HPV vaccine introduction in the Americas: a decade of progress and lessons learned

ABSTRACT

Introduction

Human papillomavirus (HPV) is an important public health concern due to its causative role in many cancers, especially cervical cancer, and other conditions that lead to serious health consequences in both men and women. In Latin America and the Caribbean, nearly 60,000 new cases of cervical cancer and another 7,000 HPV-associated cancers are diagnosed annually.

Areas covered

HPV vaccination combined with comprehensive cervical cancer control programmingis paving the way for eliminating cervical cancer as a major public health problem and drastically reducing other HPV-associated diseases. To date, 44 countries and territories in the Americas have introduced HPV vaccines as part of their national immunization programs and cervical cancer control strategies. Early lessons from HPV vaccine introduction suggest that transparent and credible evidence-based decision-making, information, education and communication about HPV and cervical cancer, coordination with existing cervical cancer control initiatives, and precise planning for ensuring effective uptake of the vaccine in target groups are all critical elements of success.

Expert opinion

There is an urgent need for strategies to increase HPV vaccine coverage, and as the integrated control programs evolve and other HPV-associated disease becomes important for public health, there will be a need for continued program and policy evaluation.

KEYWORDS:

• HPV vaccination
• cervical cancer
• immunization
• Latin America
• Caribbean

1. Introduction

Human papillomavirus (HPV) is responsible for nearly all cervical cancers globally, is a known necessary underlying cause to a proportion of other anogenital and oropharyngeal cancers, and can lead to other serious health complications in adults and children [1]. Almost all sexually active men and women will acquire HPV infection in their lifetime from one or more of the 200 known types [1,2]. Although most infections spontaneously self-resolve, persistent infection with high-risk, oncogenic HPV types can lead to invasive cancers with devastating repercussions for families and communities [3,4]. This is especially common in low- and middle-income countries where approximately 80% of all HPV-associated cancer deaths occur due to suboptimal coverage of cervical cancer screening and early cancer treatment options[5].

In Latin America and the Caribbean, even with improvements in cervical cancer screening and treatment, the HPV-associated disease burden is largely borne by women due to the persistently high regional incidence of cancer of the cervix, especially in the Caribbean, compared to other HPV-associated cancers and diseases that affect both men and women [6]. Regionally, cervical cancer is the leading cause of cancer death among women in five countries and the second leading cause in 14 others. Every year roughly 69,500 women are newly diagnosed with cervical cancer and another 32,000 die due to this cancer in the region [7]. An estimated 72% of cancers of the cervix globally are linked to HPV 16 and HPV 18 and another 17% of cervical cancers are caused by HPV types 31, 33, 45, 52, and 58 [5].

The introduction of vaccines that protect against high-risk HPV types 16 and 18 and other types along with improvements in cervical cancer screening technologies and treatment availability is promising for women’s health in Latin America and the Caribbean and globally [8]. In 2008, the ministries of health of the Americas adopted a Regional Plan of Action for Comprehensive Control of Cervical Cancer and, in doing so, committed to strengthening prevention strategies to reduce the burden of cervical cancer regionwide [8]. With the wider availability and affordability of vaccines that now can prevent up to 90% of cervical cancers [9] and regional progress in expanding screening and treatment, there have been calls for countries to set clear targets toward the elimination of cervical cancer. In 2018, PAHO Member States responded to these calls by setting a goal of reducing cervical cancer incidence and mortality rates in the Region by one-third by 2030 [10]. These calls were further transformed into global commitments, in 2020, with the launch of a worldwide initiative to end cervical cancer as a public health problem by 2030 [11]. To do so, PAHO, WHO, and other partners have called on countries to achieve 90% HPV vaccination coverage of girls by age 15, 70% screening coverage, with a high-performance test among women aged 35 and 45 years, and 90% treatment of women with pre-cancer and invasive cervical cancer [11].

