Updated April 2022 Single-dose HPV vaccination: Current evidence - PowerPoint Presentation

1. Updated April 2022Single-dose HPV vaccination: Current evidence

2. Why Single-Dose HPV Vaccination?Single-dose HPV vaccination could: accelerate introduction for countries that have yet to introduce the vaccine​facilitate new options for current national programs by simplifying delivery costs, lowering program costs, and potentially increasing coverage​reduce the potential for supply shortages and delivery challenges, such as those faced during the COVID-19 pandemic​accelerate achieving the vaccination target of WHO’s cervical cancer elimination initiative

3. Executive Summary Problem statement The overall case for single-dose regimen Potential solution1. Barnabas R, Brown E, Onono M, et al. Efficacy of Single-Dose HPV Vaccination Among Young African. NEJM Evidence. 2022. doi: 10.1056/EVIDoa2100056. HPV causes almost all cases of cervical cancer and the burden is disproportionate. Around 90% of cervical cancer deaths occur in low- and middle-income countries (LMICs). Additionally, worldwide vaccine coverage in girls under 15 years of age is only about 13%. Recent studies provide high-quality data showing ~98% efficacy1 and durable protection for a single-dose regimen. There is strong evidence that single-dose HPV vaccines could substantially reduce the incidence of HPV-attributable cervical precancer and cancer. Ultimately, a single-dose regimen could promote global equity in HPV vaccine access, increase vaccine uptake in LMICs and globally, as well as decrease rates of cervical cancer and related deaths in high burden, low-income regions. Ongoing research will continue providing insights in the coming years.

4. WHO SAGE recommends updating HPV vaccination dose schedules1 as follows (April 2022): One or two-dose schedule for the primary target of girls aged 9-14.One or two-dose schedule for young women aged 15-20.Two doses with a 6-month interval for women older than 21.Immunocompromised individuals, including those with HIV, should receive three doses if feasible, and if not at least two doses. 1. One-dose Human Papillomavirus (HPV) vaccine offers solid protection against cervical cancer [press release]. Geneva, Switzerland: WHO; April 11, 2022. Available at https://www.who.int/news/item/11-04-2022-one-dose-human-papillomavirus-(hpv)-vaccine-offers-solid-protection-against-cervical-cancer.

5. Additional considerationsHPV & cervical cancer; HPV vaccinesEvidence & potential impact for single-dose regimen123

6. HPV & Cervical cancer; HPV vaccines

7. HPV infection can progress to cervical cancer and untimely death, especially in lower-income countriesHuman papillomavirus (HPV) is a common viral infection ​to which almost all cervical cancers can be attributed, and most of the burden lies in LMICs*2nd~342K ~90% of those deaths happen in low- and middle-income countriesannual deaths caused by cervical cancer1 most common cancer in Africa and 4th among women worldwide2 2019 Age-standardized mortality rate (ASMR) for cervical cancer by sociodemographic index areas2 ASMR (per 100,000 women)Income levelMiddleHigh Low-middleHigh-middleLow1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians. 2021;71(3):209-249. doi: 10.3322/caac.21660. | 2. Zhang X, Zeng Q, Cai W, Ruan W. Trends of cervical cancer at global, regional, and national level: data from the Global Burden of Disease study 2019. BMC Public Health. 2021;21(1):894. doi:10.1186/s12889-021-10907-5. *HPV types 16 and 18 are responsible for over 70% of cases.

8. HPV vaccination is the primary prevention tool to accelerate cervical cancer elimination Focus of this deckPrimary: HPV vaccination for girls 9-14 years of ageSecondary: Regular screening for women starting at age 30Tertiary: surgical, therapeutic, or palliative treatment of cervical cancer Screening programs and medical services for cervical cancer in low-income regions are either unavailable or on a limited scale3 Real-world data1 indicates that HPV vaccination cuts cervical cancer cases by ~90% Prevention and Interventions21. Falcaro M, Castañon A, Ndlela B, et al. The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study. Lancet. 2021;398(10316):2084-2092. doi:10.1016/S0140-6736(21)02178-4. | 2. World Health Organization (WHO). WHO guideline for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention guideline for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention. Second edition. 978 92 4 003082 4. Geneva: WHO; 2021. | 3. Herrero R, Cervical cancer screening in low and middle-income countries. HPVWorld, No. 2. https://www.hpvworld.com/articles/cervical-cancer-screening-in-low-and-middle-income-countries/.

9. Four safe and highly efficacious HPV vaccines are WHO prequalified 9 1. HPV working group – Gavi Secretariat and partners. Gavi-supported HPV vaccines profiles to support country decision making, May 2021. Available at https://www.gavi.org/sites/default/files/support/Gavi_HPV_vaccine_profiles.pdf. Efficacy>95%Dosage*Distributed by GaviWHO Prequalification2018202120092009HPV types covered6, 11, 16, 18, 31, 33, 45, 52, 5816, 186, 11, 16, 1816, 18Year of initial registration2014201920062007Bivalent (2vHPV, Cervarix)Nonavalent (9vHPV, Gardasil 9)Quadrivalent (4vHPV, Gardasil)Bivalent (2vHPV, Cecolin)1 2Contingent on country program discussionsContingent on having an appropriately priced productWHO prequalified HPV vaccines1 *For females less than 15 years; 3 doses for females 15 or older, HIV positive, or immunocompromised.

