B. Walker R. Dobbelaer J.Thole