There are currently four vaccines available in the global market: two bivalent (HPV2), a tetravalent (HPV4), and a nonavalent (HPV9). Countries in the Americas were among the first globally to introduce them into their national immunization programs. Over the last decade, the region has made enormous progress with HPV vaccine introduction and developing resilient, high performing programs [12]. With this experience, several programs throughout the region are contributing early evidence on the effectiveness and impact of HPV vaccines and specific vaccination strategies [12–14]. However, HPV vaccination coverage data in Latin America and the Caribbean reveal a concerning trend of suboptimal uptake compared with other vaccines recommended for routine use in publicly financed immunization programs [15]. Improving vaccination coverage will be critical to realizing the regional goals of cervical cancer elimination and ensuring broader impact against HPV-associated diseases. This review aims to summarize the progress made on HPV vaccination in Latin America and the Caribbean while proposing strategies to overcome the challenges of low coverage and drop-out using lessons learned from countries that have successfully tackled these issues. This article also aims to summarize evidence updates that have led to revising policy decisions regarding the selection of target groups, vaccination schedules, vaccination strategies, coverage monitoring, integration with existing cervical cancer control programs, monitoring, and evaluation of the impact of these vaccines on the numerous possible clinical endpoints that the vaccines can target, and education and communication campaigns. Identifying highly effective strategies using lessons learned is crucial for making progress toward the goal of eliminating cervical cancer and greatly reducing other HPV-associated disease region-wide.

2. HPV vaccines in the context of cervical cancer control and elimination strategies in LAC

All four commercially available prophylactic HPV vaccines prevent against HPV16 and HPV18: the bivalents (Cecolin and Cervarix), the quadrivalent (Gardasil4), and the nonavalent (Gardasil9) [1,16]. Cervarix was licensed first in 2007. Gardasil4 was licensed in 2006 and additionally protects against low-risk types HPV6 and HPV11. Gardasil9, licensed in 2014, provides added protection against HPV31, 33, 45, 52, and 58 in addition to the types included the quadrivalent. Finally, Cecolin, a second bivalent vaccine, was licensed in 2019. Using recombinant DNA technology, all vaccines were developed based on the purified L1 proteins to create noninfectious, HPV type-specific virus-like particles (VLPs) [1].

Considering the HPV type-specific protection provided by the vaccines, all four are indicated for the prevention of premalignant anogenital lesions and cancers caused by HPV16/HPV18 affecting the cervix, vulva, vagina, and anus [1]. The quadrivalent is additionally indicated for the prevention of low-risk HPV types 11 and 6 [1], which are associated with >90% of anogenital wart infections in males and females [17,18]. The nonavalent is further indicated for the protection against HPV high-risk types 31, 33, 45, 52, and 58, which are oncogenic causes for another 20% of cervical cancers beyond HPV16 and HPV18 [19,20]. In the United States, as of July 2020, the nonavalent is also approved for an expanded indication for use in the prevention of oropharyngeal and other head and neck cancers [21]. Cervarix and Gardasil4 have also shown to provide some level of cross protection against certain non-vaccine HPV types [1].

From clinical trials to post-marketing surveillance and post-introduction observational studies, HPV vaccines have demonstrated excellent safety, efficacy, and effectiveness profiles for use against several clinical HPV endpoints [1]. Since the availability of first vaccines in 2006, more than 365 million HPV vaccine doses have been administered globally and no serious adverse events causally linked to the vaccine have been observed since licensure [22,23]. The primary benefit of HPV vaccines is to prevent HPV-related precancerous lesions and cancers of the cervix [1]. In the absence of timely detection, safe surgical intervention or treatment, these cancers are often fatal [24] and the vaccines prevent against this leading cause of premature death in women. All four vaccines are considered to protect equally against HPV16/18, demonstrating close to 100% efficacy against HPV16/18-related advanced cervical precancerous lesions (CIN 2/3 and AIS) in women naïve to these HPV types, i.e. girls who have not been infected with these HPV types prior to vaccination [1,25]. For the vaccines that protect against other HPV-related endpoints, the quadrivalent and nonavalent, these vaccines show highly favorable efficacy also against type-specific cancers of the anus, head, and neck [1]. Table 1 summarizes technical characteristics of the available vaccines currently used in LAC and the most recent evidence inputs regarding their use in national immunization programs.

