GAVI Vaccine Investment Strategy

1. GAVI Vaccine Investment Strategy Rabies Analysis Final October 27, 2008

2. Rabies CONTENTS • Disease Overview • Vaccine Landscape • Vaccination Policy & Strategies • Vaccine Need & Adoption Forecast • Vaccine Cost Analysis • Implementation-Associated Cost Analysis • Analysis Summary • Key Resources

3. Disease Overview DISEASE PATHOGEN, TRANSMISSION & TARGET POPULATION* DISEASE PATHOGEN, TRANSMISSION & TARGET POPULATION1 • Disease Pathogen • Rabies Virus (lyssavirus) • Transmission • Usually dog bites in developing countries; animal to person via saliva from a bite • Incubation periods have been as short as 5-6 days, in the majority of cases is 20-60 days • Geographic Distribution • Most human cases are in rural areas of Africa and Asia • Disease Target Population • All ages are susceptible, however, rabies is most common in ages 5-15 years old, the majority of whom are male

4. Rabies Disease Overview DISEASE IMPACT2,3 • Total Morbidity • >10 million suspected cases per year in developing countries • Rural poor and children are most at risk • Total Mortality • ~55,000 cases reported annually and thought to be grossly underreported with the majority of deaths occurring in Asia and Africa • Case fatality rate is 100% once clinical symptoms present (with exception of one known survivor to date) • Epidemic Potential • Human outbreaks can occur as a result of epidemics in the animal population and/or when a rabid animal bites multiple people • Disease Sequelae • Permanent neurological sequelae in the one survivor to date

5. Rabies Disease Overview DISEASE BURDEN – GEOGRAPHIC DISTRIBUTION4 Note: “This figure is an unrealistic representation of the true epidemiological situation as a result of problems with reporting biases, e.g. dog rabies is endemic throughout Africa” - Partners for Rabies Prevention Informal Group (PRP)

6. Rabies Disease Overview 0 = None Reported Data Not Available or Non-Endemic = DISEASE BURDEN IN GAVI-ELIGIBLE COUNTRIES – MORBIDITY5 4

7. Rabies Disease Overview None Reported Data Not Available or Non-Endemic 0 = = DISEASE BURDEN IN GAVI-ELIGIBLE COUNTRIES – MORTALITY6,7 4 GAVI Vaccine Investment Strategy Vaccine Landscape Analysis_Cholera_Apr08

8. Rabies Disease Overview NON-VACCINE PREVENTION & TREATMENT INTERVENTIONS8 • Non-Vaccine Preventions • Control and vaccination of domestic dogs and wild carnivores • Treatment Interventions • Post-exposure prophylaxis rabies vaccination and passive immunoglobulin administration around the wound (to neutralize the virus before it enters the CNS) • After symptoms ensue there is no recognized effective treatment

9. Rabies Disease Overview INEQUITIES8 • Inequity of Poor • Poor access to post-exposure prophylaxis and increased inability to control and vaccinate dogs exists in low socioeconomic areas • Gender Inequities

10. Rabies CONTENTS • Disease Overview • Vaccine Landscape • Vaccination Policy & Strategies • Vaccine Need & Adoption Forecast • Vaccine Cost Analysis • Implementation-Associated Cost Analysis • Analysis Summary • Key Resources

11. Rabies Vaccine Landscape LICENSED VACCINES* (I) *PEP dosing only

12. Rabies Vaccine Landscape LICENSED VACCINES* (II) *PEP dosing only

13. Rabies First NRA Licensure WHO Pre-Qual Approval Vaccine Landscape ESTIMATED VACCINE AVAILABILITY RabAvert/Rabipur (Novartis) Rabivac (Novartis/Chiron-Behring) Imovax Rabies (Sanofi-Pasteur) Verorab (Sanofi-Pasteur) PDEV*(Zyddus Cadila) Emerging Supplier (Bharat, SII) BioRab (BioPort) Rabies Vaccine (Vaccine China Biol) (if motivated) Prior to 2009 2009 2010 2011 2012 2013

