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					GAVI Vaccine Investment Strategy
Human Papillomavirus Analysis




                                               Final
                                   October 27, 2008
                                               HPV




Human Papillomavirus (HPV)
CONTENTS


   • Disease Overview

   • Vaccine Landscape

   • Vaccination Policy & Strategies

   • Vaccine Need & Adoption Forecast

   • Vaccine Cost Analysis

   • Implementation-Associated Cost Analysis

   • Analysis Summary

   • Key Resources

                                  2
                                                                                                                      HPV




Disease Overview
DISEASE PATHOGEN, TRANSMISSION & TARGET POPULATION1-3
  •   Human Papillomavirus (HPV) infection is responsible for >95% of cervical cancers
      worldwide
      –   Anal, vulvar/penile, and head & neck cancers are also associated with HPV infection
      –   > 100 HPV strains are known
          •   HPV-16 & -18 infections can lead to cervical cancer and high-grade cervical intraepithelial neoplasia
          •   HPV-6 and -11 are mainly associated with genital warts

  •   Transmission
      –   Infection is spread through sexual contact

  •   Geographic Distribution
      –   Both HPV-16 & -18 linked cervical cancer have been reported worldwide and account for
          ~70% of the cases (~52% for high-grade cervical intraepithelial neoplasia)
      –   HPV-6 & -11 are rarely associated with cancer, but cause >90% of genital warts
      –   Regional HPV strain variance exists with HPV-45 & -33 also found in Africa, -45 & -52 in S.
          Asia, and -45 & -31 in the Americas and Europe

  •   Disease Target Population
      –   Peak of HPV infection coincides with the onset of sexual activity in girls and young women

                                                           3
                                                                                                           HPV




Disease Overview
DISEASE IMPACT4-6
  •   Total Morbidity
      –   ~500,000 women are diagnosed with cervical cancer each year, about 80% of which are in
          the developing countries

  •   Total Mortality
      –   Over half of the women diagnosed with cervical cancer die from the disease (~260,000), and
          85% of those deaths occur in the developing world where cancer screening is uncommon

  •   Epidemic Potential
      –   Endemic disease

  •   Disease Sequelae
      –   Girls and young women are generally infected with HPV when they become sexually active,
          but it can take 20 years or longer for infections to progress to cervical cancer
      –   ~5% to 10% of women infected with oncogenic HPV ultimately develop persistent infections
          that can lead to precancerous lesions that can develop into cervical cancer
      –   In the industrialized countries, the five-year survival rate is ~70%, it‟s expected to be much
          lower in the developing countries
      –   Anal cancer is of growing concern, especially among men who have sex with men, because
          HIV infection increases susceptibility to HPV-related diseases of all kinds
                                                    4
                                                                                                                     HPV




Disease Overview
DISEASE BURDEN – GEOGRAPHIC DISTRIBUTION7
     Worldwide incidence of cervical cancer/100,000 females, age-standardized to the WHO standard population, 2005




                                                           5
                                                                                                                                                      HPV


                                                                                                                   0       =     None Reported
                                                                                                                           =     Data Not Available

Disease Overview                                                                                                                 or Non-Endemic


DISEASE BURDEN IN GAVI-ELIGIBLE COUNTRIES – MORBIDITY
                          WHO           Morbidity         Morbidity Rate                                   WHO            Morbidity         Morbidity Rate
       Country                                                                          Country
                         Region      (Annual Cases)8,9   (Cases/100,000)10                                Region       (Annual Cases)8,9   (Cases/100,000)10
Haiti                     AMRO            2,774                 65             Guinea-Bissau               AFRO              124                  19
Lesotho                   AFRO             479                  46             Korea, DPR                 SEARO             2,150                 19
Bolivia                   AMRO            1,831                 42             Central African Republic    AFRO              374                  19
Guyana                    AMRO             160                  41             Ukraine                    EURO              4,885                 19
Tanzania, United Rep. of  AFRO            7,515                 41             Bangladesh                 SEARO            12,931                 19
Guinea                    AFRO            1,444                 35             Nepal                      SEARO             2,185                 19
Djibouti                  EMRO             113                  33             Bhutan                     SEARO              200                  19
Zambia                    AFRO            1,650                 31             Congo, Rep.                 AFRO              303                  19
Nicaragua                 AMRO             809                  30             Côte d'Ivoire               AFRO             1,497                 18
Malawi                    AFRO            1,766                 30             Sierra Leone                AFRO              452                  18
Zimbabwe                  AFRO            1,817                 28             Mauritania                  AFRO              259                  18
Eritrea                   AFRO             548                  27             Togo                        AFRO              435                  18
Rwanda                    AFRO            1,087                 27             Benin                       AFRO              561                  17
Papua New Guinea         WPRO              637                  27             Nigeria                     AFRO             9,922                 17
Madagascar                AFRO            2,238                 26             Kenya                       AFRO             2,635                 17
India                    SEARO           132,082                26             Angola                      AFRO             1,158                 16
Comoros                   AFRO              97                  26             Sri Lanka                  SEARO             1,544                 16
Burundi                   AFRO             899                  26             Senegal                     AFRO              804                  16
Cambodia                 WPRO             1,768                 25             Chad                        AFRO              681                  16
Solomon Islands          WPRO               58                  25             Viet Nam                   WPRO              6,224                 16
Cuba                      AMRO            1,346                 24             Burkina Faso                AFRO              921                  15
Somalia                   EMRO            1,134                 24             Indonesia                  SEARO            15,050                 14
Ethiopia                  AFRO            7,619                 23             Congo, Dem. Rep.            AFRO             3,709                 14
Gambia, The               AFRO             157                  23             Mongolia                   WPRO               171                  13
Cameroon                  AFRO            1,759                 23             Niger                       AFRO              679                  12
Mali                      AFRO            1,336                 22             Lao People's Dem. Rep.     WPRO               317                  12
Mozambique                AFRO            2,058                 22             Sudan                      EMRO              1,664                 10
Georgia                   EURO             580                  21             Uzbekistan                 EURO              1,149                  9
Moldova, Rep. of          EURO             476                  21             Azerbaijan                 EURO               345                   8
Kyrgyzstan                EURO             522                  20             Tajikistan                 EURO               232                   8
Myanmar                  SEARO            5,017                 20             Afghanistan                EMRO               511                   5
Liberia                   AFRO             320                  20             Pakistan                   EMRO              2,962                  4
Honduras                  AMRO             664                  20           4 Yemen                      EMRO               370                   4
Armenia                   EURO             380                  20             Kiribati                   WPRO
Uganda GAVI Vaccine Investment Strategy 2,429
                          AFRO                                  20           6 Timor-Leste                SEARO
Ghana Vaccine Landscape Analysis_Cholera_Apr08
                          AFRO            1,958                 19             São Tomé and Principe       AFRO
                                                                                                                                                          HPV


