Dengue Vaccine Development. Status, challenges, and WHO priorities. 24/05/2004 WHO Initiative for Vaccine Research

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1 Dengue Vaccine Development Status, challenges, and WHO priorities

2 Key issues Vaccination appears as the only sustainable strategy for disease prevention, no vaccine available until today; Circulation of 4 crossreactive serotypes that do not confer crossprotection; Pathogenesis of severe disease is poorly understood - can vaccination possibly induce DHF in some cases?

3 resulting into key challenges for dengue vaccine development Efficacy endpoints (DF vrs DHF/ hospitalisation), need to conduct large trials; Complex and changing diseases epidemiology, requires careful planning and multiple trials; Vaccine-safety, long-term follow-up to exclude vaccine-induced sensitization to severe disease, research needed; Regulatory/environmental issues related to chimeric vaccines ( GMO ).

4 Dengue Vaccine Pipeline Acambis GSK-WRAIR AvP-Mahidol Tetravalent DNA vaccines Hawaii Biotech FDA Mutant F CDC Den2Mahidol NIAID DEN4 30 Monovalent preclinical phase I phase II phase III

5 Dengue Vaccine Status & Approaches AvP-Mahidol Phase II age-desc., phase III in planning Live-attenuated tetrav, produced on PDK GSK-WRAIR Acambis Phase II adult, phase I children started Phase I adults tetra started Live-attenuated tetrav, produced on FRhL Den/YF17D chimaera, produced on Vero NIAID Monov phase II Den/Den chimaera, attenuation in 5' NTR US CDC Monov phase I starting Den/Den chimaera, Den2Mahidol backbone US FDA Preclinical Den/Den chimaera, Attenuation in 3' NTR Hawaii Biotech Phase I planning Subunit vaccine E +NS1 in adjuvants Diverse Preclinical DNA vaccination

6 Live-attenuated vaccines Features: Advanced stage of clinical evaluation Conventional technology Safety of currently tested vaccines demonstrated Issues: Attenuation profile not fully balanced, needs improvement Virus strains not cloned Currently production on primary cells

7 YF/Dengue chimeric vaccine (Acambis) c prm-e non-structural 5 -YF 17D YF 17D Dengue-1 PUO-359 Thai wt Dengue-2 PUO-218 Thai wt Dengue-3 PaH881 Thai wt Dengue Indonesia wt

8 YF/Dengue chimeric vaccine (Acambis) Features: Promising early clinical development: safety immunogenicity YF chimeric technology tested for Japanese Encephalitis Production in tissue culture, high yield Issues: Tetravalent clinical data not yet available Environmental impact assessment needs to be conducted (GMO) Theoretical safety concern from YF backbone

9 Dengue/Dengue chimeras Features Well-characterized attenuation mutations Promising animal data Safe & imunogenic in early clinical trials Issues: Still at early stage of clinical development Environmental impact assessment needs to be conducted (GMO issues)

10 Dengue Subunits Expressed in the Drosophila System C prm E NS1 80%E domain B prm80%e prm100%e NS1 (Slide from C Weeks-Levy, Hawaii Biotech)

11 Dengue subunit vaccine Features: Combines Env and NS1 antigen Production in Drosophila S2 system Promising monkey data Issues Still at early development Must prove long-lasting immunity Cost of goods?

12 A team effort within WHO Comm. Dis. (CDS) & Trop. Diseases (TDR) Regulatory oversight, Vaccine Quality & Supply (ATT) Standardization & norms (QSB) IVR: Vaccine Research Regional and Country WHO Offices Surveillance & Monitoring (VAM) Vaccine Implementation (EPI)

13 Dengue vaccines: current IVR priorities "To promote and facilitate the development and evaluation of candidate vaccines " Research on immune mechanisms in protection and disease WHO Task Force for vaccine evaluation in clinical trials Standardization of animal models for pre-clinical evaluation of dengue vaccines Standardization of assays and reagents for evaluation of vaccines in clinical trials

14 Projects on Dengue Immune Response Characterise protective antibodies induced by vaccination in human volunteers; Assess virus PrM as potential target of neutralisation / infection enhancement; Develop monoclonal competitive ELISA to determine role of cross-reactive antibodies; Longitudinal study of immune responses following primary and secondary infection;

15 Animal models for preclinical evaluation Develop standardised protocol for evaluation of dengue vaccines in monkeys Test live-attenuated vaccines Establish repository of reference and working materials

16 Standardization of assays and reagents (jointly with QSB) Preparation of anti-dengue reference human sera & their validation Establishment of reagent banks (virus, sera, cells) Establishment of reference laboratory Standardisation of neutralisation test Development of guidelines for control and production of live-attenuated tetravalent vaccines (QSB)

17 Facilitate Clinical Development Establishment of dedicated task force (with TDR) Regularly review clinical vaccine development and issue specific recommendations Update WHO guideline on dengue vaccine trials in endemic countries Provide guidance on vaccine long-term safety follow-up Support capacity building in developing countries

18 Collaborative efforts and partnerships RESEARCHERS CDC Erasmus Univ Mahidol Univ NIH USA WHO IVR, TDR NRAs Manufacturers AvP, GSK, Acambis PDVI