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REVIEW ARTICLE
Year : 2017  |  Volume : 5  |  Issue : 1  |  Page : 2-7

A case study of Gavi'S human papillomavirus vaccine support programme


1 Ingram School of Nursing, McGill University, Montreal, Canada
2 Faculty of Law, McGill University, Montreal, Canada
3 Department of Biochemistry, Biostatistics and Occupational Health, McGill University, Montreal, Canada
4 School of Environment, McGill University, Montreal, Canada
5 Faculty of Medicine, McGill University, Montreal, Canada
6 Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada

Date of Web Publication20-Jan-2017

Correspondence Address:
Danielle Cazabon
Department of Epidemiology, Biostatistics and Occupational Health, Purvis Hall, McGill University, 1020, Pine Avenue, West Montreal, QC H3A 1A2
Canada
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DOI: 10.4103/2468-6360.198797

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  Abstract 

Human papillomavirus (HPV), a sexually transmitted DNA virus that can lead to cervical cancer, is the most common cancer among women in developing regions. More than 270,000 women die per year from cervical cancer globally, and 85% of those deaths occur in developing countries. In the past, many low- and middle-income countries (LMICs) have been unable to afford the implementation of HPV vaccination programmes, resulting in high cervical cancer mortality rates. Gavi, an organisation created to improve worldwide access to vaccines, undertook an initiative that had the goal of decreasing the price of an HPV vaccine to under $5 and increasing access for adolescent girl populations in LMICs. This was done through market shaping, co-financing and implementation support. This case study will present and evaluate Gavi's intervention by assessing targets, investigating cost-effectiveness and identifying strategic challenges.

Keywords: Cervical cancer, Gavi, global health, human papillomavirus, immunisation


How to cite this article:
Castro A, Cinà M, Helmer-Smith M, Vlček C, Oghor C, Cazabon D. A case study of Gavi'S human papillomavirus vaccine support programme. J Health Spec 2017;5:2-7

How to cite this URL:
Castro A, Cinà M, Helmer-Smith M, Vlček C, Oghor C, Cazabon D. A case study of Gavi'S human papillomavirus vaccine support programme. J Health Spec [serial online] 2017 [cited 2017 Apr 25];5:2-7. Available from: http://www.thejhs.org/text.asp?2017/5/1/2/198797


  Introduction Top


Human papillomavirus (HPV) is a sexually transmitted DNA virus that infects the skin and mucous membranes. Worldwide, the prevalence of HPV is ~11.7%. The frequency of HPV cases is much higher in developing regions, with Eastern Africa (33.6%) and the Caribbean (35.4%) having the highest prevalence.[1] Although approximately 90% of HPV infections regress to a subclinical state within 2 years, a persistent infection may lead to cancer. Many of the 100+ HPV strains are oncogenic with variants 16 and 18 alone causing roughly 70% of cervical cancer cases.[2] Cervical cancer is the most common cancer among women in developing regions. With a 52% mortality rate, more than 270,000 women die per year from cervical cancer globally, and 85% of those deaths occur in developing countries. Effective screening, vaccination and treatment programmes can reduce the high mortality rate, but these programmes are not readily available in developing regions.[2]

There are currently several HPV vaccines available: Cervarix ® produced by GlaxoSmithKline (GSK), Gardasil ® (Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine, Recombinant), and Gardasil ® 9 (Human Papillomavirus 9-valent Vaccine, Recombinant) which are both produced by Merck and Co. These products are virus-like particle (VLP) vaccines containing complex protein structures.[3] By 2016, national HPV vaccination programmes were active in many regions including North America, Australia, most of South America, the majority of Europe and a handful of African countries.[4] These vaccine programmes target children between 9 and 13 years of age and are typically administered in three doses over 6 months. Recently, however, the World Health Organization (WHO) has suggested that two doses of the HPV vaccine may be effective.[5]

When the first HPV vaccine, Gardasil, was released in 2006, it cost between $100 and $233 per dose in developed countries and between $30 and $100 per dose in developing countries.[6] This pricing left the vaccine beyond the means of many low- and middle-income countries (LMICs); hence, in 2011, the Pan American Health Organization negotiated a price of $14 per dose for its member countries.[6] Despite this decrease in price, it is still too expensive for many LMICs. In comparison, the HPV vaccine would need to be offered at $2 per dose to be comparable in cost-effectiveness to the vaccines against Haemophilus influenzae type B and hepatitis B, which have achieved high uptake in African countries.[7]

Problem statement

HPV infection leads to over 70% of cervical cancer cases, which in turn causes more than 270,000 deaths of women every year, mostly in the developing world. Although effective and safe vaccinations are available to prevent HPV infection, many of the countries most burdened by HPV and cervical cancer have been unable to afford the implementation of HPV vaccination programmes. Innovative and cost-effective strategies are therefore needed to lower the price of HPV vaccines and ensure that they reach those who need them most.