                                                                                                                                   None Reported
                                                                                                                      0       =
                                                                                                                                   Data Not Available
                                                                                                                              =
  Disease Overview                                                                                                                 or Non-Endemic


  DISEASE BURDEN IN GAVI-ELIGIBLE COUNTRIES – MORTALITY
                              WHO            Mortality          Mortality Rate                                WHO             Mortality          Mortality Rate
       Country                                                                                Country
                             Region      (Annual Deaths)8,11 (Deaths/1,000,000)12                            Region       (Annual Deaths)8,11 (Deaths/1,000,000)12
Lesotho                       AFRO              391                  376            Benin                     AFRO               448                  133
Haiti                        AMRO              1,484                 346            Angola                    AFRO               926                  132
Tanzania, United Rep. of      AFRO             6,009                 325            Kenya                     AFRO              2,111                 132
Guinea                        AFRO             1,138                 273            Nicaragua                AMRO                354                  132
Djibouti                     EMRO                90                  268            Chad                      AFRO               555                  131
Zambia                        AFRO             1,340                 248            Senegal                   AFRO               640                  129
Malawi                        AFRO             1,405                 237            Burkina Faso              AFRO               724                  115
Zimbabwe                      AFRO             1,492                 229            Congo, Dem. Rep.          AFRO              3,058                 111
Bolivia                      AMRO               987                  226            Honduras                 AMRO                361                  108
Eritrea                       AFRO              438                  219            Myanmar                  SEARO              2,594                 106
Rwanda                        AFRO              878                  219            Cuba                     AMRO                567                  101
Madagascar                    AFRO             1,795                 211            Moldova, Rep. of         EURO                220                   99
Burundi                       AFRO              722                  209            Ukraine                  EURO               2,578                  99
Comoros                       AFRO               79                  209            Bhutan                   SEARO               105                   96
Somalia                      EMRO               906                  185            Nepal                    SEARO              1,129                  96
Ethiopia                      AFRO             6,081                 183            Bangladesh               SEARO              6,561                  94
Cameroon                      AFRO             1,419                 182            Niger                     AFRO               532                   92
Guyana                       AMRO                71                  182            Sri Lanka                SEARO               840                   89
Gambia, The                   AFRO              124                  179            Sudan                    EMRO               1,354                  84
Mali                          AFRO             1,076                 178            Georgia                  EURO                225                   83
Mozambique                    AFRO             1,654                 173            Viet Nam                 WPRO               3,334                  83
Liberia                       AFRO              256                  159            Kyrgyzstan               EURO                186                   73
Guinea-Bissau                 AFRO               99                  157            Mongolia                 WPRO                 92                   71
Central African Republic      AFRO              306                  155            Indonesia                SEARO              7,566                  70
Ghana                         AFRO             1,572                 155            Armenia                  EURO                130                   67
Uganda                        AFRO             1,932                 155            Lao People's Dem. Rep.   WPRO                159                   57
Congo, Rep.                   AFRO              242                  148            Korea, DPR               SEARO               558                   50
Sierra Leone                  AFRO              362                  148            Uzbekistan               EURO                379                   29
Côte d'Ivoire                 AFRO             1,192                 147            Azerbaijan               EURO                113                   28
India                        SEARO            74,118                 147            Tajikistan               EURO                 70                   23
Mauritania                    AFRO              209                  146            Afghanistan              EMRO                254                   22
Togo                          AFRO              349                  146            Pakistan                 EMRO               1,605                  22
Papua New Guinea             WPRO               341                  142          4 Yemen                    EMRO                206                   21
Cambodia                     WPRO               949                  135            São Tomé and Principe     AFRO
Nigeria     GAVI Vaccine Investment Strategy 8,030
                              AFRO                                   135          7 Kiribati                 WPRO
            Vaccine
Solomon Islands Landscape Analysis_Cholera_Apr08
                             WPRO                31                  135            Timor-Leste              SEARO
                                                                                                                HPV




