key: cord-1012638-e6jh6zs8 authors: Kumar, Somesh; Khanduri, Arunima; Sidibe, Anissa; Morgan, Christopher; Torode, Julie; Basu, Partha; Bhatla, Neerja; Schocken, Celina; Bloem, Paul title: Acting on the call: A framework for action for rapid acceleration of access to the HPV vaccination in low‐ and lower‐middle‐income countries date: 2020-12-16 journal: Int J Gynaecol Obstet DOI: 10.1002/ijgo.13482 sha: 0d68920218149d5dc2aca693b65d729880260a63 doc_id: 1012638 cord_uid: e6jh6zs8 Cervical cancer, caused by HPV infection, is responsible for more than 311 000 preventable deaths every year. A global call to accelerate efforts to eliminate this disease has generated a new global strategy proposing ambitious, but achievable, targets for HPV vaccination of girls, and screening and treatment of women. The present paper addresses the suboptimal access to HPV vaccination in low‐income and lower‐middle‐income countries (LICs/LMICs), where the burden of disease weighs most heavily, in part through co‐infection with HIV. A proposed framework for action was formulated by first reviewing the reasons underlying gaps in HPV vaccine coverage. Good practices from recent introductions of HPV vaccine at scale in LICs/LMICs were then assessed based on targeted literature reviews and the experience and views of the authors. Difficulties in uptake and coverage of the HPV vaccine relate to the costs of the vaccine and service delivery, lack of prioritization, the challenges of vaccinating adolescents, and shortage of vaccines as the supply failed to keep pace with the rapid expansion in global demand, including from LICs/LMICs. The framework for action calls for new strategic thinking to consolidate global learning and invigorate operationalization at a country level. less than four cases per 100 000 women. In response, a global strategy for elimination using primary prevention (vaccination) and secondary prevention (screening and treatment of cervical pre-cancers) has been developed 5 and approved by WHO Member States 6 through the modified World Health Assembly process in 2020. According to the WHO Cervical Cancer Elimination Modelling Consortium (CCEMC), if 90% coverage of HPV vaccination of girls (by 15 years of age) could be achieved, together with 70% coverage of screening (twice in a lifetime with a highly sensitive test), followed by 90% uptake of treatment, by 2030; then cervical cancer could be eliminated globally by 2100. 7 In doing so, more than 74 million cases would be averted over the next century, 61 million of these by vaccination alone. 7 Given the critical role of the HPV vaccination for the elimination of cervical cancer, the aim of the present paper was to understand the reasons behind the suboptimal access to the HPV vaccination in LICs and LMICs thus far 4 and to suggest a multidimensional framework for reaching the 2030 goal of vaccinating 90% of eligible girls. Such a framework can demonstrate the need for multiple and synchronized strategies to move from the current 15% global coverage of the HPV vaccination 4, 8, 9 to the targeted 90% by the year 2030. Convergence, synergy, and harmonization across all stakeholder efforts are needed to reach these targets. The proposed framework for action was formulated using a threestep process. First, the reasons behind the gaps in coverage of the HPV vaccination in LMICs were analyzed, covering finances, products, health systems, and community engagement. This was followed by a review of the demonstrated best practices and promising innovations based on targeted literature reviews, 10 and the experience and views of the authors. Lastly, based on the present analysis and review, a pragmatic multidimensional framework for action was proposed to provide actionable guidance to the global and in-country stakeholders. This aims to help plan and coordinate strategies for actualizing the global call to action for the elimination of cervical cancer. cination. This has resulted in less than 25% of girls living in LICs and LMICs having access to the HPV vaccination. 11 This inequity of access is driven by the cost of vaccines, cost of delivery, prioritization below other new vaccines, and, lately, shortage of vaccine supply. The HPV vaccine is among the more expensive vaccines in the national immunization schedule. However, in 2011, an opportunity was made available by Gavi Organization (PAHO). 12 The cost of HPV vaccines for middle-income countries (MICs) is still about three times the cost of the price of HPV vaccines for Gavi-eligible countries and this has contributed to financial barriers for these countries to introduce the vaccine. 12 The recurrent cost of delivery of the HPV vaccine is an additional financial barrier to the access of the vaccines in LICs and LMICs. 13 As per a costing study of the early introduction efforts, the financial cost of delivery of HPV vaccines through a school-based vaccination, proven to be the most effective route of delivery to date, is US$1.80 per dose, much higher than the facility or outreach-based strategies used for other pediatric vaccines. 13 This does not take account of the introduction costs related to generating demand and social mobilization needed for high coverage, which are greater for HPV than other vaccines. Introduction and maintenance at scale in LICs and LMICs requires policy and leadership commitment to the elimination of cervical cancer. Competing priorities such as the introduction of other vaccines against pneumococcal and rotavirus disease, with support from pediatric interest groups, may have taken precedence over the introduction of the HPV vaccine in some countries. 14 While HPV vaccine costs are similar or lower than other new vaccines, delivery costs appear higher than the childhood vaccines. 13, 15 Countries with larger populations such as India (which bears nearly one-fifth of the global burden of cervical cancer) have been slower to introduce the HPV vaccine, and localized efforts there demonstrate the critical importance of both political commitment and evidence of cost-effectiveness. 16 Other constraints on prioritization can include the fact this is specifically a women's disease, often under-recognized where cancer registries are weak, and that returns on investment take 30 years or longer to become apparent. Although HPV vaccines require a new immunization platform, LICs and LMICs can perform as well as HICs: a majority of countries have coverage over 50% and many exceed 80%. 