The intervention: Gavi's human papillomavirus vaccine support programme

Gavi's background

Gavi, the vaccine alliance, is a global health alliance whose goal is to improve worldwide access to vaccines. Gavi was founded upon a variety of public-private partnerships between national governments, UN agencies, private sector and nongovernmental organisations and foundations. The Alliance received initial funding of $750 million from the Bill and Melinda Gates Foundation and is now funded by governments (77%), corporations and foundations (22%), and private individuals (1%).[8]

Gavi's human papillomavirus vaccine targets

In 2011, Gavi announced that it would offer HPV vaccine procurement and implementation support to qualified countries.[9] To achieve Gavi's goal of making HPV vaccines affordable and accessible to the world's poorest, the organisation set three primary targets:

  • Negotiate with HPV vaccine manufacturers to reduce the price of the vaccine from $30 to $100 per dose range to a more affordable price of under $5 per dose. While Gavi has not commented directly on the origin of this price target, it corresponds with cost-effectiveness benchmarks suggested by the WHO and other studies [5],[7],[10]
  • Increase access to the vaccine. Gavi's targets were to immunise one million girls against HPV by 2015 and to immunize 33 million girls by 2020.[11] To promote this target, Gavi set an additional target to implement its first HPV vaccination programme in 2013
  • Collaborate with other pharmaceutical producers to encourage the development of more HPV vaccines by 2018.[9]


Gavi's strategy

What makes Gavi's intervention notable is its three-pronged business model of market shaping, co-financing and implementation support. Furthermore, Gavi's HPV vaccination support programme focuses on a hard-to-reach population (adolescent girls) in nations with an annual per capita gross national income (GNI) below or equal to its eligibility threshold. Gavi defines a country as eligible if its GNI per capita over the past 3 years is equal to or below $1,500.[12] Gavi aims to ensure the sustainability of HPV vaccination programmes through shifting the terms on which vaccines are supplied: Moving from the whims of charity to the profit and marketing motives that strongly resonate within pharmaceutical companies. Thus, countries working with Gavi do not receive vaccines for free but must account for their real cost.

Market shaping

Market shaping is a strategy whereby both the demand and, therefore, the supply of a product (the vaccine) are intentionally altered to make a large number of cheap units be as, if not more, profitable than a small number of expensive units. This is achieved when a number of countries pool and guarantee their demand. This gives pharmaceutical companies leeway to provide the vaccine at a lower price.

Gavi's strategy requires influencing “pull factors” to change the demand for the drug. To do this, Gavi must ensure that participant countries include the HPV vaccine on their policy agendas so that funding from both countries and Gavi's donors for vaccine procurement is predictable and stable. Measures to strengthen healthcare delivery systems must also be put in place.[13]

Gavi's market-shaping strategy also involves influencing the “push factors” to change the supply of the vaccine. This is done by pooling the demand of many countries to gain bargaining power in negotiations with pharmaceutical companies. Other supply-side interventions include leveraging existing capacities to improve vaccine delivery, guaranteeing stable and accurate demand forecasts and providing incentives to new manufacturers to work with this model. Using this model, pharmaceutical companies can go from a low-volume-high-cost strategy to a high-volume-low-cost strategy, thus creating a market where more individuals can pay for the drug and the company is able to sell more.

Co-financing

To ensure the financial sustainability of their model, Gavi establishes a co-financing model with each country that it supports. The co-financing model requires governments of participating countries to contribute towards the cost of the vaccines.[14] Co-payments for the HPV vaccine are calculated according to the country's economic status: Countries that are classified as low-income will be required to contribute less than stronger situated countries. A country's ability to co-finance is determined at the application stage. As a country's GNI increases, the proportion of the vaccination costs paid directly by its government will increase. Once the country's GNI reaches the upper threshold for Gavi support, the country graduates from Gavi funding.[12]

Implementation support

Gavi has created two paths by which a country can gain its support in implementing HPV vaccination programmes. To receive funding, a country must demonstrate its capacity to immunise >50% of adolescent girls (ages 9 - 13) in an average-sized district. If this is demonstrated, Gavi will begin working with the country to implement a national scale HPV vaccination programme.[15] If a country cannot demonstrate this capacity, Gavi will assist the country in running a demonstration programme. Gavi's board established three purposes of a demonstration programme. First, it is meant to assess the delivery strategy coverage, feasibility, acceptability and cost in order to create evidence supporting a national scale Gavi-supported intervention. Second, a programme is meant to examine how HPV vaccine delivery can be integrated with other adolescent health interventions already in place in the country. Third, the demonstration programme is an opportunity to encourage the integration of HPV vaccination into a national cervical cancer prevention and control strategy.[16] After 1 year of running a demonstration programme, the country must be able to show that the extant programme can be successfully scaled up to receive Gavi support for the introduction of a national-level programme.