Table 1. Characteristics and technical aspects of the available^‡ HPV vaccines.

	Bivalent	Quadrivalent	Nonavalent
Manufacturer	GSK	Merck	Merck
Composition	20 µg HPV16 L1 protein20 µg HPV18 L1 proteinAdjuvant: AS04	20 µg HPV6 L1 protein40 µg HPV11 L1 protein40 µg HPV16 L1 protein20 µg HPV18 L1 proteinAdjuvant: AAHS	30 µg HPV6 L1 protein40 µg HPV11 L1 protein60 µg HPV16 L1 protein40 µg HPV18 L1 protein20 µg HPV31 L1 protein20 µg HPV33 L1 protein20 µg HPV45 L1 protein20 µg HPV52 L1 protein20 µg HPV58 L1 proteinAdjuvant: AAHS
Indication	Use in females and males from the age of 9 years for the prevention of premalignant anogenital lesions affecting the cervix, vulva, vagina and anus, and cervical and anal cancers causally related to specific HPV types.	Use in females and males from the age of 9 years for the prevention of premalignant lesions and cancers affecting the cervix, vulva, vagina, and anus caused by high-risk HPV types, and anogenital warts causally related to specific HPV types.
Recommended schedule	9–14 years old: two doses six month apart≥15 years old or known immunodeficiency: three doses, 0-2-6 months intervalNote: there is no upper limit on the duration of interval between doses; however, every effort should be made to initiate the recommended series before sexual debut.
Recommended age for vaccination	For the prevention of cervical cancer: girls ages 9–14, prior to sexual debut. Selection of specific age cohort or range should align with delivery strategy.For prevention of secondary outcomes: boys and older girls only once after achieving coverage >80% in girls and if considered feasible, affordable, and complementary to the existing cervical cancer control objectives.
Route of administration	Intramuscular injection
Presentation	Single or two dose vial	Single dose vialPre-filled single dose syringe	Single dose vialPre-filled single dose syringe
Efficacy	Hildesheim et al., 2014Lehitenen et al., 2012Against CIN2+ regardless of genotype: 64.9%Against CIN3+ regardless of genotype: 93.2%	Kjaer et al., 2009Munoz et al. 201098.2% (95 CI: 93.3–99.8) against HPV16/18 related CIN2+ in women naïve to HPV16/1851.5% (95 CI: 40.6–60.6) against HPV16/18 related CIN2+ in women who had prevalent HPV16/18 infection at vaccination100% (95 CI:) against anogenital warts HPV6/1190.4% (95 CI: 69.2–98.1) against external genital lesions related to HPV16/18/11/6 in men (Giuliano et al. 2011) and 77.5% (95 CI: 39.6–93.3) against anal intraepithelial neoplasia related to vaccine targeted genotypes in men (Palefsky et al., 2011).	97.4% (95 CI: 85–99.9) against high-grade cervical, vulvar, and vaginal lesions related to HPV genotypes 31, 33, 45, 52, and 58; and immune responses non-inferior to HPV4 against HPV6, 11, 16, and 18.Huh et al., 2017
Safety	HPV vaccine has an excellent safety profile, with a lower number of Adverse Events Following Immunization (AEFIs) than many other vaccines
Cost-effectiveness	Most published cost-effectiveness analyses (n = 24) regarding the introduction of HPV vaccine (any product) compared to no vaccination or screening alone have yielded economically favorable incremental cost-effectiveness ratios (cost per incremental unit of health) in Latin America and the Caribbean. ICERs (standardized to International Dollars) ranged from <0 to 214,000 I$, with more than 60% of studies reporting a ICER below a willingness-to-pay threshold equal to 1 GDP per capita, concluding that HPV vaccination, specifically in young girls, is cost-effective or cost-savings in most country contexts in the region (Tejada, Malgon, Franco 2022).
Price/affordability	Not currently offered via PAHO Revolving Fund; country negotiated prices vary and not publicly available	US$9.98 per dose(PAHO Revovling Fund, 2020)	Not currently offered via PAHO Revolving Fund; country negotiated prices vary and not publicly available

