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Potential prophylactic BCG Prime-booster Gaëlle Noël Kidist Bobosha Subgroup A2 March 16 th, 2011.

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Presentation on theme: "Potential prophylactic BCG Prime-booster Gaëlle Noël Kidist Bobosha Subgroup A2 March 16 th, 2011."— Presentation transcript:

1 Potential prophylactic BCG Prime-booster Gaëlle Noël Kidist Bobosha Subgroup A2 March 16 th, 2011

2 Enhance and prolong the protective immunity induced by BCG immunization Enhance and prolong the protective immunity induced by BCG immunization Goal Goal

3  Live attenuated strain of Mycobacterium bovis  Protects children from severe forms of TB (milliary and meningitis)  Safe and inexpensive  Over 3 billion people got the vaccination globally Limitations o BCG protection wanes through time o Does not prevent against pulmonary disease in adults o Does not protect against re-occurrence or latency o Repeated BCG vaccination failed in enhancing immunity o Risk of disseminated BCG in HIV-infected children o Interferes with Tuberculin-Skin-Test BCG vaccine BCG vaccine

4  Safe  Cost effective  Long term protection  Prevention of infection: pre exposure  Prevention of reactivation: post exposure General aims of TB vaccination General aims of TB vaccination

5 Best strategies are subunit boosters like:  Protein/ fusion protein  Recombinant viral vector  DNA vaccine Prophylactic heterologous prime-boost Prophylactic heterologous prime-boost Boosting BCGNew vaccine

6 Fusion protein Fusion protein Safe Reproducible Can be freeze-dried Not expensive Not compromised by BCG or environmental mycobacteria exposure … But needs adjuvant …Why not DNA vaccine : delivery system (complex and costy) Live viral vector : previous exposure, expensive

7 5-10 % of active TB disease % of latent TB infection

8  Ag85A (Rv3804c)  Early stage  Rv2660c  Dormant stage  PPE44 (Rv2770c)  Multi-stage Multi-stage fusion protein Multi-stage fusion protein

9 Ag85A protein (Rv3804c)  Part of the Ag85 complex (Ag85A, Ag85B and Ag85C)  Shared by BCG and Mtb  true booster  Mycolyl transferase A: enzyme involved in the cell wall synthesis  Largely expressed  Secreted and also retained in the cell membrane during early stage of infection  Ag85A/B largely used in new vaccine candicates for their immunogenic capacity

10 Preclinical data demonstrated:  Large proportion of memory CD4 T cells in the lung recognize Ag85A in young mice (Cooper et al., 1997)  Significant Th1-type cytokine production by splenocytes and significant CTL activity against Ag85A and Ag85B in mice (Lozes et al., 1997) Ag85A protein (Rv3804c)  Ag85A has the potential to boost existing memory immunity in BCG- vaccinated mice - Lung tissue damage dramatically reduced (Brooks et al., 2001)

11 Rv2660c protein  Starvation protein  Belongs to the Region of Differences RD11  Deleted in BCG Preclinical/Clinical data demonstrated:  Govender et al., 2010: Expression shown to be associated with non-replicating persistence in vitro Persons with latent TB infection preferentially recognize Rv2660 and induced IFN- γ production in a greater proportion compared with patients with TB disease (ex vivo experiments by using patients’ PBMC)  Betts et al., 2002: Expression increased in nutrient-starved cultures (300 fold change) – Effective in the late persistent stage – In the late persistent stage of infection, the effect of adding Rv2660c was particularly pronounced

12  Aagaard et al., 2011 Immune response against Rv2660c increases during persistent stage Having Rv2660c in a fusion protein increases protection in late stage Rv2660c protein

13  Belongs to the PPE protein family  Secreted by the type VII secretion system encodes by ESAT-6 loci  Romano et al., 2008 PPE44-specific immune responses in acutely, chronically and latently Mtb infected mice PPE44 vaccinated mice showed B and T cell responses with IFN-  and IL-2 release PPE44 seems to be protective PPE44 protein (Rv2770c) (Rv2770c)

14 IC31 ® adjuvant Intercell product Cationic particles composed of:  Antimicrobial peptide (KLKL 5 KLK)  TLR-9 ligand Oligonucleotide (ODN1a) Combined at a molar ratio of 25:1, respectively  Generates a strong Type 1-dominant humoral and cellular immune response with induction of CTL (Schellack et al., 2006)  Able to slowly release antigen: two month depot effect of IC31 ® may allow single shot protection (Schellack et al., 2006)  Used and seen to be safe  Mouse subcutaneous injection (Schellack et al., 2006)  Guinea pig intramusculary (Skeiky et al., 2010)  Human intramusculary injection (up to 500 nmol KLK + 20 nmol ODN1a) (Dissel et al., 2010)

15 + IC31® adjuvant Ag85A Rv2660c PPE44 PFP A multi-stage BCG booster candidate Thank you for your attention…


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