Disease Overview
NON-VACCINE PREVENTION & TREATMENT INTERVENTIONS13-15

  •   Non-Vaccine Preventions
      –   Condoms
      –   Early detection/Screening/and Pre-cancer treatment
      –   Supplements
          •   Studies indicate that some supplements and higher levels of fruit and vegetable consumption may
              decrease the risk of HPV persistence (e.g. vitamin C, E, and carotenoids)


  •   Treatment Interventions
      –   Currently, no drug treatment for HPV infection; potential drugs are currently in development
      –   Following options are available for treating invasive cancer:
          •   Surgery
          •   Radiation Therapy
          •   Chemotherapy




                                                         8
                                                                                                               HPV




Disease Overview
INEQUITIES16

  •   Inequity of Poor



  •   Gender Inequity




          Gender Based Criteria           Applies                          Rationale

                                                    • Primary disease burden in women where >90% of cervical
       Do men or women suffer from
          the disease differently?
                                            √         cancer is caused by HPV infection
                                                    • Men tend to be more susceptible to genital warts
        Is disease prevalence greater
              in men or women?
                                            √       • Yes, primary disease burden in women

      Does the disease adversely affect
        women during pregnancy?
                                             -                            Not applicable




                                                     9
                                               HPV




HPV
CONTENTS


   • Disease Overview

   • Vaccine Landscape

   • Vaccination Policy & Strategies

   • Vaccine Need & Adoption Forecast

   • Vaccine Cost Analysis

   • Implementation-Associated Cost Analysis

   • Analysis Summary

   • Key Resources

                                  10
                                                                                                                   HPV




Vaccine Landscape
LICENSED VACCINES17
       Supplier (1° Partner)                     Merck18-21                               GSK21-23

             Vaccine                              Gardasil                                Cervarix

                                    HPV-6/L1                      HPV-16/L1              HPV-16/L1
          Strain / Antigen
                                    HPV-11/L1                     HPV-18/L1              HPV-18/L1

        Adjuvant / Platform         Amorphous Al(OH)(PO4) sulfate / VLP         AS04 (MPL, Al(OH)3) / VLP

       Administration Route                          IM                                      IM

           Formulation                             Liquid                                  Liquid

           Presentation               5 dose vials & pre-filled syringes      2 dose vials & pre-filled syringes

         Dosing Schedule                          0, 2, 6mo                               0, 1, 6mo

  Target Population for Licensure             Females ≥ 9 yo                          Females ≥ 10 yo

              Safety                     No major safety concerns                No major safety concerns

             Efficacy                 100% against HPV-6, 11, 16 & 18           100% against HPV-16 & 18

  Expected Duration of Protection          At least 5 yrs, to date                At least 6.4 yrs, to date

                                                Jun06 (US)                              Sep07 (EU)
     Licensure Date (Location)
                                                Sep06 (EU)                              ~2009 (US)

     Estimated WHO PQ Date              4Q08 (submitted in May 07)              1Q09 (submitted in Sept 07)




                                                             11
                                                                                            HPV




Vaccine Landscape
VACCINES IN CLINICAL DEVELOPMENT17

             Supplier (1° Partner)                    YST Biotech/China24,25
                   Vaccine                                 HPV-16 & -18
                                                             HPV-16/L1
                Strain / Antigen
                                                             HPV-18/L1
              Adjuvant / Platform                          Al(OH)3 / VLP
             Administration Route                                IM
                 Formulation                                   Liquid
                 Presentation                                   TBD
               Dosing Schedule                                  TBD
        Target Population for Licensure                   > 10yo females
                    Safety                                      TBD
                   Efficacy                                     TBD
        Expected Duration of Protection      At least 5 yrs, but likely to be much longer
             Stage of Development                              Ph 1/2
                                                                2016
           Estimated Licensure Date
                                                               (China)
      Estimated WHO Prequalification Date                       2017


                                            12
                                                                                           HPV


                                                                     First NRA Licensure


 Vaccine Landscape                                               WHO Pre-Qual Approval



 ESTIMATED VACCINE AVAILABILITY




Gardasil (Merck)



Cervarix (GSK)




HPV-16 & -18 (YST Biotech)
                                                                                            ~2016
or                                                                                           (NRA)
                                                                                            ~2017
                                                                                           (WHO PQ)
Another Emerging Supplier



                             Prior to
                             2009       2009    2010   2011   2012          2013
                                               13
                                                                                            HPV




Vaccine Landscape Analysis
COST EFFECTIVENESS LITERATURE SUMMARY

•   The average of projected DALYs for cervical cancer (for yrs 2005: 2,102,262 yrs lost; 2015:
    2,677,213 yrs lost; and 2030: 3,664,099 yrs lost), under the baseline scenario, is estimated
    to be ~ 2,814,525 yrs lost annually in the developing countries26