9, 15, 17 This is enabled for most through a school-based delivery strategy 18 ; however, policy makers and program managers raise increasing concerns with its costs 18, 19 and the inequity of missing girls who are not in school. 15, 18, 20 While out-of-school girls could be vaccinated in health facilities, 17 in reality the uptake is inconsistent, and reaching this marginalized group is not yet adequately planned, resourced, measured, and monitored. 18, 20 Other constraints on school-based vaccination may relate to rumors and reluctance from the community or staff. 21, 22 School managers may also add barriers by requiring procedures of written consent and, in some cases, not allowing the vaccination on the school premises, more often in private institutions, and especially important in urban areas. 20 Reaching a consistent high coverage of a second dose has also been a challenge for some contexts 20,23 due to weak mechanisms for tracking girls for follow-up after their first dose. Identifying the number and location of out-of-school girls, 18 Understanding these challenges is an important first step to plan towards achieving the 2030 targets of 90% coverage with the HPV vaccination. It is only fair to note that introduction of the HPV vaccine in LICs/LMICs only began at scale over the last few years. However, there is sufficient experience now to highlight key opportunities for acceleration and identify where innovation can best contribute to move from the current global coverage levels of 15% 11 towards the targets of 90% coverage by the year 2030. From analysis of the challenges presented above, a framework for action was proposed for global and in-country stakeholders to organize and harmonize efforts to reach the levels of access needed to achieve the 2030 targets. This multidimensional framework addresses most of the determinants of consistent, high, and equitable coverage and identifies potential new levers and drivers for rapidly expanding access in LICs/LMICs. Innovation is needed in multiple areas to improve vaccine products as well as delivery, especially in resource-constrained settings. Thankfully, some promising developments are currently in progress that can alleviate some of the challenges discussed above. The price and supply of the HPV vaccine had been a major barrier for countries with the highest disease burden, despite Gavi's suc- Another innovation applicable to HPV vaccines is the controlled temperature chain (CTC). CTC is a program innovation that promotes "on-label" deployment of suitable, accredited vaccines at temperatures outside of the traditional cold chain of +2°C to +8°C. 25 Although Gardasil (HPV 4) has already been licensed and prequalified for CTC, and other vaccines may be candidates, this advantage has rarely been exploited. Countries could leverage the capacity of CTC to save costs and enable easier outreach in schools and small facilities, and in going the last mile through community outreach to reach out-of-school girls. 26 Microarray patches (MAPs, also known as microneedle patches), or other needle-free solutions, are a promising innovation as a potential alternative method of vaccine delivery; however, their potential for HPV vaccines is not yet known. MAPs offer clear advantages in easier delivery through self-administration or by lesser-trained staff as well as easier waste disposal. Some may also offer better vaccine thermostability, easing burdens on the cold chain. 27 All these are especially beneficial to low-resource settings, including for school-based vaccinations where teachers or community health workers for out-of-school girls could act as potential administrators of the vaccine. For the priority target population of girls aged 9-14 years, the HPV vaccine is currently delivered under a two-dose regimen, at intervals of at least 6 months. 28 LICs/LMICs are challenged to finance two doses of a relatively expensive vaccine, and institute tracking and follow-up to ensure good coverage of the second dose. 28 Mongolia, will be reporting in the near future and the evidence is expected to be evolving rapidly. The WHO Strategic Advisory Group of Experts on Immunization (SAGE) will continue to review evidence on the single dose as it becomes available, 30 such that global policy may change in some years. A single dose could be a game changer, by reducing the financial cost of the vaccine, increasing the ease of delivery, and balancing the supply-versus-demand scenario. In November 2019, WHO SAGE reinforced the continuing benefits of programmatic innovation, including maximizing service delivery efficiencies in the light of global supply constraints. These included that "Countries introducing HPV vaccine should consider initially targeting an older cohort of girls (e.g. 13 or 14 years old), as this strategy will retain the maximum disease impact…" while noting the inherent challenges of reaching an older age group and achieving a high coverage of the second dose. 32 Gavi and alliance partners adopted a similar strategy to maximize the number of HPV vaccine launches, in asking countries to introduce with a single age cohort only until sufficient supply is available. 33 The same deliberations proposed consideration of an extended interval between doses: "Countries could adopt a '1 + 1' schedule with an extended interval of 3-5 years between doses for younger girls (e.g. first dose provided at 9 or 10 years old or lower school grade) and taking measures to ensure that the girls receive two doses each. This strategy constitutes an off-label use of the vaccine". 30, 32 One caution is that countries adopting this approach will also need to overcome the programmatic challenges of tracing, registering, and reminding girls for catch-up, and carefully consider the risks related to the age of onset of sexual activity in their setting. 