Evaluating Gavi's intervention

Progress towards targets

Lower vaccine price

Gavi negotiated the supply and costing with two pharmaceutical companies: Merck and Co and GSK. By doing so, the price of the HPV vaccine was reduced to $4.50/dose from Merck and $4.60/dose from GSK.[17]

Increase access to the vaccine

Gavi's demonstration programme strategy reached its target to implement the first programme in 2013 with Kenya. Since then, Gavi-supported programmes have vaccinated one million girls reaching its second target.[18] Gavi's targets, however, should be evaluated beyond individual countries given that its market sharing strategy hinges on pooling the demand from many countries participating in the programme.

Gavi forecasted that by 2015, 21 countries would conduct demonstration projects and 8 countries would launch national HPV vaccination programmes. As of October 2015, 22 countries had implemented demonstration projects, in line with the forecast. Only three countries, however, had been approved for national-level vaccination programmes: Rwanda and Uganda, who launched their national programmes in 2014 and 2015, respectively, and Uzbekistan, who will launch its programme in 2017.[11]

Encourage new producers

Data regarding the third target, to work with more pharmaceutical companies by 2018 to produce a cheaper vaccine, were unavailable.

Human papillomavirus prevention and cost-effectiveness

Several studies have concluded that HPV vaccination of pre-adolescent girls is cost-effective for a large majority of Sub-Saharan African countries when the cost per vaccinated girl is less than US$25.[5],[7],[10] This represents the cost of 3 doses at $5 per dose and estimates for vaccine wastage, transportation, administration, immunisation support and other programmatic costs. This is in line with the prices offered to countries through Gavi. These studies also note the importance of various methods of screening in preventing cervical cancer. Many of these alternatives have proven to be difficult if not impossible to implement in resource-poor settings.[7] In addition, screening requires a bolstering of healthcare infrastructure on a larger scale than that of a primary prevention vaccination programme.

Due to the lack of data, the best proxy available for effectiveness is the number of girls vaccinated to date. As it has been shown that the HPV vaccine prevents infection with the most cancer-related and death-associated HPV types (16 and 18), it can be anticipated that high vaccination coverage will reduce the mortality of cervical and related cancers.[10],[19] A full cost-effectiveness evaluation of Gavi's HPV programmes could be furthered by comparing the cost and number of deaths averted in this intervention to results from other related interventions (such as expanding pap smear access and cervical cancer treatment). Unfortunately, there are no data directly comparing the results of Gavi-supported programs with other programs addressing HPV and cervical cancer in the same regions. While all available data indicate that Gavi-supported vaccination programmes are cost-effective, the true impact of Gavi's intervention on health outcomes will only become clear after several decades of implementation and monitoring. In addition, these data do not paint a full picture of the opportunity cost of choosing HPV vaccination over other interventions.

Strategic challenges

Many new vaccine programs face implementation difficulties, in part due to anti-vaccination organisations' campaigns.[20] Still, due to its higher cost, older target population and connection to sexual behaviours, the HPV vaccine likely faces more implementation challenges than most.

Delivery challenges

An HPV vaccination programme requires a new vaccination delivery platform for adolescents since the vast majority of vaccination programmes in developing countries are targeted at infants.[20] Creating a platform for the HPV vaccine that targets older girls contributes to the HPV vaccine's higher cost. Yet, vaccinating a large number of adolescents is needed for developing countries' populations to benefit from herd immunity.[20] Reaching marginalised adolescent girls makes widespread HPV vaccination in Gavi-supported countries difficult.[21] As a protein-based injectable drug that is temperature and time sensitive, the vaccine itself is also unsuited for delivery in many LMIC climates.[22] Edible vaccines (as opposed to injections by healthcare workers) are being considered for the second-generation HPV vaccine developments.[22] Perhaps, Gavi's future procurement negotiations (Target 3) should include manufacturers researching these more practical options.

