GAVI Vaccine Investment Strategy

1
GAVI Vaccine Investment Strategy

• Cholera Analysis

Final October 27, 2008
2
Cholera
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
POPULATION1

• Cholera is an acute diarrheal infection caused by
  ingestion of the bacterium Vibrio cholerae
  
• There are two serogroups of V. cholerae that can
  cause epidemic cholera, O1 and O139
  
• Immunity to serogroup O1 Vibrio does not confer
  immunity to serogroup O139
  
• Transmission
• Mainly by the fecal-oral route, through
  contaminated food and water
  
• Geographic Distribution
• Serogroup O1 is found worldwide
• Serogroup O139 seems to be isolated to Asia for
  the time being (responsible for the 1992 cholera
  epidemic in Asia)
  
• Disease Target Population
• Cholera cases occur in children and adults
  people of low socioeconomic status are at greater
  risk due to low access to clean water and
  sanitation
• People with blood type O are more susceptible to
  the severe form of the cholera infection, while
  those with blood type AB are the most resistant

4
Disease Overview
DISEASE IMPACT2

• Total Morbidity
• Cholera cases are under reported because of poor
  surveillance (WHO estimates that only 5-10 of
  the worldwide cases get officially reported), but
  its likely to exceed 1M cases annually, mostly
  from Africa and Asia
• Total Mortality
• Globally an estimated 120,000 deaths from cholera
  occur each year, with most of the cholera deaths
  occurring in Asia and Africa
  
• Epidemic Potential
• Large Epidemics
• Disease Sequelae
• Among people developing symptoms, 80 of episodes
  are of mild or moderate severity, however, severe
  cholera is characterized by acute diarrhea and
  vomiting which can lead rapidly to dehydration
  and death
• Within 3-4 hours of the onset of symptoms, a
  previously healthy person may become hypotensive
  and may die within 6-8 hours

5
Disease Overview
DISEASE BURDEN GEOGRAPHIC DISTRIBUTION2
6
Disease Overview
DISEASE BURDEN IN GAVI-ELIGIBLE COUNTRIES
MORBIDITY
4
GAVI Vaccine Investment Strategy
Vaccine Landscape Analysis_Cholera_Apr08
Refer to Appendix for reference data
7
Disease Overview
DISEASE BURDEN IN GAVI-ELIGIBLE COUNTRIES
MORTALITY
4
GAVI Vaccine Investment Strategy
Vaccine Landscape Analysis_Cholera_Apr08
Mortality Morbidity x Average Case Fatality
Rate of 2.78
8
Disease Overview
NON-VACCINE PREVENTION TREATMENT
INTERVENTIONS1,10

• Non-Vaccine Preventions
• Improve sanitation
• Hygiene promotion / Health Education
• Water chlorination
• Treatment Interventions
• WHO recommends using antibiotics only with signs
  of severe dehydration
  
• Tetracycline is typically used as the primary
  antibiotic (other antibiotics include
  doxycycline, cotrimoxazole, erythromycin,
  chloramphenicol, ciprofloxacin)
• Some strains have shown resistance to
  tetracycline
  
• Water electrolyte replacement (Oral Rehydration
  Salts)
  

9
Disease Overview
INEQUITIES2,11,12

• Inequity of Poor
• Africa alone accounts for 99 (2006 estimate) of
  total global cholera cases lack of access to
  better sanitation and clean water supply in the
  developing countries makes them more susceptible
  to cholera epidemics
• Gender Inequity

10
Cholera
CONTENTS

• Disease Overview
• Vaccine Landscape
• Vaccination Policy Strategies
• Vaccine Need Adoption Forecast
• Vaccine Cost Analysis
• Implementation-Associated Cost Analysis
• Analysis Summary
• Key Resources

11
Vaccine Landscape
LICENSED VACCINES13
Assumes Viet Nam NRA gets recognized by WHO and
Vabiotech is up to cGMP standards
12
Vaccine Landscape
VACCINES IN CLINICAL DEVELOPMENT
13
Vaccine Landscape
ESTIMATED VACCINE AVAILABILITY