14. RABIES Vaccine Landscape Analysis COST EFFECTIVENESS LITERATURE SUMMARY • Post-exposure rabies prophylaxis is estimated to prevent 330,304 (90% CI: 141,844 - 563,515) deaths in Asia and Africa. Rabies is responsible for an estimated 1.74 million (90% CI: 0.25M – 4.57M)DALYs. Global expenditure for rabies prevention is over $1 billion.16 • A 1996 study demonstrated that pre-exposure rabies prophylaxis for the international travelerwas worth$275,000 per case averted.17 • Cost comparison of rabies pre-exposure vaccination to post-exposure vaccination in Thai childrenshowed that pre-exposure vaccination was cost-effective when the dog bite incidence is 2% to 30% of the population.18

15. Rabies CONTENTS • Disease Overview • Vaccine Landscape • Vaccination Policy & Strategies • Vaccine Need & Adoption Forecast • Vaccine Cost Analysis • Implementation-Associated Cost Analysis • Analysis Summary • Key Resources

16. Vaccination Policy & Strategies CURRENT POLICY

17. Vaccination Policy & Strategies VISP DECISION FRAMEWORK GAVI VIS Rabies Decision Framework Support Strategies for Financial Planning Purposes PEP Only Offer Vaccine Financing to GAVI-Eligible Countries • Develop & implement pilot programs in 2-3 countries • Monitor & evaluate impact and develop recommendations Pilot Regional Bite Center & District Hospital Studies to Demonstrate Impact of GAVI Support • Develop educational programs aligned with national rabies prevention control strategies • Implement pilot programs in 2-3 countries • Monitor & evaluate impact and develop recommendations Pilot Rabies Education Programs to Demonstrate Reduced Disease Burden Impact Provide Alternative Investment Support Fund RIG Capacity Building in GAVI Countries To Eliminate Shortages and Reduce Treatment Costs • Accelerate tech transfer of RIG to emerging suppliers • Motivate supplier capacity development Don’t Support in 2009 - 2013

18. Rabies CONTENTS • Disease Overview • Vaccine Landscape • Vaccination Policy & Strategies • Vaccine Need & Adoption Forecast • Vaccine Cost Analysis • Implementation-Associated Cost Analysis • Analysis Summary • Key Resources

19. Vaccine Need & Adoption Forecast GAVI-ELIGIBLE COUNTRY VACCINE NEED Vaccine Need: 49 VISP Scope: 49 • The vast majority of deaths due to rabies occur in Asia and Africa (WHO position paper, Dec07); the current countries in scope represent countries with high rabies incidence or countries in need of rabies education and vaccination with safe rabies vaccines (F. Meslin, WHO & D. Briggs, Alliance for Rabies Control)

20. Vaccine Need & Adoption Forecast INTEGRATED ADOPTION FORECAST Vaccine Need: 49 VISP Scope: 49 Armenia Benin CAR Lao Mali Nepal Pakistan Rwanda Tajikistan Uzbekistan Bangladesh Bolivia Djibouti Georgia Haiti Honduras Korea Nicaragua Uganda Bolivia Burkina Faso Cameroon Ethiopia India Tanzania Togo Sri Lanka Viet Nam Cambodia Cameroon Chad Cote d’Ivoire Kenya Malawi Senegal Sudan Zimbabwe Angola Indonesia Mozambique Zambia Azerbaijan Kyrgyzstan Ukraine Madagascar Nigeria DR Congo Ghana Afghanistan