•   In Kenya, an estimated range of $8-$25 per vaccinated girl (including delivery and
    administration) was assessed, which would cost an additional 1%-3% of all public spending
    on health - a sizable amount, considering competing priorities and the small margins that
    countries have for reallocation in the short term from their own resources27

•   Using primary and published data from Brazil, a cost-effectiveness analysis was conducted
    in which the cost per vaccinated woman (inclusive of three doses of vaccine, wastage, and
    programmatic costs of delivery) was assumed to be $25, $50, or $755,28




                                               14
                                               HPV




HPV
CONTENTS


   • Disease Overview

   • Vaccine Landscape

   • Vaccination Policy & Strategies

   • Vaccine Need & Adoption Forecast

   • Vaccine Cost Analysis

   • Implementation-Associated Cost Analysis

   • Analysis Summary

   • Key Resources

                                15
                                                                                                                                                        HPV




Vaccination Policy & Strategies
CURRENT POLICY

    Policy Type
                              Category                                                     Policy Statement
      Source

  WHO Technical                               • If a two-dose schedule could be used, or if HPV vaccines could be given at an earlier age with other
                           Usage strategies
   Information                                  vaccines (e.g. at school entry or even in infancy), vaccine delivery could be greatly facilitated.
• HPV vaccines:                               • HPV vaccines will reduce, but not eliminate, the risk of cervical cancer. Screening programs will still be
  technical information
  for policy-makers and
                             Programmatic       needed to prevent cervical cancer, even after HPV vaccines are introduced, although the procedures
  health professionals,    recommendations      used for screening may need to be adapted.
  WHO 2007                                    • Innovative methods will be needed to finance the introduction of HPV vaccines.
                                              • SAGE noted that HPV infection is now designated a “necessary” cause of cervical cancer.
                               Vaccine
                                              • Two candidate HPV vaccines that protect against the most common cancer-causing HPV types (HPV 16
                            considerations
                                                and 18) appear to be safe and effective.
                                              • SAGE concluded from clinical trial evidence that introduction of vaccines is likely to bring great benefits
    SAGE                                        worldwide and particularly to those developing countries where cervical cancer is a major cause of
Recommendation                                  mortality and screening programs are limited or absent.
                                              • The impact of the availability of vaccination on screening programs for cervical cancer will require
• Weekly Epi. Record,
                                                careful evaluation.
  No. 1, 2006, 81: 1-12
                                              • Vaccine introduction should be coordinated with school health programs and provide opportunities to
• Weekly Epi. Record,        Programmatic
  No. 21, 2007, 82: 181-                        educate young people about pregnancy and prevention of sexually-transmitted infections including HIV.
                           recommendations
  196                                         • SAGE stressed that strong political commitment would be required for the introduction of these
                                                vaccines, given the financial implications even if tiered prices become available to facilitate vaccine
                                                introduction into developing countries.
                                              • SAGE noted that the current high price of vaccines is a major barrier to their introduction. WHO should
                                                monitor vaccine candidates suitable for manufacture in developing countries and simplified schedules
                                                that could increase future vaccine uptake


                                                                                     •   Updated SAGE recommendation expected in Nov08
                                                                            16
                                                                                     •   WHO recommendation expected in 1Q09
                                                                           HPV




Vaccination Policy & Strategies
VISP DECISION FRAMEWORK


                                              Vaccination Strategies for
                   GAVI VIS
                                             Financial Planning Purposes
              Decision Framework




            Offer Vaccine Financing                Routine Vx of
           to GAVI-Eligible Countries              ~10yo females




                Do Not Support
                 in 2009 - 2013




                                        17
                                               HPV




HPV
CONTENTS


   • Vaccination Policy & Strategies

   • Disease Overview

   • Vaccine Landscape

   • Vaccine Need & Adoption Forecast

   • Vaccine Cost Analysis

   • Implementation-Associated Cost Analysis

   • Analysis Summary

   • Key Resources

                                  18
                                                                                                                                           HPV




Vaccine Need & Adoption Forecast
GAVI-ELIGIBLE COUNTRY VACCINE NEED                                                                                            Vaccine Need: 72
                                                                                                                                VISP Scope: 60

  • Cervical cancer is the most common cancer affecting women in developing countries, 5
    12 countries not expected to adopt by 2020 (PATH HPV Team)

                                                            GAVI-Eligible Country Vaccine Need
  Category
(# out of 72)                      AFRO                            AMRO           EMRO             EURO            SEARO            WPRO
                                 (34 of 36)                        (6 of 6)       (6 of 6)        (8 of 8)         (9 of 9)         (6 of 7)
                                                                                                  Armenia
                                                                   Bolivia
Least Poor                                                                                       Azerbaijan       Indonesia
                 Cameroon                                          Guyana         Djibouti                                          Kiribati
 (10 of 12)                                                                                       Georgia         Sri Lanka
                                                                  Honduras
                                                                                                  Ukraine
                                                                                                 Kyrgyzstan
                                                                                                                                   Mongolia
Intermediate       Ghana                                            Cuba                          Moldova            India
                                 Zimbabwe                                        Pakistan                                            PNG
  (12 of 16)       Kenya                                          Nicaragua                      Tajikistan       Korea DPR
                                                                                                                                   Viet Nam
                                                                                                 Uzbekistan
                   Benin          Lesotho
                Burkina Faso    Madagascar        Senegal
                   Chad           Malawi        Sierra Leone                                                     Bangladesh        Cambodia
  Poorest        Comoros            Mali          Tanzania                                                         Bhutan             Lao
                                                                                  Yemen
 (29 of 31)       Ethiopia       Mauritania         Togo                                                          Myanmar          Solomon
                  Gambia        Mozambique        Uganda                                                           Nepal            Islands
                  Guinea           Niger           Zambia
                Guinea-Bissau     Rwanda
                   Angola        Congo DR                                       Afghanistan
   Fragile                                        Eritrea
                   Burundi        Congo                             Haiti         Somalia                        Timor-Leste
  (9 of 13)                                       Liberia
                    CAR         Côte d'Ivoire                                      Sudan