10. In the past 16 years, national HPV vaccination programs have been introduced, but global coverage remains low and varies by income levelGlobal coverageis ~13% worldwide and only 8%in LMICs410208030405060709020062007200820092010201120122013201420152016201720182019202020212022**Gavi alliance HPV program formedFirst HPV vaccine introduction in Africa (Gardasil/Rwanda)WHO PQ of Gardasil and CervarixGardasil and Cervarix LicensedWHO PQ of CecolinWHO PQof Gardasil 9WHO recommends2 doses (2014) and multi-age cohort vaccination (2016) for girls aged 9-142 Number of countries who have introduced a vaccine program on a national scale1 (#) WHO issues extended interval guidance for considerationLMICHIC**For US populations covered, approvals/recommendations are not shown for 9-valent if already shown in the past for 4-valent vaccine. **Projected country introductions by PATH PATH. Global HPV Vaccine Introduction Overview. Seattle: PATH; 2022, Available at https://path.azureedge.net/media/documents/Global_Vaccine_Intro_Overview_Slides_Final_PATHwebsite_MAR_2022_qT92Wwh.pdf. | 2. World Health Organization (WHO). Meeting of the Strategic Advisory Group of Experts on immunization, April 2014 — conclusions and recommendations. Weekly Epidemiological Record, 89 (‎21)‎, 221 - 236. https://apps.who.int/iris/handle/10665/242217. | 3. One-dose Human Papillomavirus (HPV) vaccine offers solid protection against cervical cancer [press release]. Geneva, Switzerland: WHO; April 11, 2022. Available at https://www.who.int/news/item/11-04-2022-one-dose-human-papillomavirus-(hpv)-vaccine-offers-solid-protection-against-cervical-cancer. | 4. HPV vaccine cuts cervical cancer cases by nearly 90% [blog]. Geneva, Switzerland; November 8, 2021. Available at https://www.gavi.org/vaccineswork/hpv-vaccine-cuts-cervical-cancer-cases-nearly-90. WHO SAGE recommends 1- or 2- dose schedule3

11. HICs have introduced twice as many national HPV immunization programs than LMICs* Decision pending on national introductionAs of 17 Mar 2022*PATH. Global HPV Vaccine Introduction Overview. Seattle: PATH; 2022, Available at https://path.azureedge.net/media/documents/Global_Vaccine_Intro_Overview_Slides_Final_PATHwebsite_MAR_2022_qT92Wwh.pdf.

12. In addition to vaccine introduction, both vaccine uptake and cervical cancer burden differ significantly between HICs and LMICs1. Zhang X, Zeng Q, Cai W, Ruan W. Trends of cervical cancer at global, regional, and national level: data from the Global Burden of Disease study 2019. BMC Public Health. 2021;21(1):894. doi:10.1186/s12889-021-10907-5. | 2. Spayne J, Hesketh T. Estimate of global human papillomavirus vaccination coverage: analysis of country-level indicators. BMJ Open. 2021;11(9):e052016. doi:10.1136/bmjopen-2021-052016. | 3. WHO (World Health Organization). 2020 WHO/UNICEF Estimates of National Immunization Coverage. Presented at: Gavi HPV Subteam Meeting, July 15, 2021; Geneva, Switzerland. HICsLMICsPercentage of eligible women who receive a first dosePercentage of eligible women who receive a second doseLower middleHighUpper middleLow  12Cervical cancer incidence is inversely correlated to the income level of countries and their rate of vaccinationEligible women from HICs are 3x more likely to receive HPV vaccines than their LMIC counterparts2Cervical cancer incidence rate per 100,000 females, 20191Vaccine uptake in HICs and LMICs, 2020369%52%37%58%