^‡Only these 3 HPV vaccine products were used or are currently used in the region. Another bivalent vaccine product (Cecolin) is available, but not currently in use.

3. Policy development at the regional level: PAHO and SAGE recommendations regarding HPV vaccination

Following regulatory approval and WHO-prequalification of HPV vaccines, both the WHO Strategic Advisory Group of Experts (SAGE) on Immunization and the PAHO Technical Advisory Group (TAG) on Vaccine-Preventable Diseases (VPDs) have made strong recommendations in support of the adoption of HPV vaccines for the control and reduction of cervical cancer [1]. Recommendations from SAGE and PAHO’s TAG emphasize the use of HPV vaccines to prevent cervical cancer morbidity and mortality primarily and, therefore, prioritize the use of HPV vaccines in adolescent girls naive to the virus. Prioritizing adolescent girls for vaccination is supported by several studies that have demonstrated that high vaccination coverage of girl cohorts against HPV (>80%) is a cost-effective approach to reducing overall transmission of HPV and therefore providing indirect protection to unvaccinated males [26,27]. During PAHO’s meeting of the TAG, in 2019, the advisory body underscored the importance of prioritizing girls for HPV vaccination considering the overwhelming evidence that the HPV-associated disease burden in the region is generally driven by cervical cancer. PAHO’s TAG re-iterated the urgent need to scale-up coverage of the two-dose HPV vaccination schedule among girls aged 9–14 years of age, which implies ensuring that girls are being reached with the second dose with a minimum interval of 6-month between the first and second dose [28]. However, recent updates from SAGE on HPV vaccination included the endorsement of a 1-dose schedule and multi-age cohort vaccination strategies through the age of 18 years [29]. Additionally, SAGE has urged countries to develop a prioritization framework that guides decisions about identifying secondary target groups, such as boys, older women and men, HIV-infected individuals, based on decision criteria covering feasibility, cost-effectiveness, and distributional disease burden impacts [29]. PAHO’s TAG and National Immunization Technical Advisory Groups (NITAGs) at the country-level will need to review these recommendations and consider the feasibility of adopting them based on regional and national decision-making priorities in the context of the region’s goal toward ending cervical cancer as a public health problem.

4. Policy development at national level for the introduction of HPV vaccines

There are many considerations at the national level when developing and implementing immunization policy. Adding to the general complexities of these considerations, HPV vaccination decisions require proactive engagement with actors that historically have not played a role in implementing immunization programs, such as cancer control partners, and education systems when school-based vaccine delivery is being used. As such, PAHO and Member States have worked together over many years to strengthen the immunization decision-making infrastructure in the region and evidence-based planning process [30]. With the support of PAHO’s ProVac Initiative, 14 countries in the region undertook model-based simulation analyses to evaluate the cost-effectiveness of introducing HPV vaccines and strengthening cervical cancer screening programs [31]. These studies served as a framework for summarizing the available evidence on disease and economic burden associated with cervical cancer, documenting the financial and logistical details of the proposed vaccine strategies, defining the existing standards for screening and treatment, and estimating the effectiveness of HPV vaccines in terms of disease and healthcare cost reductions. As a framework, these evidence inputs were used to project the potential impact of HPV vaccination strategies and identify gaps in the evidence base that required further work prior to making plans for vaccine adoption [32]. In addition to PAHO’s technical cooperation for decision support, countries in the region convened annually at the TAG and during other interprogrammatic meetings to discuss progress on HPV introduction within the context of comprehensive cervical cancer control. These meetings have been critical for sharing many of the lessons learned summarized in this article and promoting interprogrammatic planning between the cervical cancer control and immunization programs.