• Timing assumes WHO Priority Review is granted
  based on
  
• Enteric Infectious Diseases Committee
  recommendation in 1Q09
  
• SAGE recommendation in Apr09
• WHO recommendation in 3Q09

Dukoral (Crucell/SBL Vaccin AB) Reform
ulated Bivalent Vaccine (Shantha Biotechnics/IVI)
CholeraGarde (Avant Immunotherapeutics/IVI)
ORC-Vax (VABIOTECH) Vibrio cholerae 63
8 (Cuba)
2016
Prior to 2009
2013
2012
2011
2010
2009
14
Vaccine Landscape
COST EFFECTIVENESS LITERATURE SUMMARY

• No long-term sequelae associated with cholera23
• In industrialized countries, a typical dose of
  Dukoral can cost 49 for just the vaccine alone
  (100/Tx _at_ 2 doses)24
  
• A mass vaccination campaign in Aceh, Indonesia
  (MarchAugust 2005) with 69.3 coverage of the
  78,870 people initially targeted, and
  administering two doses of whole-cell killed
  vaccine, the direct costs of the campaign reached
  958,649, or 18 per fully immunized person23
• IVIs preliminary data on the cost-effectiveness
  of the Vietnamese vaccine, ORC-Vax, showed that
  the cost per DALY averted was persons in Bangladesh, India, and E. Africa, and
  much less than 1,000 for children 1-14 yrs
  (Unpublished data personal communication A.L.
  Lopez, IVI)

15
Cholera
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 Decision Framework
Vaccination Strategies for Financial Planning
Purposes
Periodic Campaign Strategy
Vaccine
Doses
Cohort
1 15yo every 3 years
WC-rCTB 2 5 15yo WC-Only 2 1 15
yo WC-rCTB 2 5 49yo WC-Only 2
1 49yo
Offer Vaccine Financing to GAVI-Eligible Countrie
s
1 49yo every 3 years
Wait for SAGE (Apr09) or WHO Position Paper then
Decide Vaccine Financing
Dont Support in 2009 - 2013
WC-rCTB Dukoral WC-Only Reformulated bival
ent
18
Cholera
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 32 VISP Scope 31

• Assumed to be endemic if the estimated country
  morbidity is 25,000 or morbidity rate is 100
  cases/100,000 annually (International Vaccine
  Institute, Jul08)

No consensus on definition of endemicity
within global community Adopted in 1997 with
locally produced vaccine will not seek GAVI
financing support
BLUE adopted
Source IVI Cholera Team
20
Vaccine Need Adoption Forecast
INTEGRATED ADOPTION FORECAST
Vaccine Need 32 VISP Scope 31
Angola Gambia Ghana Uganda Zambia
Bangladesh Indonesia Mozambique Myanmar
Burkina Faso Congo, DR Ethiopia Guinea
Liberia Malawi Nepal Togo
CAR Chad Niger Nigeria
Burundi Djibouti Pakistan Somalia
Cambodia India Tanzania
Sao Tome
Sudan
Sierra Leone
Viet Nam adopted in 1997 with locally produced
vaccine
21
Vaccine Need Adoption Forecast
VACCINE DEMAND GIVEN INTEGRATED ADOPTION FORECAST
1 15yo
22
Vaccine Need Adoption Forecast
VACCINE DEMAND GIVEN INTEGRATED ADOPTION FORECAST
1 49yo
23
Cholera
CONTENTS

• Disease Overview
• Vaccine Landscape
• Vaccination Policy Strategies
• Vaccine Need Adoption Forecast
• Vaccine Cost Analysis
• Implementation-Associated Cost Analysis
• Analysis Summary
• Key Resources

24
Vaccine Cost Analysis
ANALYSIS INPUT SUMMARY GENERAL
25
Vaccine Cost Analysis
ANALYSIS INPUT SUMMARY STRATEGY-SPECIFIC
Used market share weighted average to assess
analysis based deaths dases averted
26
Cholera
CONTENTS

• Disease Overview
• Vaccine Landscape
• Vaccination Policy Strategies
• Vaccine Need Adoption Forecast
• Vaccine Cost Analysis
• Periodic Campaigns with revaccination every 3
  years (1-15yo)
  
• Periodic Campaigns with revaccination every 3
  years (1-49yo)
  
• Stockpile
• Implementation-Associated Cost Analysis
• Analysis Summary
• Key Resources

27
Periodic Campaigns (1 15yo)
KEY OUTPUT SUMMARY Integrated Demand Forecast
2009-2020
28
Periodic Campaigns (1 15yo)
ANNUAL ANALYSIS RESULTS Integrated Demand
Forecast
2009-2020
29
Cholera
CONTENTS