13. Several obstacles across health building blocks may contribute to lower HPV vaccination levels in LMICsSupplyGovernanceFacilities/delivery Data and digitalFinancesDemandHuman resourcesThe costs of a vaccination program are prohibitive for many LMICs, as even with Gavi or donor support, many will not be able to afford the cost after support ends1 Logistical challenges and patient hesitancy to multidose vaccines negatively impact demand5Staff and training resources are often limited in LMICs2 Lack of government support or facilitation can hinder national vaccine introduction4 Tracking the immunization status and following up on subsequent doses is difficult with limited technology and resources6 Many young females in LMICs do not interact with the healthcare systems and might be out of school, so community and non-traditional channels are often required7Reports indicate that a worldwide shortage in HPV vaccines is expected to last until 2024 or 2025 due to limited manufacturing capacity3 1. Shinkafi-Bagudu Z. Global Partnerships for HPV Vaccine Must Look Beyond National Income. JCO Global Oncology. 2020;6:1746-1748. doi:10.1200/GO.20.00504. | 2. Wigle J, Coast E, Watson-Jones D. Human papillomavirus (HPV) vaccine implementation in low and middle-income countries (LMICs): health system experiences and prospects. Vaccine. 2013;31(37):3811-3817. doi:10.1016/j.vaccine.2013.06.016. | 3. Garland SM, IPVS Statement on Temporary HPV Vaccine Shortage. Implications Globally to Achieve Equity. HPVWolrd, No. 152. https://www.hpvworld.com/articles/ipvs-statement-on-temporary-hpv-vaccine-shortage-implications-globally-to-achieve-equity. | 4. Brandt HM, Pierce JY, Crary A. Increasing HPV vaccination through policy for public health benefit. Human Vaccines & Immunotherapeutics. 2016;12(6):1623-1625. doi:10.1080/21645515.2015.1122145. | 5. Mitchell KR, Erio T, Whitworth HS, et al. Does the number of doses matter? A qualitative study of HPV vaccination acceptability nested in a dose reduction trial in Tanzania. Tumour Virus Research. 2021;12:200217. doi:10.1016/j.tvr.2021.200217. | 6. World Health Organization (WHO). Report of the SAGE Working Group on Quality and Use of Immunization and Surveillance Data. Geneva: WHO; 2019. Available at https://terrance.who.int/mediacentre/data/sage/SAGE_Docs_Ppt_Oct2019/8_session_immunization_data/Oct2019_session8_SAGE-WG_executive_summary.pdf. | 7. Dorji T, Nopsopon T, Tamang ST, Pongpirul K. Human papillomavirus vaccination uptake in low-and middle-income countries: a meta-analysis. EClinicalMedicine. 2021;34:100836. Published 2021 Apr 17. doi:10.1016/j.eclinm.2021.100836.

14. A single dose regimen could address some of these implementation challengesLowered cost of operations and vaccine vialsMore palatable and easier for people to logistically plan and financially afford Fewer appointments to schedule and serviceSimplified campaign coordinationNo need for scheduling and tracking follow upsLess inventory and fewer deliveries required Lower supply of vaccines required for a given populationLikely some improvementLikely significant improvementA single-dose regimen addresses several obstacles disproportionately felt by LMICs by reducing the quantity of doses to be procured (or begin buying after initial support) and subsequently distribute, store, track and administerSupplyGovernanceFacilities/delivery Data and digitalFinancesDemandHuman resources

15. Evidence and potential impact for single-dose regimen

16. Evidence for a single dose Key statistics based on evidence 98%A single dose delivers high levels of protection similar in magnitude to multidose regimens30+%Single-dose regimens may present significant cost savings and can help with overall delivery challengesEfficacy demonstrated for preventing persistent HPV 16 or 18 infections with a single dose1A single-dose regimen could reduce economic costs by ~30-40+% based on a decrease of recurrent costs such as number of vaccine doses >90%Single dose regimens promote global health equityof cervical cancer cases that could be averted over next 100 years according to modeling studies2 would be in LMICs1. Barnabas R, Brown E, Onono M, et al. Efficacy of Single-Dose HPV Vaccination Among Young African. NEJM Evidence. 2022. doi: 10.1056/EVIDoa2100056. | 2. Prem K, Choi YH, Bénard É, et al. Global impact and cost-effectiveness of one-dose versus two-dose human papillomavirus vaccination schedules: a comparative modelling analysis. medRxiv. Preprint posted online February 8, 2021. https://doi.org/10.1101/2021.02.08.21251186. 64MA single dose regimen will increase access and uptakeCervical cancer deaths are projected to be avoided in the next 98 years by reducing the recommended regimen from two to one dose (assuming no multi-age cohorts****) based on dynamic modeling2There is substantial evidence supporting the benefits of a single-dose HPV vaccine regimen*Based on cost analysis**Excluding India****Multi-age cohorts (MAC): more than one age or birth cohort is targeted 