5. Status of HPV vaccine introduction and vaccination coverage in Latin America and the Caribbean

By the end of 2021, 44 countries and territories in Latin America and the Caribbean had implemented HPV vaccines in their national immunization programs – providing access to adolescent girls in 89% of PAHO Member States [33]. The United States was the first country to adopt the HPV vaccine in 2006 following the FDA approval of the quadrivalent vaccine. Panama and Canada next introduced the vaccine in 2008. From 2011 to 2015, another 14 countries in Latin America and the Caribbean introduced HPV vaccines into their national immunization programs. Since 2016, the remaining 27 HPV vaccine introductions have occurred in the region. Currently, 42 countries use the quadrivalent HPV vaccine, 1 uses the nonavalent vaccine, and another has all three vaccines in use [33] (Table 2). The cecolin bivalent vaccine was only prequalified in 2021 by WHO and has not yet been used in the region.

Table 2. HPV vaccine introduction and program characteristics in Latin America and the Caribbean, 2020, by country^‡,†.

Country	Vaccine, year(s) introduced	Primary target population	Secondary target populations	Primary vaccination schedule	Delivery approach	Complete series primary target group coverage in females, 2020	Dropout^§ among females in target group, 2020
Anguilla	Bivalent, 2016 Quadrivalent, ...	Girls 9–11 years	…	…	…	…	…
Antigua and Barbuda	Quadrivalent, 2018	Girls and boys 9–13 years	Males and females 14–26 years	2-doses at 0 and 6 months 14–26: 3-doses	Facility-based	…	…
Argentina	Quadrivalent, 2011	Girls and boys 11 years	Males and females age 11–26 living with HIV and/or organ transplants	2-doses at 0 and 6 months	School-based and facility-based, varies by province	46%	26%
Aruba	Quadrivalent, 2014	Girls 11–12 years	…	…	…	…	…
Bahamas	Quadrivalent, 2015	Girls and boys 9–10 years	…	3-doses at 0, 1–2, and 6+ months	School-based	4%	8%
Barbados	Quadrivalent, 2014	Girls and boys 11 years	…	2-doses at 0 and 6 months	School-based	7%	57%
Belize	Quadrivalent, 2016	Girls 9–14 years	Boys on request and availability of vaccine	2-doses at 0 and 6 months	School-based	11%	40%
Bermuda	Quadrivalent, 2017	Girls 9–13 years	…	…	…	…	…
Bolivia	Quadrivalent, 2017	Girls 10 years	…	2 doses at 0 and 6 months	School-based	24%	36%
Bonaire	Quadrivalent, 2015	Girls 11–12 years	…	…	…	…	…
Brazil	Quadrivalent, 2013	Girls 9–14 years; Boys 11–14 years	Males and females 9–26 years of special risk groups	2 doses at 0 and 6 months	…	72%	16%
British Virgen Island	Bivalent, 2019 Quadrivalent, current	Girls 10 − 11 years	…	…	…	…	…
Canada	Quadrivalent, 2007–2009 Nonavalent, current	Girls and boys 12–13 years	Catch-up for girls and boys grades 8–12	2-doses at 0 and 6 months		87%	…
Cayman Islands	Quadrivalent, 2019	Girls 10–11 years	…	…	…	…	…
Chile	Quadrivalent, 2014	Girls and boys 9 years	Catch-up >14 years	2-doses at 0 and 12 months	School-based	74%	4%
Colombia	Quadrivalent, 2012	Girls 9–17 years	…	2-doses at 0 and 6 months	School-based	34%	23%
Costa Rica	Quadrivalent, 2019	Girls 10 years	…	2-doses at 0 and 6 months	School-based	…	…
Dominica	Quadrivalent, 2019	Girls and boys 11–12 years	…	2-doses at 0 and 6 months	School = based	69%	11%