Moral considerations

HPV vaccination initiatives also face ethical challenges: Considering that HPV can affect both boys and girls (although girls face the worst effects and bear the burden of cervical cancer), is it fair that only girls are being targeted for vaccination? Kane et al., explained that many men will not be protected from HPV for years (i.e., until heterosexual herd immunity results), and men who have sex with men will continue to face HPV contraction risks. Furthermore, considering that HPV is spread through sexual activity, vaccinating boys could contribute to further herd immunity, especially if the female target population only achieves lower coverage levels.[20],[23]

Negative attitudes towards the vaccine may also be an obstacle to programme implementation. Anti-immunisation groups have already targeted the HPV vaccine, claiming that HPV vaccines have had deadly results.[20] The HPV vaccine's connection to sexual behaviour can pose a problem in sexually conservative cultures.[20] One strategy that can help adjust countries' attitudes towards the vaccine is a marketing campaign. Kane et al., found that programme marketing which focused on the drug's ability to prevent cervical cancer, rather than on how HPV is transmitted, was more successful.[20]

Demonstration projects

Gavi-supported HPV demonstration programmes may prove to be a structural weakness in the initiative. The demonstration projects are meant to be used as learning opportunities for countries to determine their capacity to scale up vaccinations programmes to a national level. However, Gavi itself has admitted that there is “a degree of misalignment between the demonstration project's learning objective and the requirement for countries to have a demonstrated ability to qualify for support for national introduction”.[24] This incentivises countries to choose target sites for demonstration projects that will provide the easiest access to and strongest uptake by the target population. High-coverage resulting from choosing easier target sites signifies that countries are more likely to be deemed eligible for Gavi support.[24] However, these results from locations most amenable to a vaccine programme could suggest an inflated portrayal of the country's actual capabilities in creating HPV vaccination programmes that would reach adolescent girls on a national scale.

Changing policies and reduced demand

Finally, vaccine policy changes have challenged Gavi's market-shaping abilities. For its market-shaping strategy, Gavi forecasted the demand for the HPV vaccine based on the recommended course of three doses per individual. Soon after the demand was calculated, the WHO suggested that a two-dose schedule might be sufficient. The UNICEF, which procures the vaccine for Gavi-eligible countries, reported that 4 million doses were bought as of May 2015, which is less than was forecasted.[15] The WHO recommendation could, in theory, cause the demand for vaccine doses to decrease, which in turn could reduce Gavi's negotiating power with pharmaceutical companies. This indicates that seemingly beneficial policy changes could negatively affect Gavi's strategy.

Cost of vaccine

Ultimately, just under $5 per dose is still a high price for LMICs, especially from the perspective of long-term, independent sustainability. Padmanabhan et al., believe that in low-income countries, doses should cost under $2 for the vaccine to be broadly adopted in the long-term.[3] The high costs of new vaccines have played a factor in Gavi's decision to drop 16 LMICs, such as Honduras and the Democratic Republic of the Congo, from Gavi support.[25] Numerous factors contribute to vaccines' high costs, including the vaccine's demand, as well as the length of time the vaccine has been on the market.[25]

One of the biggest challenges that mass HPV vaccination campaigns face is overcoming its cost as a new vaccine. Médecins Sans Frontières has noted that in only 10 years, the cost of a recommended set of vaccines to protect a child has risen 25 times to nearly $40, in part due to newer vaccines being more expensive.[26] With limited budgets, developing countries must prioritise their spending and have to ask whether vaccinating against HPV (one relatively expensive treatment) is worth the opportunity cost of other treatments that could have been provided with that money.[20] Older vaccines cost as low as $0.19 per dose so even at $4.50 per dose the HPV vaccine is still relatively costly.[25] Countries might feel that the HPV vaccine does not offer enough “bang for its buck,” especially once countries graduate from receiving Gavi support and must pay for each dose themselves.

Lack of competition

As target 3 implies, the lack of HPV vaccine competitors is a weakness in Gavi's current strategy. After all, they have negotiated a long-term deal with two companies (Merck and GSK) at once, and these are the only two companies that currently have approved HPV vaccines on the market. This Gavi agreement is not the first time that Merck and GSK have shared resources on an HPV vaccine project: To avoid lawsuits from each other and to get both of their HPV vaccines to market in a timely fashion, GSK and Merck cross-licensed their technologies to each other.[27]

Gavi is determined to bring HPV vaccines to LMICs as soon as possible; it is not waiting for cheaper vaccines to be produced (even though HPV vaccines have only been around for ten years). In Gavi's 2012 procurement strategy, it planned to negotiate deals with Merck and GSK for the period lasting from 2013 through 2017.[9] Gavi's procurement strategy noted that it did not expect any new HPV vaccine to be available before 2018.[9] The alliance's challenge, at least for now, is to sustainably support the development of national HPV vaccination programmes in LMICs when there are no cheaper alternatives available in the near future. Gavi and its countries (via co-payments) must pay for large amounts of trade-named (although admittedly lower-priced) vaccines to vaccinate enough girls.