                                                                     19                                       Source: WHO & PATH HPV Team
          ORANGE: countries expecting to adopt after 2020
                                                                                                                                                               HPV




Vaccine Need & Adoption Forecast
                                                                                                                                                    Vaccine Need: 72
INTEGRATED ADOPTION FORECAST                                                                                      Armenia
                                                                                                                Bangladesh
                                                                                                                                                     VISP Scope: 60*
                                                                                                                   Bhutan
                                                                                                                  Ethiopia                Angola
                       25                                                                                         Georgia              Burkina Faso
                                                                                                                    Haiti                  CAR
                                                                                                                    India                  Chad
                                                                                                                 Indonesia              Congo, DR
                                                                                                                Kyrgyzstan                Congo
                                                                                                                  Lao PDR                 Guinea
                       20                                                                                         Lesotho              Guinea-Biss
                                                                                                                  Moldova               Korea, DPR
                                                                                                                Mozambique                Liberia
                                                                                                                                           PNG
 Number of Countries




                                                                                                                 Myanmar
                                                                                                        Benin                              Niger
                                                                                                                   Nepal    Cameroon
                                                                                                      Cambodia                         Sierra Leone
                                                                                                                            Comoros
                       15                                                                               Ghana              Cote d’Ivoire
                                                                                                                                           Togo
                                                                                                         Mali                Djibouti
                                                                                                       Senegal               Eritrea
                                                                                                      Sri Lanka            Madagascar
                                                                                                      Tanzania              Mauritania
                                                                                                       Zambia
                       10                                                                             Zimbabwe
                                                                                                                           Solomon Isl
                                                                                                                             Ukraine


                                                                                           Burundi
                                                                                           Gambia
                                                 Cuba                            Kenya     Mongolia
                       5                       Nicaragua                         Malawi    Rwanda
                                                Uganda                          Viet Nam
                                                                      Bolivia
                                                                      Guyana
                                                           Honduras

                       0
                            2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020

                                                                        Year of Adoption

                                                                           20
                                                                                                * Remaining 12 GAVI countries may adopt after 2020
                                                                                                                                                 HPV




Vaccine Need & Adoption Forecast
VACCINE DEMAND GIVEN INTEGRATED ADOPTION FORECAST

                                           Vaccine Demand including Wastage
               180
               160
               140
               120
   Doses (M)




               100
                80
                60
                40
                20
                 0
                      2009       2010     2011      2012       2013       2014     2015       2016     2017          2018        2019    2020

                Routine Vaccination     Catch-up Campaign       Periodic Campaign         Boost Vaccination    Buffer Stock        Stock Pile

         Vaccine Demand including Wastage
                                        2009     2010   2011     2012      2013    2014      2015    2016     2017     2018       2019    2020
                 Routine Vaccination      0        0       1          1        2     4          6     15       24           34      44      51
                 Catch-up Campaign        0        0       0          0        0     0          0      0        0            0       0       0
                  Periodic Campaign       0        0       0          0        0     0          0      0        0            0       0       0
                   Boost Vaccination      0        0       0          0        0     0          0      0        0            0       0       0
                        Buffer Stock      0        0       0          0        0     0          1      2        2            3       2       2
                           Stock Pile     0        0       0          0        0     0          0      0        0            0       0       0
                              Total       0        0       1          1        3     4          6     17       26           37      46      52

                                                                          21
                                                 HPV




HPV
CONTENTS

   •   Disease Overview

   •   Vaccine Landscape

   •   Vaccination Policy & Strategies

   •   Vaccine Need & Adoption Forecast

   •   Vaccine Cost Analysis

   •   Implementation-Associated Cost Analysis

   •   Analysis Summary

   •   Key Resources



                                         22
                                                                                                                        HPV




Vaccine Cost Analysis
ANALYSIS INPUT SUMMARY – GENERAL



           VARIABLE                 INPUT                           RATIONALE/SOURCE
Country Vaccine Need                        Globacon incidence rate > 10/100,000 & country
                                     60
(Number of GAVI countries)                  political will (PATH HPV team)
Earliest WHO PQ Date                4Q08    Gardasil (Merck)
                 Auto-Disable
                 Syringe             
Equipment
Needs            Reconst. Syringe     -     IM, liquid formulation
($/dose)
                 Safety Box          