Dominican Republic	Bivalent, 2017 Quadrivalent, ,,,	Girls 9–14 years	…	2-doses at 0 and 6 months	School-based	7%	11%
Ecuador	Bivalent, 2014 Quadrivalent, current	Girls 9 years	…	2-doses at 0 and 6 months	School-based	36%	39%
Guadeloupe	Quadrivalent, 2008	Girls 11–14 years	…	…	…	…	…
Guatemala	Quadrivalent, 2018	Girls 10–14 years	…	2-doses at 0 and 6 months	School-based	20%	18%
Guyana	Quadrivalent, 2012–2017 (phased)	Girls and boys 9–16 years	…	9–14 years: 2-doses at 0 and 6 months 15–16 years: 3 doses doses at 0, 1–2, and 6 months	School-based	25%	7%
Grenada	Quadrivalent, 2019	Girls 10–11 years	…	…	…	32%	25%
Honduras	Quadrivalent, 2016	Girls 11 years	…	2-doses at 0 and 6 months	School-based	47%	20%
Jamaica	Bivalent, 2017 Quadrivalent, ...	Girls 11–12 years	…	2-doses at 0 and 6 months	School-based	3%	5%
Mexico	Quadrivalent, 2012	Girls 9–11 years	HIV+ females 11–49 years	2-doses at 0 and 6 months	School-based	5%	12%
Monserrat	Bivalent, 2017 Quadrivalent, current	Girls and boys 10–11 years	…	…	…	…	…
Panama	Quadrivalent, 2008	Girls and boys 10 years	Sexual abuse victims and HIV+ individuals	2-doses at 0 and 6 months	School-based and facility-based	44%	23%
Paraguay	Quadrivalent, 2013	Girls 10 years	…	2-doses at 0 and 6 months	School-based and facility-based	37%	19%
Peru	Quadrivalent, 2015	Girls 10 years	…	2-doses at 0 and 6 months	School-based	16%	63%
Puerto Rico	Quadrivalent, 2006	Girls and boys 11–12 years	…	…	…	…	…
Saba	Bivalent, 2013 Quadrivalent, current	Girls 11–12 years	…	…	…	…	…
Saint Lucia	Quadrivalent, 2019	Girls and boys 10–11 years	…	2-doses at 0 and 6 months	School-based	74%	…
Saint Maarten	Quadrivalent, 2013	Girls 11–12 years	…	…	…	…	…
Saint Eustatius	Bivalent, 2013 Quadrivalent, current	Girls 11–12 years	…	…	…	…	…
Saint Kitts and Nevis	Quadrivalent, 2019	Girls and boys 10–11 years	…	2-doses at 0 and 6 months	School-based	12%	…
Saint Vincent and Grenadines	Bivalent, 2017 Quadrivalent, current	Girls 11 years	…	2-doses at 0 and 6 months	School-based	12%	…
Suriname	Bivalent, 2013 Quadrivalent, current	Girls 9–13 years	…	2-doses at 0 and 6 months	School-based	4%	13%
Trinidad and Tobago	Quadrivalent, 2012	Girls and boys 11–14 years	Females 15–45 years; Males 15–26 years	2-doses at 0 and 6 months	School-based and facility-based	…	…
Turks and Caicos	Bivalent, 2019 Quadrivalent, ...	Girls 11–12 years	…	…	…	…	…
USA	Quadrivalent, 2006 Nonavalent, 2015	Girls and boys 11–12 years	Catch-up through age 26; Shared clinical decisionmaking ages 27–45	2-doses at 0 and 6–12 months	Facility-based	49%	19%
Uruguay	Quadrivalent, 2013	Girls and boys 11 years	…	2-doses at 0 and 6 months	Facility-based	25%	13%

^‡… refers to no data is available

^†The table summarizes data reported to PAHO/WHO via the PAHO/WHO/UNICEF Joint Reporting Form on Immunization: https://ais.paho.org/imm/IM_JRF_COVERAGE.asp

^§Dropout refers to the proportion of the target population who do not complete the second dose of the schedule, where recommended. The coverage of a single dose of HPV vaccine is the sum of last two columns. Single dose coverage is much higher than two-dose coverage of the HPV vaccine in the region.

