Public health opportunities resulting from sufficient HPV vaccine supply and a single-dose vaccination schedule

Abstract

Many countries with the highest burdens of cervical cancer have not yet offered human papillomavirus (HPV) vaccines to most of their age-eligible girls, who as adults also have limited or no access to effective cervical cancer screening or treatment. There are now 2 complementary developments that could make HPV vaccines more accessible and affordable: 1) the current and projected increases in HPV vaccine supply; and 2) the permissive recommendation for single-dose HPV vaccination schedules. This change in policy paired with the healthier HPV vaccine supply is an incredible opportunity to facilitate rapid access and expansion of HPV vaccination. Female adolescent vaccination including multiage cohorts must be prioritized. In the coming decades, this is the most cost-effective approach to avert millions of projected cervical cancer cases, which account for most HPV-related cancers globally.

Sixteen years after the first human papillomavirus (HPV) vaccine registration, hundreds of millions of HPV vaccine doses have been administered globally (1). Postmarketing surveillance studies have confirmed initial observations in clinical trials of a strong safety record and sustained high efficacy (2). Country-wide vaccine linkage studies have now documented substantial reductions in invasive cervical cancer and other disease endpoints among HPV-vaccinated girls and women, with the greatest impact in younger girls vaccinated before sexual debut (3-5). While 60% of World Health Organization (WHO) Member States have introduced HPV vaccination into their national immunization schedule, as of 2020-2021, only 13% of female adolescents in the world were fully vaccinated (6). This discrepancy has arisen because many countries do not yet have national HPV vaccination programs or, if implemented, have inadequate uptake. Countries without national vaccine programs often have the highest burden of cervical cancer (7): 84% of the cervical cancer burden occurs in low- and low–middle-income counties (8). And yet, only 19% of low–middle-income countries introduced HPV vaccination as of 2019 (9) compared with 85% of countries in the Americas and 77% of countries in Europe, the majority of which are middle to higher income. Cervical cancer screening is inaccessible or infeasible in many of the countries struggling to introduce HPV vaccination; thus, girls and women have no access to cervical cancer prevention in their lifetime (10). Our global community is not on track to achieve the WHO cervical cancer elimination goal of HPV vaccination of 90% of age-eligible girls by 2030.

Rapid access and expansion of HPV vaccination is needed now, with female adolescent vaccination including multiage cohorts being prioritized: this is the most cost-effective approach to avert the millions of projected cervical cancer cases, which account for most global HPV-related cancers expected to occur over the coming decades.

In 2020, we published a commentary emphasizing HPV vaccine supply shortages and advising that HPV vaccination efforts exclusively focus on young girls to maximize the potential public health impact of the existing HPV vaccine doses (11), as per the WHO recommendation in 2019 (12). The WHO recommendation rightly indicated that although the HPV vaccine shortage persisted, HPV vaccines should not be offered to boys because the number of vaccinations needed to prevent 1 HPV-related cancer in men (including oropharyngeal, penile, and anal cancers) was dramatically greater than the number of girls who would need to be vaccinated to prevent 1 cervical cancer in women (13). Thus, from a public health perspective, more cancers could be averted with the same number of HPV vaccine doses by simply administering them to girls and not including boys or adult HPV vaccination. The ability of the HPV vaccine to induce herd protection also means that widespread vaccination of girls can indirectly protect most boys (and then men) against HPV infection and disease (14).

Rationale for commentary

There are 2 complementary developments in HPV vaccination that prompted this follow-up commentary: 1) the current and projected increases in HPV vaccine supply and 2) the first recommendations for single-dose HPV vaccination. Together, these changes imply that it may be possible to greatly expand the number of people who are (fully) vaccinated.

Update on HPV vaccine supply

Supply constraints have already lessened and will likely continue to ease for several reasons, including 1) additional supply from existing manufacturers because of increased production capacity; 2) multiple new HPV vaccines that achieved market authorization (Innovax; Xiamen Biotech Co. with Chinese market authorization and WHO prequalification; Walvax; Beijing Wantai Biological with Chinese marketing authorization); 3) reduced implementation of multiage cohort HPV vaccination of young girls over the past few years during the peak of the HPV vaccine supply limitation and school closures during COVID-19, even though multiage cohorts are strongly recommended to accelerate the public health benefits of vaccination; and 4) decreased HPV vaccine demand during the COVID-19 pandemic (15).

Global demand is expected to fully recover. Resource-limited countries, including Gavi-eligible countries, continue to display high interest in vaccinating girls against HPV, and additional resource-rich countries continue to introduce male vaccination in their national programs (approximately 10 additional countries since 2020) (15). Noting the increased demand, the global supply will likely be sufficient to meet global demand in the near term (ie, next 3 years), although with limited supply buffer. Moving forward, completion of the manufacturing capacity scale-up from current HPV vaccine manufacturers and planned increases in production capacity for new HPV vaccines (pending licensure) assure that there may soon be a more-than-adequate supply. Country willingness to use any of the available HPV vaccines deemed efficacious and safe by WHO or national regulatory authorities will be key to ensure timely access and earlier impact as well as to enhance a competitive and sustainable marketplace (15). Toward the end of the decade, the market is expected to be dominated by higher valency products as well as those with cross-protection beyond HPV16/18, which have the potential for greater impact on cancer prevention. Pricing policies by companies will also be key to enhanced access because HPV vaccines remain one of the most expensive vaccines (15).