17. A single dose delivers high levels of protection similar in magnitude to multidose regimensData from clinical studies across multiple geographies suggest a single-dose regimen provides significant protection against HPVStudyKey findings1. Barnabas R, Brown E, Onono M, et al. Efficacy of Single-Dose HPV Vaccination Among Young African. NEJM Evidence. 2022. doi: 10.1056/EVIDoa2100056. | 2. Watson-Jones D, Changalucha J, Whitworth H, et al. Immunogenicity and Safety Results Comparing Single Dose Human Papillomavirus Vaccine with Two or Three Doses in Tanzanian girls - the DoRIS Randomised Trial. Lancet. Preprint posted online March 11, 2022. https://dx.doi.org/10.2139/ssrn.4055429. | 3. Basu P, Malvi SG, Joshi S, et al. Vaccine efficacy against persistent human papillomavirus (HPV) 16/18 infection at 10 years after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre, prospective, cohort study [published correction appears in Lancet Oncol. 2022 Jan;23(1):e16]. Lancet Oncology. 2021;22(11):1518-1529. doi:10.1016/S1470-2045(21)00453-8. | 4. Kreimer AR, Sampson JN, Porras C, et al. Evaluation of Durability of a Single Dose of the Bivalent HPV Vaccine: The CVT Trial. Journal of the National Cancer Institute. 2020;112(10):1038-1046. doi:10.1093/jnci/djaa011. Costa Rica HPV Vaccine Trial (CVT)4Comparable efficacy from one and three doses of Cervarix in protecting against HPV 16/18 infection after 10 years post-vaccination 10X level of antibody induced after a single dose as compared to after natural infectionInternational Agency for Research on Cancer (IARC)3 Start year *Location20042009Costa RicaIndiaKEN SHE1 Single dose vaccination with Gardasil9 or Cervarix was ~98% effective in preventing new onset persistent HPV 16/18 infection in African adolescent girls and young women2018KenyaDoRIS22017TanzaniaSingle dose showed ~95% efficacy of Gardasil against persistent HPV 16/18 infection for at least 10 years Comparable vaccine efficacy regardless of the dose regimen of Gardasil (1, 2 or 3 doses) Antibody levels among girls receiving a single dose of Gardasil9 or Cervarix were at least as high as those in women from CVT or IARC studies where efficacy was shown. Data suggest the efficacy of a single dose of HPV vaccine may apply to additional geographies in the targeted 9–14-year-old age group6*All studies in long-term follow-up.

18. KEN SHE randomized controlled study demonstrates high efficacy for a single dose of HPV vaccineStudy descriptionKenyan women aged 15-20 were randomized to three study groups: single dose Cervarix, single dose Gardasil9 or delayed vaccination, to evaluate persistent vaccine-type HPV infection by month 18 and 36Sample: 2,250 women aged 15-20 with 1,518 participants receiving a single dose of Cervarix or Gardasil9Objectives: Compare the efficacy of single-dose of Cervarix or Gardsail9 vaccination to delayed HPV vaccination and compare antibody titers between the KEN SHE participants and the 9–14-year-old girls and adolescents in the DoRIS study* Single doses of Cervarix and Gardasil9 are highly efficacious in preventing incident persistent HPV infections in African adolescent girls and young women1Immunobridging data planned in 2022 to compare KEN SHE and DoRIS trial to support efficacy in girls 9-14 years of ageIncidence of persistent HPV 16/18 infection and Vaccine Efficacy (VE) by Month 1811. Barnabas R, Brown E, Onono M, et al. Efficacy of Single-Dose HPV Vaccination Among Young African. NEJM Evidence. 2022. doi: 10.1056/EVIDoa2100056. Number in modified intent-to-treat setNumber eventsIncidence/100 woman year of ageVE (%)97.547348949636116.830.170.1797.5VE 95% CI81.6; 99.781.7; 99.7Single dose Nonavalent N = 758Single dose Bivalent*N = 760Delayed VaccinationN = 757SYNTHESIS*Immunobridging data is not yet available.

19. DoRIS immunobridging study suggests the high single-dose efficacy from IARC and CVT studies may apply to young girlsStudy descriptionRandomized-controlled trial conducted in Tanzania in girls 9-14 years of age receiving either three-, two- or one-dose regimens of Cervarix or Gardasil9. Follow-up for immunogenicity to three years (three-dose recipients) and to five years (one- and two-dose recipients) post-vaccination. Available results are from the two-year analysis.Sample: 930 girls aged 9-14 years; 310 participants received a single dose of Cervarix or Gardasil9Objectives: Evaluate the quality and durability of immune responses of reduced dose schedules in a population with high burden of malaria and other infections that may affect vaccine immune responses as well as immunobridge to cohorts of women in the IARC, CVT and KEN SHE studies in which single dose HPV vaccine efficacy was demonsrated* Antibody levels in the DoRIS trial were immunological non-inferior to the levels in women from CVT and IARC studies, supporting the conclusion that the efficacy results from the CVT and IARC trials also apply to young girls aged 9-14 in sub-Saharan AfricaSYNTHESISHPV-16/18 antibody titers at Month 24 of DoRIS, CVT and IARC studies after a single dose1(Bivalent)(Quadrivalent/Nonavalent)Concentration (IU/mL)DoRISCVTDoRISCVTDoRISIndiaDoRISIndiaHPV-16HPV-1810,000100010010011. Watson-Jones D, Changalucha J, Whitworth H, et al. Immunogenicity and Safety Results Comparing Single Dose Human Papillomavirus Vaccine with Two or Three Doses in Tanzanian girls - the DoRIS Randomised Trial. Lancet. Preprint posted online March 11, 2022. https://dx.doi.org/10.2139/ssrn.4055429. *KEN SHE and DoRIS immunobridging data is not yet available