21. Vaccine Need & Adoption Forecast RABIES DEMAND METHODOLOGY Total Country Population Rural Population Urban Population % Rural % Urban AFRO: 100% AMRO: 50% EMRO: 50% EURO: 50% SEARO: 100% WPRO: 100% AFRO: 75% AMRO: 50% EMRO: 50% EURO: 50% SEARO: 100% WPRO: 100% % Rural at Risk % Urban at Risk At Risk Rural Population At Risk Urban Population (Based on UN data) Rural Suspect Bites Urban Suspect Bites Rural Suspect Bite Rate Urban Suspect Bite Rate % Rural Bites Presen-ting % Urban Bites Presen-ting 90% AFRO: 1000/M AMRO: 500/M EMRO: 500/M EURO: 500/M SEARO: 1000/M WPRO: 1000/M AFRO: 1000/M AMRO: 500/M EMRO: 500/M EURO: 500/M SEARO: 1200/M WPRO: 1200/M 75% Rural Bites Presenting Urban Bites Presenting Rural Bites Tx with ID Urban Bites Tx with ID 30% ID 90% ID 10% IM 70% IM Rural Bites Requiring RIG Urban Bites Requiring RIG % Rural Bites Req. RIG % Urban Bites Req. RIG Rural Bites Tx with IM Urban Bites Tx with IM 66% 66%

22. Vaccine Need & Adoption Forecast CURRENT COUNTRY SUPPORT AS PERCENT OF TOTAL NEED • Rabies experts provided estimate of current country-by-county vaccine usage as percent of total need* • Approximately 35% of total GAVI-eligible country vaccine requirements are currently being supported by countries themselves * F. Meslin, WHO & D. Briggs, Alliance for Rabies Control

23. Vaccine Need & Adoption Forecast GAVI VACCINE FINANCING POLICY • As a matter of policy, GAVI does not replace country funds already allocated to rabies vaccines • However, most countries are under resourcing rabies vaccination due to: • High cost of vaccine and rabies immunoglobulin • Vaccine and immunoglobulin supply shortages • Therefore, GAVI would only plan to financially support the difference between actual vaccine need and percent of need currently covered by country • This incremental need assessment will be complicated given a country’s level of funding in any given year is influenced by many factors and may differ year on year • This analysis is focused on GAVI-eligible countries’ total need

24. Vaccine Need & Adoption Forecast VACCINE DEMAND GIVEN INTEGRATED FORECAST

25. Rabies CONTENTS • Disease Overview • Vaccine Landscape • Vaccination Policy & Strategies • Vaccine Need & Adoption Forecast • Vaccine Cost Analysis • Implementation-Associated Cost Analysis • Analysis Summary • Key Resources

26. Vaccine Cost Analysis ANALYSIS INPUT SUMMARY – GENERAL

27. Vaccine Cost Analysis ANALYSIS INPUT SUMMARY – STRATEGY-SPECIFIC

28. Rabies CONTENTS • Disease Overview • Vaccine Landscape • Vaccination Policy & Strategies • Vaccine Need & Adoption Forecast • Vaccine Cost Analysis • Post-Exposure Prophylaxis (PEP) • Additional Investment Alternatives • Implementation-Associated Cost Analysis • Analysis Summary • Key Resources

29. PEP KEY OUTPUT SUMMARY Integrated Demand Forecast 2009-2020

30. PEP ANNUAL ANALYSIS RESULTS Integrated Demand Forecast 2009-2020

31. Rabies CONTENTS • Disease Overview • Vaccine Landscape • Vaccination Policy & Strategies • Vaccine Need & Adoption Forecast • Vaccine Cost Analysis • Post-Exposure Prophylaxis • Additional Investment Alternatives • Implementation-Associated Cost Analysis • Analysis Summary • Key Resources

32. Additional Investment Opportunities BACKGROUND OF UNDERSTANDING • Although rabies has the highest case fatality rate of any disease known to mankind, preventing human rabies in reality is not a complicated issue as it is one of the easiest diseases to prevent • There are three basic steps to preventing human rabies: • Increase educational awareness activities to reduce exposures, increase professional expertise and improve diagnoses and surveillance • Administer prompt and appropriate post-exposure prophylaxis (PEP) when exposures do occur • Conduct preventative immunization (PreP) to protect the relatively few numbers of the populace that are living in high-risk, remote geographic locations with no access to PEP • It has been proven in many countries that if and when these three steps are instituted the number of human rabies deaths quickly and dramatically decreases