• Disease Overview
• Vaccine Landscape
• Vaccination Policy Strategies
• Vaccine Need Adoption Forecast
• Vaccine Cost Analysis
• Periodic Campaigns with revaccination every 3
  years (1-15yo)
  
• Periodic Campaigns with revaccination every 3
  years (1-49yo)
  
• Stockpile
• Implementation-Associated Cost Analysis
• Analysis Summary
• Key Resources

30
Periodic Campaigns (1 49yo)
KEY OUTPUT SUMMARY Integrated Demand Forecast
2009-2020
31
Periodic Campaigns (1 49yo)
ANNUAL ANALYSIS RESULTS Integrated Demand
Forecast
2009-2020
32
Cholera
CONTENTS

• Disease Overview
• Vaccine Landscape
• Vaccination Policy Strategies
• Vaccine Need Adoption Forecast
• Vaccine Cost Analysis
• Periodic Campaigns with revaccination every 3
  years (1-15yo)
  
• Periodic Campaigns with revaccination every 3
  years (1-49yo)
  
• Stockpile
• Implementation-Associated Cost Analysis
• Analysis Summary
• Key Resources

33
Stockpile
KEY OUTPUT SUMMARY Integrated Demand Forecast
2009-2020
34
Stockpile
ANNUAL ANALYSIS RESULTS Integrated Demand
Forecast
2009-2020
35
Cholera
CONTENTS

• Disease Overview
• Vaccine Landscape
• Vaccination Policy Strategies
• Vaccine Need Adoption Forecast
• Vaccine Cost Analysis
• Implementation-Associated Cost Analysis
• Analysis Summary
• Key Resources

36
Implementation-Associated Cost Analysis
TYPICAL IMPLEMENTATION CHALLENGES
37
Implementation-Associated Cost Analysis
UNIQUE IMPLEMENTATION CHALLENGES
38
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
• Potential to enhance diarrheal monitoring and
  surveillance (rotavirus)
  
• Potential to leverage other school-based
  vaccination campaigns (HPV, typhoid)
  
• Other Synergies
• Enhances awareness of need for health education
  and clean water sanitation initiatives
  
• Potential to motivate the creation or expansion
  of adolescent health programs
  
• Potential to integrate with reproductive and
  maternal health programs
  
• Potential to integrate with gender-based
  initiatives

39
Implementation-Associated Cost Analysis
RELATIVE COST ASSESSMENT
40
Implementation-Associated Cost Analysis
QUANTITATIVE COST ASSESSMENT PERIODIC CAMPAIGN
(1-15yo)
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)
41
Implementation-Associated Cost Analysis
QUANTITATIVE COST ASSESSMENT PERIODIC CAMPAIGN
(1-49yo)
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
Cholera
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
Cholera
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

• Product Development Program (IVI)
• A. Lena Lopez, Cholera Coordinator
• Michael Favorov, Director of VIVA Program
• John Clemens, Director General of IVI
• Suppliers
• Olga Popova, Director Government Affairs,
  Crucell
  
• Varaprasad Reddy, Managing Director, Shantha
• Independent Experts
• Jan Holmgren, Göteborg University, Sweden
• Duncan Steele, PATH Rotavirus Vaccine Program
  (ex-WHO)
  
• Bernard Ivanoff, Independent consultant (ex-WHO)
• Myron Levine, University of Maryland
• Heikki Peltola, Independent consultant

46
Appendix
REFERENCES (I)

• Plotkin, S, Orenstein, W, Offit, P. Vaccines,
  5th edition, Chapter 9, 2008
  
• WHO Weekly epidemiological record,
  76(16)117-124, 2001 (WHO position paper)
  82(31) 273284, 2007
  
• 3. WHO estimates that the officially reported
  cases represent around 5-10 of actual cases
  worldwide (http//www.who.int/topics/cholera/surve
  illance/en/index.html) 7.5 (average of 5 and
  10) was used as the adjusting factor to
  determine our estimated Morbidity (number of new
  cases of cholera in a given year) from the
  Officially Notified Morbidity (Morbidity
  Officially Notified Morbidity / 0.075)
• http//web.gideononline.com (EBM Evidence Based
  Medicine database, sources from WHO, PubMED,
  ProMED, etc)
  