The majority of countries have focused their HPV vaccination efforts in girls and used a school-based delivery approach (Table 2). However, as of 2019 data, 17 countries and territories have opted for gender neutral strategies: Antigua y Barbuda, Argentina, Bahamas, Barbados, Belize, Bermuda, Brazil, Canada, Chile, Dominica, Greneda, Guyana, Monserrat, Panamá, Saint Lucia, San Kitts y Nevis, Trinidad y Tobago, United States, Uruguay [33] (Table 2). There has been mixed results for vaccination coverage when countries have expanded the eligibility for vaccination. Some countries have seen improved acceptability, measured by increases in coverage, whereas the coverage in other countries has remained stable but often well below optimal thresholds [15].

To evaluate the performance of HPV vaccination strategies, a standardized approach to estimating vaccination coverage at the national and region-level has been needed. However, since the first HPV vaccine introductions, national immunization programs have used varying methods to calculate HPV vaccination coverage and uptake in the region [34]. Some countries historically only reported total doses administered without distinguishing between first or second doses or clearly defining a target population denominator to track partial and complete vaccination series. Other countries commonly reported coverage only, as a proportion of doses applied in the country-specific HPV vaccination target group, neglecting to report numerators and denominators or stratification by multi-year aged target groups. Causing even further confusion, several countries used the number of girls who received the first dose of HPV administered as the denominator for subsequent doses. Combined, all of these inconsistencies in reporting have led to serious challenges for accurately monitoring trends in access and demand across time and place.

In response to this lack of standardization, the PAHO TAG on Vaccine-preventable Diseases, at its XXIV meeting in July 2017 in Panama, recommended that countries and territories in the Region improve their documentation and monitoring of HPV vaccination coverage at the subnational and national levels that was deemed critical for prioritizing areas and defining targeted strategies to achieve optimal coverage of the full vaccination series. PAHO since then has developed and published guidance, in 2019, for standardizing the reporting and monitoring of HPV vaccination coverage and built capacity of immunization program managers on standardized reporting for HPV vaccine coverage. Regionwide, countries have sought to revise their approach to coverage reporting and monitoring. The data reported through the PAHO-WHO/UNICEF Joint Reporting Form (JRF) reflects the proportion of target population in a given age/gender cohort vaccinated for partial and complete HPV vaccine series. Partial vaccination series is monitored for evaluating access to HPV vaccines, and complete vaccination (with a second or third dose based on the population-specific recommendations) is measured over time to evaluate vaccination protection and overall program performance [34]. Specifically, to understand the cohort-specific vaccination protection, PAHO/WHO estimates the proportion of the female population vaccinated by age 15, accumulating the number of doses historically administered to ages 9–14 over the prior period divided by the UN population projection for girls aged 15 in a given year [34]. This latter method provides a consistent and comparable approach to monitoring population-level protection regionally and globally.

By 2019, among 14 countries with 5 or more years of historical coverage data, the mean national coverage among girls by the age of 15 years was 57% [33]. However, this proxy for assumed levels of protection varied greatly between countries, ranging from 1% in Jamaica to a reported 99% in Mexico [33]. Even though Jamaica only introduced HPV vaccine in 2017 compared to Mexico’s long-standing HPV program since 2012, this range is an example of the extreme variation of coverage levels achieved in the region over time. While in some countries, vaccine coverage has improved over the years, in general these improvements have been at modest levels. Only countries that managed to reach high coverage in the first years after introduction in the specific gender target cohorts have generally sustained high levels of coverage, and most still are well below the regional and global coverage targets of 80% and 90%, respectively. For example, considering the most recent 3 year HPV coverage trends for girl target groups in the region, excluding the pandemic period, only three countries maintained coverage levels greater than or equal to 70% for three consecutive years from 2017 to 2019 [33].