33. Additional Investment Opportunities OPTION A* Pilot PEP in Select Countries To Demonstrate GAVI Impact • Experience over two decades has proven that reduced dose regimens for PEP are both efficacious and cost-effective • Updated Thai Red Cross (TRC) intradermal (ID) regimen or “2-2-2-0-2” is most cost effective PEP regimen recommended by WHO • TRC has increased access to vaccines in poor countries and has reduced the PEP cost per patient from 40 to 80% • Awareness as to the utilization and benefit of reduced dose regimens is lacking in most poor countries where it could be of great value • By piloting ID PEP in 4 select countries (2 in Asia & 2 in Africa), GAVI can demonstrate the health impact and cost reduction potential of this approach • With pilot PEP data, GAVI can then decide whether to extend support to all relevant GAVI-eligible countries • Estimated Total 5-Year Budget: $6M ($300K/year/country) • Vaccine + RIG: $2 million • Service Delivery: $400,000 annually • Social Mobilization/Education: $400,000 annually * Potentially eligible for GAVI Operations Research funding, if available

34. Additional Investment Opportunities OPTION B Support Rabies Education Programs to Reduce Disease Burden • Rabies is one of few diseases that can be dramatically reduced through increased education • Activities to improve educational awareness is inadequate in most poor developing countries • Educational initiatives specifically targeted for national governments, professional public health staff and the general public are clearly the least expensive of investments that would result in the highest return in lives saved within the shortest amount of time. • Education for professionals in poor developing countries would include: • Use of intradermal (ID) administration for PEP • Dissemination of latest WHO recommendations • Increased awareness of source of rabies • Training on modern diagnostic tools currently available for rabies confirmation • Estimated 5-Year Budget per Country: $1.2M • Education materials development: $200,000 • Education and training: $200,000 annually

35. Additional Investment Opportunities OPTION C Fund RIG Capacity Building To Eliminate Shortages and Reduce costs • Rabies immunoglobulin (RIG) is the most expensive component of rabies treatment needed for approximately 66% of all suspect bites • Strengthening the production of equine RIG and supporting the development of alternative technologies to replace equine RIG is critical for ensuring adequate supplies and lowering the current price • Estimated 5-Year Budget: $4M • Equine RIG: $3M • Monoclonal antibody preclinical and clinical testing: $1M

36. Rabies CONTENTS • Disease Overview • Vaccine Landscape • Vaccination Policy & Strategies • Vaccine Need & Adoption Forecast • Vaccine Cost Analysis • Implementation-Associated Cost Analysis • Analysis Summary • Key Resources

37. Implementation Associated Cost Analysis typical IMPLEMENTATION CHALLENGES

38. Implementation Associated Cost Analysis UNIQUE IMPLEMENTATION CHALLENGES

39. Implementation Associated Cost Analysis POTENTIAL IMPLEMENTATION SYNERGIES Traditional = Routine EPI vaccines includes Baccillus Calmette-Guérin (BCG), Diphtheria-tetanus-pertussis (DTP) , measles containing vaccines (MCV), oral polio (OPV), Tetanus toxoid (TT) • Vaccine-Specific Synergies • No vaccine-specific synergies were identified • Other Synergies • No other synergies were identified

40. Implementation Associated Cost Analysis RELATIVE Cost Assessment

41. Implementation Associated Cost Analysis Quantitative Cost Assessment – PEP WHO GIVS Study: Wolfson LJ, Gasse F, et.al., WHO, Estimating the costs of achieving the WHO-UNICEF Global Immunization Vision and Strategy, 2006-2015, BLT (2008) 86(1)