20. IARC India HPV trial demonstrates 1-dose has comparable efficacy to 2- or 3-dose against persistent HPV 16/18 infection over 10 yearsStudy descriptionIn 2009, a cluster randomized clinical trial in India was initiated to compare 2 and 3 dose-regimens of Gardasil in 10-18-year-old females. A substantial portion (4,950 subjects) had only received a single dose when country-wide HPV vaccination was halted by Indian MOH. Participants were followed for efficacy and immunogenicity; 1,541 age- and residence-matched unvaccinated women were recruited 2013-2015.Duration:; Follow-up up to 15 years post vaccination;10-year efficacy1 and 4-year immunogenicity data available2Objective: Evaluate the efficacy of HPV4 vaccination in preventing persistent HPV-16/18 infectionsAcross the different schedules (single dose, 2-doses on 0,6 months and 3-dose on 0,1,6 months schedule) Gardasil efficacy against HPV-16/18 persistent infections remains similarly high (>90%) up to at least 10 years post vaccination1Persistent HPV 16 and/or 18 infections (new onset persistent infections 12+ months)GroupSample SizeObserved EventsCrude attack rate %Unvaccinated1,260322.54Adjusted VE %(95% CI)-Single-dose2,13610.0595.4 (85.0-99.9)2-dose (Days 1 and ≥180)1,45210.073 dose (Days 1, 60 and ≥180)1,46010.0793.1 (77.3-99.8)93.3 (77.5-99.7)Summary of results at year 101 Basu P, Malvi SG, Joshi S, et al. Vaccine efficacy against persistent human papillomavirus (HPV) 16/18 infection at 10 years after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre, prospective, cohort study [published correction appears in Lancet Oncol. 2022 Jan;23(1):e16]. Lancet Oncology. 2021;22(11):1518-1529. doi:10.1016/S1470-2045(21)00453-8. | 2. Sankaranarayanan R, Prabhu PR, Pawlita M, et al. Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre prospective cohort study. Lancet Oncology. 2016;17(1):67-77. doi:10.1016/S1470-2045(15)00414-3. SYNTHESIS

21. CVT in Costa Rica demonstrates similar efficacy in prevention of prevalent HPV infections at Y9 & Y11 for 1-, 2- and 3-dose regimensStudy description1Long-term follow-up of study participants enrolled (2004/2005) in a randomized clinical trial comparing 3 dose-regimen of Cervarix to inactive control (Hep A vaccine) including evaluations of single-dose recipients (incomplete vaccination schedule) Sample: 7,466 women 18-25 years of age enrolled; 275 participants received a single dose of Cervarix 2,836 age- and geography-matched unvaccinated screening-only control group in long-term extension phaseObjectives: Evaluate efficacy of Cervarix in preventing HPV-16/18 infections at more than a decade after vaccination; and evaluate the durability of antibody response Antibody levels up to 11 years post-vaccination11. Kreimer AR, Sampson JN, Porras C, et al. Evaluation of Durability of a Single Dose of the Bivalent HPV Vaccine: The CVT Trial. Journal of the National Cancer Institution. 2020;112(10):1038-1046. doi:10.1093/jnci/djaa011. SYNTHESISEfficacy estimates against prevalent HPV 16/18 infections are comparable to multi-dose regimen after a single dose of CervarixHPV-16 and HPV-18 antibodies in all subjects, though lower than after a multidose regimen, persist at levels several-fold above natural infection up to 11 years after a single dose of Cervarix100001000100103 doses1 doseNatural immunity2345678910114x10xHPV 16 Antibody Geometric Means, (EU/mL)YearVaccine Efficacy at Year 9 & 11 post-vaccination11 Dose (N= 112)2 Dose (N = 62)3 Dose (N = 1365)Unvaccinated (N=1783)HPV-16/18 Prevalent infections1.8% (0.3; 5.8%)1.6% (0.1; 7.7)2.0% (1.3; 2.8%)10.0% (8.7; 11.4%)Vaccine Efficacy82.1% ( 40.2; 97.0%)83.8% (19.5; 99.2%)80.2% (70.7; 87.0%)