Wastage Factor                      10%     Liquid formulation; 2 or 5 dose vials
                                            (www.who.int/immunization_delivery/systems_policy/logistics_projected_wastage/en/)




                                            23
                                                                                                                                            HPV




  Vaccine Cost Analysis
  ANALYSIS INPUT SUMMARY – STRATEGY-SPECIFIC
                          VACCINATION STRATEGY
      VARIABLE                 Routine Vaccination                                         RATIONALE/SOURCE
                                    (10yo fm)

Doses per Treatment                        3                    Based on Gardasil (Merck) & Cervarix (GSK) package insert
                                        90%                     If <50% of the girls are not vaccinated in school, then a community based
Proxy Coverage Rate        (of female school attendance rate)   vaccination program is included to reach additional 10yo girls
                                                                All countries – 4yr except Indonesia & Viet Nam – 5yrs and India - 7yrs
Time to Peak Coverage              4, 5 or 7yrs
                                                                (PATH HPV Team)
Deaths Averted
                                          13                    S. Goldie & PATH HPV Team analysis
(per 1000 vaccinated)
                                     25
Years to Deaths Averted                                         15 – 30yrs to develop cervical cancer, a conservative estimate is applied
                                (modeled as 0)
% Deaths Averted < 5yo                   0%                     10yo cohort
Cases Averted
                                          16                    S. Goldie & PATH HPV Team analysis
(per 1000 vaccinated)
                                     25
Years to Cases Averted                                          15 – 30yrs to develop cervical cancer, a conservative estimate is applied
                                (modeled as 0)
% Cases Averted < 5yo                    0%                     10yo cohort
Average Cost per Case                   $296                    Best estimate for GAVI countries (S. Goldie, & PATH HPV Team analysis)


                                                                        24
                                                                                                    HPV




Vaccine Cost Analysis
KEY OUTPUT SUMMARY                                                Integrated Demand Forecast
                                                                                  2009-2020



                         Cost Component                       Cost

              GAVI Vaccine Cost ($M)                          1,261

              Country Vaccine Co-Pay Cost ($M)                 31

              Total Vaccine Cost ($M)                        $1,293




Deaths    <5 Deaths        Cases            Cost
                                                      GAVI Cost ($)/   GAVI Cost ($)/   GAVI Cost ($)/
Averted    Averted        Averted          Savings
                                                      Death Averted    Case Averted       $ Saved
(x1000)    (x1000)        (x1000)           ($M)

 707         n/a            870              $258        $1,784           $1,449            $4.90




                                                 25
                                                                                                                                                 HPV




Vaccine Cost Analysis
ANNUAL ANALYSIS RESULTS                                                                                      Integrated Demand Forecast
                                                                                                                             2009-2020
                         Vaccine Impact
                                                            2009   2010   2011   2012   2013   2014   2015    2016   2017   2018   2019   2020
                              Total1 Cost - High ($M)         0      4      7     12     27     39     65     137    204    279    344    392
                                                Low ($M)       0      3      6     11     23     33     55     118    171    233    197    225


               Total2 Cost to GAVI - High ($M)                0      4      7     12     27     38     64     134    200    273    336    383
                                                Low ($M)       0      3      6     10     23     32     54     115    167    227    190    216


        Total3 Cost to Countries - High ($M)                  0      0      0      0      0      1      1       3      4      6      7      9
                                                Low ($M)       0      0      0      0      0      1      1       3      4      6      7      9


              Vaccine Cost to GAVI - High ($M)                0      4      7     12     26     38     63     132    197    269    331    378
                                                Low ($M)       0      3      6     10     22     32     53     113    164    223    185    211


      Vaccine Cost to Countries - High ($M)                   0      0      0      0      0      1      1       3      4      6      7      9
                                                Low ($M)       0      0      0      0      0      1      1       3      4      6      7      9


          Vaccination Equipment Cost ($M)                     0      0      0      0      0      0      0       1      2      2      3      3
            Shipping & Insurance Cost ($M)                    0      0      0      0      0      0      0       1      1      2      2      3

         Projected Deaths Averted (x1000)                     0      1      3      4      9     14     23      58     94    134    170    197
          Projected Deaths Averted of < 5yo (X1000)            0      0      0      0      0      0      0       0      0      0      0      0


                      Cases Averted (x1000)                   0      1      3      5     12     17     28      71    116    165    209    243
     Costs Savings from Cases Averted ($M)                    0      0      1      2      3      5      8      21     34     49     62     72

               Total Doses Demanded (M)                       0      0      1      1      3      4      6      17     26     37     46     52
       Doses Demand without Wastage (M)                       0      0      1      1      2      3      6      15     24     33     41     47
          Total Potential Vaccinations (M)                    0      0      0      0      1      1      2       5      8     11     14     16

                                             M = millions
          1
              Vaccine cost + Equipment cost + S&I cost
                    2
                        GAVI pays Equipment and S&I costs
               3
                   Country pays equipment and S&I costs
                                when GAVI support ends
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                                                 HPV




HPV
CONTENTS

   •   Disease Overview

   •   Vaccine Landscape

   •   Vaccine Need & Adoption Forecast

   •   Vaccination Policy & Strategies

   •   Vaccine Cost Analysis

   •   Implementation-Associated Cost Analysis

   •   Analysis Summary

   •   Key Resources



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                                                                                                                   HPV