30, 32 A priority for programmatic innovation is to more explicitly define and promote the hybrid approach to service delivery that complements school-based vaccination with stronger facility-based vaccination, 17 Achieving the goals for the elimination of cervical cancer will need a significant increase over current levels of global health investments, with a revision to spending priorities. Accounting for one-quarter of health spending in LICs, 32.1% of development assistance for health was aimed at reproductive, maternal, newborn, and child health services, and only 2% of Development Assistance for Health was allocated to cancers and other non-communicable diseases that account for over 60% of the global disease burden. 34 Both maternal health and cervical cancer are women's health issues, but cervical cancer receives significantly less funding than maternal health. 35 Additionally, while there is strong recognition of the relationship between HIV and HPV infections, there is a need to leverage the investments in HIV prevention efforts for increasing access to the HPV vaccination. 36 The diversion of funding to and projected reductions in government budgets due to the COVID-19 emergency will also have a major effect, as discussed below. Of the total US$10.5 billion financing needs for the elimination of cervical cancer, 59% are for vaccination programs, with 41% for cancer prevention programs. Countries can leverage external support to introduce the HPV vaccine in the short term, but for longer-term sustainability, their own long-term funding solutions must be developed. 41 An analysis of 12 Gavi HPV demonstration programs 13 found that the greatest share of financial costs at the country level were social mobilization at approximately 30% (range 6%-67%) and service delivery at about 25% (range 3%-46%), while vaccine costs were the main economic cost driver. Although achieving the highest coverage for the second dose, a school-based strategy did have the highest service delivery cost per dose in comparison with outreach or facilitybased vaccination. 13 From a sustainability perspective, without an existing infrastructure for school-based delivery, countries will incur higher costs for school delivery. Countries are encouraged to take a long-term view to invest in school health programs to advance a range of health interventions for adolescents, including the HPV vaccination. 13 Sri Lanka integrated the HPV vaccine in their existing school medical health inspection program and achieved 82% coverage for the second dose, as of 2019. 9, 42 Advocacy efforts for sensitizing country policy makers on appropriate and adequate investments for achieving and sustaining high coverage should be prioritized. Integration of the HPV vaccination with other adolescent health services advances progress to 90% coverage targets in several ways. First, it can help share costs of delivering other life-saving interventions, noting evidence that that cost per vaccine dose was lower when delivery was integrated into existing health services. 43 Beyond efficiency, integrated services can be more attractive to girls and their families, boosting demand. 44 Most importantly, this can expand equitable access to HPV vaccines and other important adolescent health services with high intrinsic benefits, 40 with vaccination as one gateway of entry to the health system for young people. There is already a significant body of evidence on the successful integration of adolescent health priorities in school programs. 45 WHO endorses a menu of evidence-based and short-duration adolescent health interventions to integrate with the HPV vaccination. 41, 46 The challenge for countries is to choose a limited set of highest priorities feasible in their programs. Some of these are being applied in settings such as Malaysia and South Africa and were recently tested by Gavi and Jhpiego in Tanzania. 20 There is room to strengthen facility-based adolescent-friendly platforms further in LMICs, including ensuring sufficient human resource capacity, interdepartmental coordination, more integrated planning across HIV and FP programs, and supporting the Expanded Program on Immunization (EPI) team to collaborate with new partners. 20 Tailoring integration packages to the preferences of families and girls is of proven effectiveness, 44 but needs more consistent application, possibly through more widespread use of formal tools to incorporate families' perspectives such as human-centered-design approaches. Inter-generational promotion of cervical cancer screening has been demonstrated in South Africa, 47 Thailand, the Philippines, 48 and Cameroon. 49 Greater synergy and convergence across global strategies and investments can help ensure these country integration experiences work to accelerate the HPV vaccination. An inter-agency coordination mechanism including funders, technical partners, and implementers could facilitate the exchange of information and ideas on integrated programming and collaborate on joint operational frameworks to harmonize across funders. There may be scope for a pooled funding mechanism for investments to promote co-design and delivery of integrated services. Vaccination goals would also be advanced by consensus on integrated program metrics, both in schools and beyond, linking these to broader movements in measuring global progress in adolescent well-being. 50 The availability of quality data related to different dimensions of HPV vaccination programming has been a limitation in designing effective and sustainable strategies for vaccine delivery in resource-limited settings, 51 as discussed above. Stronger data systems at scale are needed to better identify eligible populations and define better quality denominators, including better use of census or school enrolment data in micro-planning and progress assessments. 17,18,20,51 Improved paper-based or scalable electronic registers, tally sheets, vaccination cards, and reminder systems are critical gaps to be addressed in many countries. 20, 23, 41 Investing in the training of teachers and healthcare providers to involve them more actively in information systems can enable better application of eligibility criteria. For some settings, an age-based strategy can be successful, in which case it is critical to define age by calendar year of births, while in other settings, grade-based eligibility criteria will be optimal. Mechanisms to enumerate, estimate, and monitor coverage of out-of-school girls is a critical issue about equity, given that girls who are not in school are more vulnerable to health disparities. 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