22. Several additional studies are ongoing and may provide more insight on the efficacy and duration of a single-dose HPV vaccine in years to comePrimaveraESCUDDOThailand Impact StudyCountryCosta RicaCosta RicaThailandEvidence typeImmunogenicityEfficacyEffectivenessDescriptionNon-Inferiority of one dose of Cervarix in girls aged 10 to 13 years compared to 3 doses of Gardasil in women 18-25-year-oldNon-inferiority efficacy trial of 1 or 2 doses of Cervarix or Gardasil9 in girls 12 to 16 years old; efficacy for each vaccine compared to an unvaccinated cohort Cross-sectional surveys in grades 10 and 12 after vaccination in grade 8 with 1 or 2 doses of Cervarix. Effectiveness in terms of reduction of vaccine type prevalenceStudy nameData releaseHANDSThe GambiaImmunogenicityComparison 1 or 2 doses of Gardasil9 in 4- to 8-year-old girls to 15–26-year-old girls receiving 3 doses2023 – Y22024 – Y32022 - 2Y2023 - 3Y20252022 - Y22024 - Y4Cross-sectional surveys in 17 to 18 years old females either unvaccinated, 1-dose catch up (15-16 years old) or 2-dose routine (9-year-old) cohorts to determine impact of Cervarix in protecting against prevalent HPV infections and whether HIV status affects the impact of an HPV vaccineHOPESouth AfricaEffectiveness2022 1-dose2023 2-doseSingle-Dose HPV Vaccine Evaluation Consortium. Evidence Review - Review of the current published evidence on single-dose HPV vaccination (Third Edition - November 2020). Seattle: PATH; 2020. Available at https://path.azureedge.net/media/documents/SDHPV_Evidence_Review_Edition_3_Final_Fin3p80.pdf.

23. 1 DoseCurrent regimenPer dose***3Total***3 10% decrease in recurrent costs****30% decrease in recurrent costs****50% decrease in recurrent costs**** $2.00$3.99$3.99$3.99$3.99$4.50$9.00$4.50$4.50$4.50Example scenarios show a single-dose regimen may reduce economic costs by ~30 to 40+ percent  ABC$1.84$3.69$3.32$2.58$1.841. Levin A, Wang SA, Levin C, Tsu V, Hutubessy R. Costs of introducing and delivering HPV vaccines in low and lower middle income countries: inputs for GAVI policy on introduction grant support to countries. PLoS One. 2014;9(6):e101114. doi:10.1371/journal.pone.0101114. | 2. Gavi page. Human papillomavirus vaccine support website. Available at https://www.gavi.org/types-support/vaccine-support/human-papillomavirus. Accessed April 5, 2022. | 3. Brew J, Sauboin C. A Systematic Review of the Incremental Costs of Implementing a New Vaccine in the Expanded Program of Immunization in Sub-Saharan Africa. MDM Policy & Practice. 2019;4(2):2381468319894546. doi:10.1177/2381468319894546. | 4. Burger EA, Campos NG, Sy S, Regan C, Kim JJ. Health and economic benefits of single-dose HPV vaccination in a Gavi-eligible country. Vaccine. 2018;36(32 Pt A):4823-4829. doi:10.1016/j.vaccine.2018.04.061. 50% decrease in all costs*****4D$2.00$4.50$1.842 DosesLess likely scenarioMore likely scenarioDescriptionScenarioNon-vaccine costs: introduction*1 Vaccine costs**2 Total costNon-vaccine costs: recurrent*1Percentage saving from current regimenN/A29%34%$8.34$16.68$11.81$11.07$10.3338%50%$8.34When introduction costs are no longer needed, the cost savings per vaccinated girl could increase*Breakdown of introduction and recurrent costs from four low-income scaled up HPV vaccination studies.**Based on Gavi price *** Baseline non-vaccine price per dose taken as median of 8 HPV routine and campaign studies in Sub-Saharan Africa ****Assumes having only one dose per individual will decrease recurring costs *****50% reduction in costs when decreasing HPV dosage from 2 to 1

24. To inform scenarios, eight Sub-Saharan African HPV vaccination studies were assessed to find the median delivery cost per dose1AuthorArticleYear of dataCountryThe above eight studies, all conducted throughout Sub-Saharan Africa, used different methods of data collection and administration strategies to calculate an average cost per doseQuentinCost of delivering human papillomavirus vaccination to schoolgirls in Mwanza Region, Tanzania2011-2015Mwanza region, Tanzania1UmehMothers' willingness to pay for HPV vaccines in Anambra state, Nigeria: a cross sectional contingent valuation studyNot specifiedNigeria3HutubessyA case study using the United Republic of Tanzania: costing nationwide HPV vaccine delivery using the WHO Cervical Cancer Prevention and Control Costing Tool2011-2015Tanzania4NgaboA cost comparison of introducing and delivering pneumococcal, rotavirus and human papillomavirus vaccines in RwandaNot specifiedRwanda5BotwrightExperiences of operational costs of HPV vaccine delivery strategies in GAVI-supported demonstration projects**32013-2016Multi-country7LevinDelivery cost of human papilloma virus vaccination of young adolescent girls in Peru, Uganda, and Vietnam2008-2010Uganda8HildeCost of a human papillomavirus vaccination project, Zimbabwe2014-2016Zimbabwe6TracyPlanning for human papillomavirus (HPV) vaccination in sub-Saharan Africa: A modeling-based approach*22006-2011Mali2163248572468101214MeanMedian Average cost (excluding vaccine) per dose for each study, (USD$ as of 2015)1StudyAverage price per dose ($)12345678$3.84 $5.20 Brew J, Sauboin C. A Systematic Review of the Incremental Costs of Implementing a New Vaccine in the Expanded Program of Immunization in Sub-Saharan Africa. MDM Policy & Practice. 2019;4(2):2381468319894546. doi:10.1177/2381468319894546. | 2. US. Congress. House of Representatives. The Tuareg Revolt and the Mali Coup. 2012. Updated June 28, 2012. Accessed April 5, 2022. https://www.govinfo.gov/app/details/CHRG-112hhrg74863/CHRG-112hhrg74863. | 3. Botwright S, Holroyd T, Nanda S, et al. Experiences of operational costs of HPV vaccine delivery strategies in Gavi-supported demonstration projects. PLoS One. 2017;12(10):e0182663. doi:10.1371/journal.pone.0182663. *High price may be due to the conflict in Mali, particularly the Tuareg Conflict, which began in 2006**High price likely due to small scale of demonstration projects