Implementation-Associated Cost Analysis
TYPICAL IMPLEMENTATION CHALLENGES


  Challenge
                                                 Typical Implementation Challenges
  Category
                • Complexity caused by the multi-dose vaccines
 Vaccination     − If a girl misses her first dose, do you wait [1-2mo] for the next round before giving her 1st
  Strategy         vaccination?
                • Crisis management preparedness
  Supply &
                • Building cold chain capacity
  Capacity
                • Establishing monitoring & evaluation systems
 Monitoring &    − Strengthening Adverse Events Following Immunization (AEFI) systems, especially for older
                   children
 Evaluation,
                 − „Enhanced‟ post-introduction evaluation in selected countries due to difficulty of complex
 Surveillance      surveillance on routine basis [high sensitization requirement or cultural misperception]
                 − Collecting data, keeping track, and incorporating info into information record systems
  Training of
                • Implementation training (e.g., HCW)
  Personnel



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                                                                                                      HPV




Implementation-Associated Cost Analysis
UNIQUE IMPLEMENTATION CHALLENGES

 Challenge Category                                 Unique Implementation Challenges
                      • Non-EPI vaccination schedule required
                       – School-based delivery - more difficult to reach age cohort >10yo
    Vaccination        – New immunization cards required
     Strategy
                      • Increased costs due to transport of immunization teams into schools or
                        community outreach sites
                      • Requires high level of community sensitization including teachers and healthcare
                        workers

    Perception        • Significant misperceptions need to be overcome
   Management          –   Cost prohibitive vaccine
                       –   Poor school enrollment in low income countries
                       –   Vaccination affects fertility
                       –   Vaccine approved for use in males
     Program
                      • Requires coordination with MoE (for school-based programs)
    Integration

   Health Impact      • Measuring impact of HPV vaccine requires over 20 years



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                                                                                                                        HPV




Implementation-Associated Cost Analysis
POTENTIAL IMPLEMENTATION SYNERGIES

           Traditional   HepB     Hib     YF     Pneumo     Rota     MenA    Cholera    JE     Rabies Rubella Typhoid

   HPV                                                                          √                                   √


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 leverage school-based vaccination campaigns (cholera, typhoid)

           Other Potential Synergies
           • Potential to motivate the creation or expansion of adolescent health programs
           • Potential to integrate with gender-based initiatives




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                                                                                                                           HPV




Implementation-Associated Cost Analysis
RELATIVE COST ASSESSMENT

                                    Incremental Vaccine Implementation Cost Relative to Traditional EPI Costs
 Implementation Cost
      Categories                                         Routine Vaccination (10yo females)


      Cold Chain
                           • Less than typical (fewer subjects in 10yo vs. birth cohort)
  Waste Management


       Transport           • More than typical due to both school & community delivery requirements


 Training of Personnel     • Common route of administration (IM), but significant disease training required

   Communication,
                           • More than typical due to high level of community sensitization required and need for school
   Education, Social
                             based and community education
     Mobilization
Monitoring & Evaluation,   • More than typical given cervical cancer disease impact cannot be measured for ~20 years or
     Surveillance            more

    Service Delivery       • More than typical due to need to reach schools and clinics



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 Implementation-Associated Cost Analysis
 QUANTITATIVE COST ASSESSMENT – ROUTINE

             Metric                   2009      2010       2011      2012      2013       2014      2015      2016      2017       2018      2019      2020      Total

Total Doses (M)                         0        0.34      0.70      1.15       2.57      3.66      6.12        16        25        35        43         49       183

Total Subjects
                                        0        0.11      0.23      0.38       0.86      1.22      2.04        5          8        12        14         16        61
Vaccinated (M)
Total Implementation-
                                        0        3.67      7.14       11         20        26        39         90       136       191        238       272      1,033
Associated Costs ($M)


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)



                                                                      GIVS Assumptions
       Proxy GIVS Vaccination Strategy                         HPV; 11yo females
                                                               • Demand forecast duration, product formulation, vial size and wastage
                                                                 estimates were harmonized with GAVI VISP product profiles
                                                               • Country-specific cost estimates per 10 min health facility visit for all
       Adjustments to Proxy
                                                                 doses outside of traditional EPI schedule
                                                               • Country-specific cost estimates were provided for 10-100% access to
                                                                 medial facilities – used 80% estimate




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                                               HPV




HPV
CONTENTS

   • Disease Overview

   • Vaccine Landscape

   • Vaccine Need & Adoption Forecast

   • Vaccination Policy & Strategies

   • Vaccine Cost Analysis

   • Implementation-Associated Cost Analysis

   • Analysis Summary

   • Key Resources


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                                                                                                                  HPV




Analysis Summary
KEY METRIC SUMMARY

                                                                   Routine
                                  Cost Component
                                                                 Vaccination

                          GAVI Vaccine Cost ($M)                    1,261

                          Country Vaccine Co-Pay Cost ($M)            31

                          Total Vaccine Cost ($M)                   $1,293




                                                              GAVI Cost/    GAVI Cost/
  Vaccination   Deaths      <5 Deaths     Cases      Cost                                GAVI Cost/    Country
                                                                Death         Case
   Strategy     Averted      Averted     Averted    Savings                               $ Saved     Imp Costs
                                                               Averted       Averted