Patent and resource capacity issues

In 2006, Merck's Gardasil was the first HPV vaccine introduced to the market.[28] Since a key patent for GSK's Cervarix technology was filed and approved in 2006[29] and Merck's Gardasil's was issued in 1998[30] and patents tend to last about twenty years, patent-related issues surrounding research and generic production of these vaccines will probably not be overcome for several more years.[27] However, according to research on HPV vaccine patents, patents probably will not be the main inhibitor of cheaper HPV vaccine manufacturing. After studying the patents involved in Cervarix and Gardasil, Padmanabhan et al., found that Indian manufacturers can probably manufacture a bivalent HPV vaccine very similar to the current vaccines as long as the combination of VLP proteins in the new product is not identical to Gardasil's or Cervarix's.[3]

It might not be patent issues, but knowledge and resource capacity issues, which prevent the development of affordable HPV vaccines. As large, complex biological molecules produced using cell lines, the active agents in HPV vaccines are considered “biologics” rather than “small molecule drugs” (such as aspirin).[28] It is very challenging to prove that two biologics are the exact same (as opposed to proving that two small molecule drugs are the same) because biologics are so much larger and more complicated than small molecule drugs.[28] Identical small molecule drugs might be produced using several different pathways; therefore, patents protect small molecule drugs as much (if not more than) knowledge of the production process. However, with complex biologics, the production process determines the final product; the same product can probably not be reproduced using alternative pathways.[28] The process is not typically patented. It is a fiercely defended corporate secret protected even further by the fact that since it is unpatented, generic drug manufacturers cannot search the patent literature for production ideas.[28] Therefore, (unlike for small molecule drugs) even once the patents on the active ingredients in Cervarix and Gardasil end; unless detailed knowledge of the cell lines, the molecules themselves, and the exact processes used to produce these vaccines become known; generic production of these specific HPV L1-VLPs will probably not be possible.

Interestingly, public universities actually developed many of the procedures critical to the downstream development of the currently available HPV vaccines. However, the universities offered the licenses for many of these critical technologies exclusively to pharmaceutical corporations.[28] If these universities had instead offered their licenses and expertise to cheaper drug companies (for example, Indian generic drug manufacturers), as the second-generation HPV vaccine researchers are now doing, the first-generation HPV vaccines might have been more affordable.[3] Perhaps, Gavi should be supporting these university-LMIC research partnerships as part of its target three goals instead of funding Merck-GSK's through negotiations.


  Conclusion Top


Gavi's strategy is significant because it provides a way for LMICs to implement sustainable national-level HPV vaccination programmes targeting an adolescent population using market forces to its advantage. Gavi managed to achieve its first two major goals as it successfully lowered the negotiated vaccine prices down to under $5 per dose and vaccinated 1 million girls by 2015. It has also managed to increase accessibility to adolescent populations in these countries as shown in its ability to implement 24 demonstration projects (its original target was 21 demonstration projects by 2015).

It is too early to determine whether Gavi's strategy will succeed or not; after all, 24 demonstration projects are still in the works. However, Gavi's results so far have been modest at best. Only two countries (Rwanda and Uganda) had implemented a national strategy when Gavi's goal was to have eight countries with national strategies by 2015. Gavi's third target (to collaborate with more pharmaceutical companies to produce cheaper vaccines) has no indication of success thus far. Gavi's strategy has faced delivery challenges, potentially inflated demonstration project results and the threat of reduced demand. However, most critical to the HPV vaccine's adoption in LMIC's is the cost of the vaccine, which many still consider to be too high relative to other treatments for countries with finite health spending resources to justify. Without competition from cheaper HPV vaccines, this cost problem will not likely resolve itself soon. Overall, while vaccines can certainly be cost-effective (especially in regions where HPV screening services are unavailable), Gavi's strategy might have had a better chance of long-term success if it waited for cheaper vaccine alternatives to be developed or focused on promoting their development. As it stands, countries may drop out of the Gavi programme if they cannot meet their co-payments (or once they graduate, their full payments); or, they may opt-out of the programme entirely. If costs were lower, countries would have a better chance of developing sustainable national HPV vaccination strategies. Gavi may be able to implement demonstration projects but to claim that those projects are likely to produce the multitude of sustainable national strategies that Gavi wants remains unconvincing.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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