25. Costs also were broken down into introduction and recurrent non-operational delivery costs1. Levin A, Wang SA, Levin C, Tsu V, Hutubessy R. Costs of introducing and delivering HPV vaccines in low and lower middle income countries: inputs for GAVI policy on introduction grant support to countries. PLoS One. 2014;9(6):e101114. doi:10.1371/journal.pone.0101114. | 2. Gavi page. Human papillomavirus vaccine support website. Available at https://www.gavi.org/types-support/vaccine-support/human-papillomavirus. Accessed April 5, 2022. Cost componentCost sub-componentAmount (USD)Elements included in the study reportTotal cost per dose$ 8.34**excludes cost of vaccine wastage Non-vaccine operational delivery costMicro-planning*, social mobilization and IEC (Information, Education and Communication), training, and purchase of cold chain storage/equipment**1Introduction$ 2.00RecurrentRoutine social mobilization and IEC, refresher training, service delivery (outreach per diems, transport), monitoring and evaluation, supervision, and waste management**1$ 1.84Vaccine cost through Gavi***Vaccine Alliance (GAVI) negotiated cost for lowest-income countries****2$ 4.50While the 8 studies previously mentioned were assessed to determine delivery cost, 4 distinct scaled-up HPV vaccination studies in Tanzania, Uganda and Bhutan were used to determine the average breakdown of how much of the overall cost of an HPV vaccine program is spent on introduction (52%) versus recurrent (48%) costs1*Micro-planning may be considered a recurrent cost as well, which could impact the breakdown of introduction and recurrent costs**Breakdown of introduction and recurrent costs from four low-income scaled up HPV vaccination studies***Country versus donor share varies ****Based on Gavi price

26. Heterogeneous methods for HPV costing studies create limitations when analyzing costs of a programOn-going researchThere are several ongoing studies, such as initiatives in 6 countries funded by PATH and the Gates Foundation, being conducted by health economists to determine broad cost implications of HPV vaccination, which may provide insights into cost-savings from a single doseIn the coming years, these data may become available and shed light on costing considerations for HPV vaccination programs26LimitationsSwing factors for countriesDescriptionHeterogeneity in vaccine programsCampaign strategiesDifferent delivery modalities (e.g., school-based versus facility-based outreach), campaign strategies (e.g., demonstration project versus national rollout) impact the percentages of girls reached and sessions conducted depending on the country or regionVarying approaches to costing analysisCost analysis approachDifferences in methodologies of data collection, variable costing assumptions and approaches (e.g., valuation of economic versus financial costs, introductory versus recurrent costs,) and discrepancies in sample sizesCountry-specific variationsGovernment/political system dynamics, donor contributionsCountries vary in terms of accumulated resources, government systems and geopolitical considerations, and countries receive different amounts of moneys from donors for national HPV programs; therefore, the cost is biased to the amount a country initially had to spendImpact of uptake on per-dose vaccine costAccessibility and population of adolescent femalesRegional differences in target age ranges, frequency of vaccination sessions, and population impact the uptake of vaccination in an analysis; when this value is used as a denominator to calculate the cost per dose, higher uptake in a country may indicate lower costs of HPV vaccination as compared to another region; however, total budget matched another region, but one program just had greater HPV vaccine uptakeChanges in cost over timeDuration of buildup costsDifferent studies and regions may require higher introductory costs for a different span of time than others (e.g., cost may remain high in one region for 4-5 years after program development, whereas in another region, costs may decrease after a year)