Update on HPV dosing regimens

Over the past decade, there has been increasingly strong evidence that a single HPV vaccine dose of either the Merck or GSK HPV vaccine products provides robust and durable protection against cervical HPV infections (16,17). Reducing by one-half the number of doses needed to fully vaccinate the same number of girls (ie, moving from 2 doses to 1 dose) would considerably reduce the overall resource investment required to protect the same number of women from cervical cancer. The Strategic Advisory Group of Experts on Immunization, charged with advising the WHO on global vaccine policies and strategies, recently provided a permissive recommendation indicating that a single-dose schedule could be used for the primary target of girls aged 9-14 years and could even be used through the age of 20 years (19). The Joint Committee on Vaccination and Immunization, an expert scientific advisory committee that advises the government of the United Kingdom, provided interim advice for moving to a 1-dose schedule for the United Kingdom’s routine HPV immunization of boys and girls (18).

Public health implications and opportunities

Transition to single-dose vaccination programs paired with adequate HPV vaccine supply presents a tremendous public health opportunity to greatly expand prevention of future HPV-driven cancers. First, the reduced cost and resources required for a single-dose schedule compared with the more complex and resource-intensive 2-dose schedule will make HPV vaccine introductions more feasible and affordable. Of course, programmatic introductions must be accompanied by resources and funding to be tangible. Second, we must programmatically return to HPV vaccination of multiage cohorts of girls. Before the pandemic, 2 doses of HPV vaccine for multiage cohorts were already recommended as best practice for accelerating the impact of HPV vaccination. Now, as cohorts of girls may have missed HPV vaccination for a multitude of reasons, including the COVID-19 pandemic, it is imperative to apply this approach wherever feasible. Last, single-dose HPV vaccination affords the opportunity for considering expansion to other cohorts who may benefit from freeing up available HPV vaccine doses and resources. For example, HPV vaccination of boys may address several needs, including increased herd immunity if uptake is inadequate in girls, direct protection against HPV infections in boys and thus HPV-related cancers in men, and issues related to equity (because males and females are both at risk for HPV-driven cancers, albeit at vastly different global risk levels) or even vaccine hesitancy (relating to stigmatization of girls in some settings or if people erroneously think girls are preferentially targeted for HPV vaccination with mal intent). HPV vaccination could also expand to young adult women, a population in which modeling suggests that HPV vaccination will modestly accelerate control of cervical cancer (20). Careful consideration of local context should be used to determine the comparative public health benefit of using saved resources from a reduced schedule for HPV-related cancer prevention vs other health priorities as well as sequential phase-in of HPV vaccination beyond young girls.

Gaps in knowledge

Current gaps in knowledge require additional research over the coming years. The newer HPV vaccines have not been evaluated using a single-dose schedule; generating these data is a priority to ensure that these vaccines create opportunities for increased access, market competition, and supply security. For all HPV vaccines, there is a dearth of data on single-dose protection in boys and men; if single-dose HPV vaccination provides durable protection against cancer-causing HPV infections in males, does it also tip the scales toward cost-effectiveness? For people who are immunocompetent at the time of HPV vaccination and later acquire HIV, it is unclear whether their protection remains robust. Understanding this is critically important, noting that the burden of HPV-related cancers is greater in both women and men living with HIV. For these differing contexts, demonstration of immunologic noninferiority to established single-dose HPV vaccines and populations may be sufficient, although protection against virologic outcomes may also be needed for widespread implementation.

Summary

We view these new policies recommending single-dose HPV vaccination, paired with the healthier HPV vaccine supply, as incredible opportunities to further advance HPV-related cancer prevention efforts. GAVI, the Vaccine Alliance, is renewing its efforts in support of HPV vaccine introduction for Gavi-eligible countries. Member States of WHO have approved the strategy to eliminate cervical cancer by 2030, and this includes 90% global coverage with HPV vaccines, a target that will be more easily achieved by using a single-dose strategy. After more than 2 tremendously difficult years of SARS-CoV-2 pandemic, renewed efforts are required to support the global introduction and high uptake of HPV vaccines, and a single-dose strategy will have a huge impact on this goal. COVID-19 vaccination has renewed political will and understanding of the incredible return on investment for vaccination. This must be leveraged now to ensure the timely control of cervical cancer, a leading cause of cancer death in women, particularly in resource-limited countries.

Funding

No funding was used for this commentary.

Notes

Role of the funder: Not applicable.

Disclosures: ARK, TC, CP, JMLB, HR- none. JTS—An inventor on U.S. government-owned patents related to the HPV vaccines that were licensed to Merck and GlaxoSmithKline.

Author contributions: ARK, TC and JTS: conceptualization. ARK and TC: writing—original draft. All authors: writing—review & editing.

Acknowledgements: We thank Drs. Douglas R. Lowy and Monica S. Sierra for their constructive feedback on this commentary.

Disclaimers: The content reflects the authors’ personal opinions and does not reflect the opinions of our individual institutions, many of which do not advocate for policy (ie,: National Institutes of Health/National Cancer Institute).

Data availability

No new data were generated or analyzed for this commentary.