• WHO, Weekly epidemiological record, No. 31, 2007,
  82, 273284
  
• WHO, Weekly epidemiological record, No. 31, 2006,
  81, 297308
  
• Morbidity Rate Morbidity / (Total Population)
  x 100,000 where Total Population sourced from
  (UN Population Division, World Population
  Prospects The 2006 revision population
  database, http//esa.un.org/unpp/index.asp?panel2
  , 2005 Total Population)
• In 2006, 52 countries officially reported a total
  of 236,896 cholera cases including 6,311 deaths
  with a CFR of 2.7 to the WHO (Deen et al., PLoS
  Negl Trop Dis 2e173, 2008) our Mortality is
  based on this CFR (Mortality Morbidity x
  0.027)
• Mortality Rate Mortality / (Total Population)
  x 1,000,000

47
Appendix
REFERENCES (II)
48
Appendix
REFERENCES (III)
49
Appendix
REFERENCES (IV)

• http//sprojects.mmi.mcgill.ca/tropmed/disease/cho
  l/treatment.htm
  
• Dhiman Barua, William B. Greenough. Cholera, 1st
  edition, p. 221, 1992
  
• Deen et al., PLoS Negl Trop Dis 2(2)e173, 2008
• Other live oral vaccines against O139 cholera
  (e.g. Bengal 15 and CVD 112) were being developed
  in the 1990's, but due to their reactogenic
  nature, it is not clear whether research on these
  vaccines are still on-going
• http//www.medbroadcast.com/drug_info_details.asp?
  brand_name_id1819 (WC-rBSwhole cell
  recombinant cholera toxin B subunit CTBcholera
  toxin B subunit Dukoral comes with a sachet
  containing buffer salts (sodium hydrogen
  carbonate, citric acid, sodium carbonate,
  saccharin, sodium citrate) to protect CTB from
  the stomach acid recent study seem to indicate
  that 2 doses for children might be sufficient to
  induce protection
• Coverage rate estimate based on coverage rate
  studies done in Viet Nam and Indonesia in the
  Aceh and Beira campaign, adults and children were
  included (http//www.searo.who.int/en/Section1257/
  Section2263/info-kit/who-cholera_vaccine.pdf
  http//www.who.int/topics/cholera/publications/fin
  al_tsunami.pdf)
• http//www.who.int/cholera/tsunami_choleravaccine/
  en/index3.html

50
Appendix
REFERENCES (V)

• Orochol comes in a double-chambered aluminum
  sachet with one chamber containing the bacterial
  lyophilate (plus sucrose, lactose, aspartame,
  ascorbic acid, casein hydrolysate) and the other
  chamber containing a neutralized sodium
  bicarbonate buffer (sodium bicarbonate, ascorbic
  acid, lactose )
• In the only randomized control trial in an
  endemic populations (Indonesia), of the 109
  preparation of Orochol, vaccine showed only 14
  efficacy retrospective analysis in Pohnpei using
  the same vaccine preparation estimated a 79
  crude vaccine efficacy, thus the true efficacy of
  this vaccine still remains to be determined
  (Personal communication with IVI Richie et al.,
  Vaccine 182399-410, 2000)
• The only vaccine in market that protects against
  both serogroups O1 O139 -- production not yet
  complies with GMP Reformulated version that
  complies with GMP being developed (Personal
  communication with A.L. Lopez, IVI Anh et al.,
  Vaccine 251149-55, 2007 http//www.who.int/topic
  s/cholera/vaccines/current/en/index.html)
• Thiem et al., Vaccine 244297-303, 2006 (Long
  term effectiveness study)
  
• Garcia et al, Infection and Immunity
  73(5)301824, 2005 (CTXPhi and hapA deleations
  leads to atoxigenic and hemagglutinin devoid
  strains)
• Oral Cholera Vaccine use in Complex Emergencies
  What Next?" WHO Meeting, 1416 Dec 2005, Cairo,
  Egypt

51
Appendix
REFERENCES (VI)

• http//www.clinicaltrials.gov/ct2/show/NCT00624975
  ?termcholeravaccinerank8 http//www.avantimm
  une.com/products/cholera.html Aimed that the
  vaccine may be given together with other vaccines
  in the EPI (Personal communication with IVI)
• http//www.saverxcanada.com/drugs/Dukoral/suspensi
  on/vaccine