27. Based on a range of initial scenarios, an additional ~45-90M girls could receive an HPV vaccine in the next decade based on implementation of a single-dose regimen271. WHO https://immunizationdata.who.int/pages/coverage/hpv.html. | 2. Prem K, Choi YH, Bénard É, et al. Global impact and cost-effectiveness of one-dose versus two-dose human papillomavirus vaccination schedules: a comparative modelling analysis. medRxiv. Preprint posted online February 8, 2021. https://doi.org/10.1101/2021.02.08.21251186. POTENTIAL TOTAL INCREASEEstimated potential increase (Million)Additional uptake may arise from the 10- to 14-year-old cohort as well as MACs developed for aging cohorts given decreased supply constraintsCountries eligible for GAVI-support*1 that have not yet introduced an HPV vaccination programExample assumptions of new introductionCountries ineligible for GAVI-support*1 that have not yet introduced an HPV vaccination programCountries eligible for GAVI-support1 that have already introduced an HPV vaccination programNew introductions50% of GAVI-eligible countries with no HPV vaccination program50% of GAVI-ineligible countries with no HPV vaccination programN/ALow-end rangeGoes from 0% coverage to 40% coverage**2 in 9-year-old girls over the next 10 yearsGoes from 0% coverage to 40% coverage**2 in 9-year-old girls over the next 10 yearsGoes from 16% coverage to 40% coverage**2 in 9-year-old girls over the next 10 yearsHigh-end range of coverageGoes from 0% coverage to 80% coverage***2 in 9-year-old girls over the next 10 yearsGoes from 0% coverage to 80% coverage***2 in 9-year-old girls over the next 10 yearsGoes from 16% coverage to 80% coverage**2 in 9-year-old girls over the next 10 years~20-38~23-44~1-5~44-87*GAVI eligibility**Initial scenario assumptions 50% of modeling coverage assumed***Initial scenario assumption of 80% as assumed

28. Through increased uptake, models suggest a single-dose regimen may help significantly decrease cervical cancer cases and deaths in the future Prem K, Choi YH, Bénard É, et al. Global impact and cost-effectiveness of one-dose versus two-dose human papillomavirus vaccination schedules: a comparative modelling analysis. medRxiv. Preprint posted online February 8, 2021. https://doi.org/10.1101/2021.02.08.21251186. LowMiddleHighCountry income level1Cervical cases averted (M)Number of girls vaccinated to avert a single cervical cancer caseFewer girls need to be vaccinated in low- income countries than in high-income countries to avert a single cervical cancer case1 Due to disparities in cervical cancer incidence rates across income levels, ~7x more cases would be averted in low-income countries than in high-income countries164M+ cervical cancer cases averted12120Impact over timeImpact across income levelsIn 98 yearsLowMiddleHigh2022

29. A single dose approach to HPV vaccination could have substantial life-saving impacts according to modeling studies Assumptions: In 192 countries, 80% coverage of 10-year-old girls (with one-year catch up for girls 11 to 14-year-old) for the years 2021–2120 receiving a nonavalent vaccineCervical cases averted1 Years of protection/Vaccine Efficacy% of cases averted by a single dose compared to 2-dose*64M20 Y/ 100%94.666.6M30 Y / 100%97.368.4MLifetime / 80%97.6Given that the assumed vaccine efficacy of the single dose, at 80%, is lower than efficacy indicated in clinical trials2, the avoided cervical cases and overall impact may be underestimated 1. Prem K, Choi YH, Bénard É, et al. Global impact and cost-effectiveness of one-dose versus two-dose human papillomavirus vaccination schedules: a comparative modelling analysis. medRxiv. Preprint posted online February 8, 2021. https://doi.org/10.1101/2021.02.08.21251186. | 2. Barnabas R, Brown E, Onono M, et al. Efficacy of Single-Dose HPV Vaccination Among Young African. NEJM Evidence. 2022. doi: 10.1056/EVIDoa2100056. Results were consistent across the three independent models** and suggest that one-dose vaccination has similar health benefits to a two-dose regime while simplifying vaccine delivery, reducing costs and alleviating vaccine supply constrain**The three published transmission dynamic models used are the Public Health England (PHE) model, the HPV-ADVISE model and the Harvard model.

30. Additional considerations for a single-dose regimen

31. Outstanding questions related to single-dose HPV vaccination HPV single-dose vaccination should be implemented when more data is generated, several years from now. With no change in approach for HPV vaccination globally, lives may be lost unnecessarily, given they could have been saved through implementing single-dose vaccination based on current data.1Additional clinical trial dataDescriptionAdditional considerationsSince HPV vaccination occurs at a pre-adolescent age, girls will likely not be infected with HIV when vaccinated; while ongoing studies are looking into the impact of vaccination on this population, it is less likely that vaccine efficacy will be impacted if HIV is acquired late. Separate guidance on dosage could be provided for these populations as data is generated.HIV positive individualsThere is limited data regarding the efficacy of a single dose of HPV vaccine on either women living with HIV at time of vaccination or in women vaccinated and acquiring HIV later in life.1. Prem K, Choi YH, Bénard É, et al. Global impact and cost-effectiveness of one-dose versus two-dose human papillomavirus vaccination schedules: a comparative modelling analysis. medRxiv. Preprint posted online February 8, 2021. https://doi.org/10.1101/2021.02.08.21251186.

32. Evan Simpson esimpson@path.orgAnne Schuindaschuind@path.org

33.