   Routine       707           n/a        870        $258      $1,784        $1,449        $4.90       $1,033




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                                               HPV




HPV
CONTENTS

   • Disease Overview

   • Vaccine Landscape

   • Vaccine Need & Adoption Forecast

   • Vaccination Policy & Strategies

   • Vaccine Cost Analysis

   • Implementation-Associated Cost Analysis

   • Analysis Summary

   • Key Resources


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                                                                                                                  HPV




Key Resources
EXPERT CONSULTATION
• Product Development Program (PATH HPV Vaccine Team)
   – Vivien Tsu, Director
   – Steve Brooke, Commercialization Advisor, Commercialization & Corporate Partnerships
   – Debbie Atherly, Senior Health & Policy Officer
   – Carol Levin, Senior Health Economist
   – Nancy Engel

• Independent Experts
   – Sue Goldie, Harvard School of Public Health

• Suppliers
   – Merck: Margaret McGlynn, President, Merck Vaccines; Elaine Esber, Executive Director, Merck Vaccines
   – GSK: John-Kenneth Billingsley, Director, Global Vaccine Policy & Public Partnerships; Eunice Miranda, Director,
     Global Commercial Affairs; Laurence de Moerlooze, Head of Project Management, HPV Vaccines; Kate Taylor, VP,
     Global Vaccine Policy & Public Health Partnerships; Kathleen Vandendael-Baudrihaye, Director, International
     Relations, Global Vaccine Policy & Public Health Partnerships
• Others
   – Nuriye Ortayli, Advisor, Reproductive Health, UNFPA



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                                                                                            HPV




Appendix
REFERENCES (I)
1.   Plotkin, S, Orenstein, W, Offit, P. Vaccines, 5th edition, Chapter 14, 2008
2.   “HPV Disease and Epidemiology”, slide presentation by M. Stanley, Dept of Pathology,
     University of Cambridge
3.   Smith et al, Int. J. Cancer 121:621–32, 2007
4.   Cancer Survival in Developing Countries, by Sankaranarayanan et al, IARCP press, 1998
5.   HPV vaccines: technical information for policy-makers and health professionals, WHO
     publication 2007
6.   PATH HPV team
7.   WHO/EPI Burden of Disease Projections
     (http://www.who.int/healthinfo/statistics/bodprojections2030/en/index.html)
8.   Morbidity & Mortality data obtained through IARC, Globocan 2002
     (http://www.who.int/hpvcentre/statistics/dynamic/ico/DataQuerySelect.cfm)
9.   Morbidity=number of new cervical cancer incident cases caused by HPV infection
10. Morbidity & Mortality rates based on the crude rates (per 100,000 female population) from
    Globocan 2002 [Morbidity Rate = Crude Morbidity Rate]

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                                                                                      HPV




Appendix
REFERENCES (II)
11. Mortality=number of death caused by HPV infection induced cervical cancer
12. [Mortality Rate = (Crude Mortality Rate / 100,000) 1,000,000]
13. Giuliano et al, J Infect Dis 188(10):1508-16, 2003
14. Goodman et al, Cancer Res 67(12):5987-96, 2007
15. Kwasniewska et al, Nutrition and cancer 28(3):248-51, 1997
16. PATH, Outlook vol. 23(1), June 2007
17. Some cross protection to HPV-45 & 31 using 16 & 18 shown (PATH, Outlook vol. 23(1),
    June 2007 )
18. Gardasil Package Insert
    (http://www.merck.com/product/usa/pi_circulars/g/gardasil/gardasil_pi.pdf)
19. http://www.dhs.ca.gov/director/owh/owh_main/pubs_events/news_articles/YM/6.2006cervi
    calvaccineyouth.pdf
20. www.medicalnewstoday.com/articles/77039.php


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                                                                                        HPV




Appendix
REFERENCES (III)

21. Both Merck and GSK conducting studies to determine safety and immunogenicity of a
    booster dose (Vaccine 25(26):4931-9, 2007 & www.clinicaltrials.gov/ct2/show/
    NCT00546078?term=nct0054 6078&rank=1, respectively); as well as safety and
    immunogenicity in HIV infected children or female adults (NCT00339040 &
    NCT00586339, respectively)

22. Cervarix Package Insert & personal communication with GSK
    (http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=20207)

23. http://www.in-pharmatechnologist.com/news/ng.asp?n=80037-glaxosmithkline-merck-
    cervarix-gardasil-cervical-cancer

24. Gao et al, "HEV and HPV Vaccine Development",8th DCVMN Annual Meeting Rio de
    Janiero, Brazil, 2007

25. http://www.ystxm.com/en

26. http://www.who.int/healthinfo/statistics/bodprojections2030/en/index.html


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                                                                                      HPV




Appendix
REFERENCES (IV)

27. H. Saxenian & R. Hecht, Stop Cervical Cancer: Accelerating Global Access to HPV
    Vaccines, Dec 2006, London (background paper from IAVI)
28. HPV Vaccine Adoption in Developing Countries: Cost and Financing Issues, Dec 2007,
    IAVI




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