1. The Challenge: How to Accelerate Eradication and the 'Endgame'?

2. 2 Historical Evolution of 'Post-Eradication' 0 2 4 6 8 10 12 Years Wild virus eradication Global Cert Comm (1995) Certification Expert Advisory Meeting (1998) Certification & containment Wild virus eradication Last WPV case OPV cessation ACPE (2004) VDPV elimination?Wild virus eradication Certification & containment VDPV elimination & validation Wild virus eradication World Health Assembly (2008) Post-OPV surveillance Certification & containment The 'Polio Endgame' refers to management of the 'post-eradication' risks due to OPV. VDPV: Vaccine-derived poliovirus ACPE: Advisory Committee for Polio Eradication

3. 3 New polio endgame: Guiding principles phased removal of Sabin viruses, beginning with highest-risk (type 2). elimination of VDPV type 2 in parallel with eradication of last wild polioviruses by switching from tOPV to bOPV for routine EPI & campaigns. early introduction of IPV, at least in high risk areas for VDPVs, to provide type 2 protection.

4. 4 A new 'Endgame' strategy: parallel instead of sequential risk management 0 2 4 6 8 10 12 Years Last wild polio case trivalent OPV cessation VDPV elimination & validation Wild virus eradication Sequential risk management Post-OPV surveillance Certification & containment VDPV2 elimination & validation Post-OPV surveillance Wild virus eradication Parallel risk management Certification & containment earlier IPV introduction & OPV2 cessation bivalent OPV 1&3 (bOPV) cessation

5. 5 Implications First: Early universal IPV introduction (priority highest cVDPV risk areas) integrated into routine immunization program (before switch). Second: Switch from tOPV to bOPV in a globally synchronized manner. Switch date as early as April 2013. Third: For outbreak control, use IPV, mOPV2, or exercise re-start tOPV option

6. 6 Product development needs REQUIRED: Licensure of bOPV in all self-producing countries. REQUIRED: Appropriate presentations and labelling change to permit use of fractional-dose IPV (1/5 of full dose). OPTIONAL: Availability of appropriate jet injectors for intradermal administration.

7. Expanded Use of bOPV

8. 8 Bivalent OPV efficacy & use Seroconversion after 2 x bOPV vs. tOPV, India, 2008-2009 Type 1 Type 3 bivalent OPV use as of Sept 2011 Introduced Dec 09-Aug 11 Planned by end-2011

9. 9 Urgent bOPV priorities Licensure of bOPV in self-producing countries: Brazil, China, Iran, Mexico, Russian Federation, Serbia, Vietnam,.... Regulatory approach: Reproduce licensing strategy that led to approval of six manufacturers. Label-change of current bOPV: Current bOPV licensed only for supplemental doses, not for primary immunization.

10. 10 bOPV data needs Clinical trial: bOPV administered in four-dose schedule ('EPI schedule'), with doses administered at 0, 6, 10, and 14 weeks. Modelling: Risk of cVDPV2 emergence, assessment of risk mitigation strategies. Mucosal immunity: Will bOPV induce type 2 mucosal immunity after IPV.

11. Fractional-dose IPV

12. The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.  WHO 2010. All rights reserved Standalone IPV IPV - hexa combo Data in WHO HQ as of Sep 2010 IPV - penta combo Unknown Not applicable Background: Countries with IPV Use

13. Affordable IPV Strategy: Approaches Enables IPV production in developing countries with less or non-infectious strain Use adjuvant to reduce antigen contents per dose Develop intradermal (ID) device or micro- needle patch to stretch doses Use fewer doses per schedule Reduce number of doses Reduce amount of dose Reduce antigen content Reduce production cost

14. 14 IPV priorities Product required: one- or two dose IPV presentation. Regulatory approval: label-change to include intradermal administration. Policy decisions: (1) fractional-dose IPV as supplemental dose(s) to current OPV schedule in routine immunization programs (either with DTP3 at 16 wks or with measles at 9 mos); and (2) fractional-dose IPV in supplemental immunization campaigns (SIAs).

15. Feasibility of Approach: Oman, GSK IPV at 2, 4, and 6 mos, Biojector2000® ID n=187 IM n=186 P values Poliovirus type 1 seroconversion, % [median titer]‡ 97.3% 228 100% 724 NS <0.001 Poliovirus type 2 seroconversion, % [median titer]‡ 95.7% 287 100% 1149 0.01 <0.001 Poliovirus type 3 seroconversion, % [median titer]‡ 97.9% 362 100% >1448 NS <0.001 Mohammed AJ, et al. N Engl J Med 2010;362:2351-9.

16. Single-dose Immunogenicity: Cuba, NVI IPV at 4 (and 8) mos, Biojector2000® P1 P2 P3 Randomized controlled trial Field work in Camaguey Province, Cuba IPV from Netherlands Vaccine Institute Enrolling 160 infants per arm Serum at 4m, 8m, 8m+7d and 8m+30d IPV at 4- and 8 m fractional vs full-dose Seroconversion (single and two-dose) Priming (8m and 8m+7d) Preliminary ResultsStudy design

17. 17 IPV data needs Clinical trial: non-inferiority of a fractional versus full- dose IPV (given with pentavalent vaccine at 14 wks and/or with measles vaccine at 9 mos) co-administration assessment (immunogenicity of different antigens, including hepatitis B) large scale-safety assessment Immunology: Assessment of priming (difference from seroconversion); duration of effect Modelling: Geographic phasing, number of doses, full versus factional dose IPV, outbreak control options

18. Intradermal needle-free devices

19. 19 Needle-free device priorities Product(s) required: intradermal device appropriate for developing countries (i.e., spring- powered). Regulatory approval: WHO-prequalification. Policy decision: use device to administer fractional-dose IPV in supplemental immunization campaigns (SIAs).

20. New Needle-free Intradermal-only Devices Pharmajet Bioject

21. 21 Device data needs Comparative evaluation: assessment of appropriate intradermal devices– immunogenicity, reactogenicity, ergonomics [planned in Cuba in 2012]. Clinical trial: non-inferiority study of supplemental full-dose (by needle & syringe) or fractional-dose IPV (by needle-free device and needle & syringe) [planned in India for 2012].

22. 22 Upcoming Consultations on new Endgame Strategy Spearheading partners+ (19 October) Polio Donor Contact Group (20 October) OPV/IPV Manufacturers (27 October) WHO's Scientific Advisory Body of Experts (SAGE) (10 Nov) Expert Consultation on VDPVs (January/February 2012) WHA Executive Board (January 2012) World Health Assembly (May 2012)

23. 23 Summary a new definition of, and strategy for, the 'endgame' could accelerate eradication & reduce long-term risks. depending on IPV price and strategy, the new endgame could be cost-neutral through certification. a number of workstreams would be needed to address major unresolved questions/risks (policy, R&D, vaccine supply, surveillance/validation, operations, financing).