42. Rabies CONTENTS • Disease Overview • Vaccine Landscape • Vaccination Policy & Strategies • Vaccine Need & Adoption Forecast • Vaccine Cost Analysis • Implementation-Associated Cost Analysis • Analysis Summary • Key Resources

43. Analysis Summary KEY METRIC SUMMARY

44. Rabies CONTENTS • Disease Overview • Vaccine Landscape • Vaccination Policy & Strategies • Vaccine Need & Adoption Forecast • Vaccine Cost Analysis • Implementation-Associated Cost Analysis • Analysis Summary • Key Resources

45. Key Resources EXPERT CONSULTATION • Vaccine Experts • Francois Meslin, Head of Zoonotic Disease, WHO • Deborah Briggs, Board of Directors, Alliance for Rabies Control • Sarah Cleaveland, Board of Directors, Alliance for Rabies Control • Charles Rupprecht, Chief of the CDC Rabies Program, CDC • Herve Bourhy, Director of the WHO Collaborating Center for Rabies, Institute Pasteur • Suppliers • Michael Attlan, Marketing Director, Sanofi • Shawn Gilchrist, Sanofi • Ferdinando Borgese, Global Brand Manager, Novartis Vaccine • John-Kenneth Billingsley, Executive Director, Novartis • Olga Popova, Director Government Affairs, Crucell

46. RABIES Appendix REFERENCES (I) • Plotkin et al, Vaccines, 5th Edition, Chap. 27, 2008. • Weekly Epi Record, No. 49/50, 2007, 82, 425-436, 7Dec07. • WHO, Disease Outbreak News, Rabies, www.who.int/csr/don/archive/disease/Rabies_disease/en/, Mar 2008. • WHO, Essential rabies maps, www.who.int/rabies/rabies_maps/en/index.html. • WHO, RabNet, “Human rabies, number of people bitten by suspected dogs per 100,000 population,” www.who.int/globalatlas/default.asp, Mar08 (data is incomplete or not reported). • WHO, RabNet, Human rabies deaths, www.who.int/globalatlas/default.asp, Mar08 [Mortality = Average of reported deaths between 2000-2007]. • UN Population Division, World Population Prospects: The 2006 revision population database, esa.un.org/unpp/index.asp?panel=2 [Mortality Rate = Mortality/(Population) x 1,000,000]. • Plotkin et al, Vaccines, 5th Edition, Chap. 27, 2008.

47. RABIES Appendix REFERENCES (II) WHO Prequalified Vaccines, www.who.int/immunization_standards/vaccine_quality/pq_suppliers/en/index.html. RabAvert Package Insert, www.novartis-vaccines.com/products/Rabavert_PI_0404.pdf; www.novartisvaccines.com/products/travel.shtml. Imovax Product Insert, www.vaccineshoppe.com/image.cfm?doc_id=5983&image_type=product_pdf. Travel Med Infect Dis. 2007 Nov;5(6):327-48. Epub 2007 Sep 17; www.ncbi.nlm.nih.gov/pubmed/17983973. Berna Biotech recently transferred to Cadila Health Ltd, an Indian manufacturer; Zyddus Cadila is currently seeking WHO prequalification according to Partners for Rabies Prevention Informal Group; RIG = rabies immunoglobulin; TRC Verorab (Thai Red Cross) Plotkin et al, Vaccines, 5th Edition, Chap. 27, 2008. Correspondence with WHO and Partners for Rabies Prevention Informal Group (PRP), June-August 2008.

48. RABIES Appendix REFERENCES (III) WHO, Weekly Epidemiology Record, No. 49/50, 2007, 82, 425-436, 7Dec07. LeGuerrier P, et al, Pre-exposure rabies prophylaxis for the international traveler: a decision analysis; Vaccine, 14(2):167-176, 1996. Chulasugandha P, et al, Cost comparison of rabies pre-exposure vaccination with post-exposure treatment in Thai children, Vaccine, 24(9): 1478-1482, 2006.