In 2020, all HPV vaccination coverage indicators in the region, including program performance measures and assumed levels of protection afforded by historical HPV vaccination, were affected by the unprecedented impacts of the SARS-CoV-2 pandemic on immunization service delivery [35]. Limited or no routine immunization services, including the delivery of HPV vaccine, were functioning in most countries in the region due to the diversion of financial and human resources to COVID-19 response efforts. The estimated mean national coverage by age 15 for girls dropped from 57% in the year prior to 53% in 2020, considering data from 18 countries with 5 or more years of HPV vaccination coverage monitoring. Further, the annual program performance indicators, which track coverage of the year/country-specific intended adolescent girl target age group, declined by 12% on average from 2019 to 2020. Considering available data from 26 countries in the PAHO Region, including the United States and Canada, 18 countries reported substantial drops in the proportion of adolescent girls in the country-specific age target group completing their HPV vaccination series from 2019 to 2020 [33]. Additionally, among adolescent girls initiating their HPV vaccination series in 2020, the proportion of girls who did not complete their vaccination series was substantial across countries, ranging from a 4% dropout rate in the Chile to as high as a reported 63% of girls initiating the HPV vaccine series in Peru who did not complete the second dose [33] (Table 2).

However, even in the face of challenges due to the pandemic and related disruptions to health services, HPV vaccination access and demand remains high among countries in the Americas compared to countries in other regions globally. Except for New Zealand and Australia, in 2020, countries in the Americas with 3 or more years of HPV vaccination experience in their national immunization programs have exceeded higher levels of coverage for the first dose of HPV than high-income countries in the EURO region and elsewhere. Prior to the pandemic, in a 2019 comparative analysis, an estimated 73% (95 CI 50–83%) of adolescent girls in Latin America and the Caribbean, among 28 countries with available data, were vaccinated with at least one dose of HPV vaccine compared to an estimated 50% (95 CI35-63%) among adolescent girls in high-income countries or only 20% (95 CI 10–36%) in all countries with HPV vaccine introduced globally [15].

6. Monitoring and evaluation of HPV vaccination impact

Due to the generally wide accessibility of HPV vaccination and the number of adolescent girl cohorts already vaccinated, with at least one dose, in the Americas, the region is uniquely suited for early monitoring of HPV vaccination on population-level outcomes. PAHO, in collaboration with ICO (Instituto Catalan de Oncologia), Member States, and experts, developed inter-programmatic guidance for ‘Evaluating the impact of the human papillomavirus vaccine in Latin America and the Caribbean’ in the context of cervical cancer prevention (Publication forthcoming). The guidance summarizes study design approaches, potential data sources, and a framework for assessing the population health impacts of HPV vaccines, considering various clinical endpoints and stages of a country’s program (Publication forthcoming). While several years of HPV vaccination must be in place in order to assess the impact of vaccination against pre-cancerous cervical changes and related cancer outcomes, some countries in the region have formally initiated monitoring and evaluation frameworks, with early results demonstrating reductions in the prevalence of HPV16/18 following HPV vaccination [13,14]. A repeat cross-sectional study in Argentina showed a reduction in any HPV type infection from 56.3% to 49.8% and a decline in HPV16/18/11/8 specific infection from 22.5% to 6.4% among sexually active girls age 15–17 years comparing those unvaccinated (April 2014 to October 2015) to those vaccinated (February 2017 to November 2018) [14]. Using the same cross-sectional approach, a larger population study among sexually active women was conducted in Brazil that demonstrated nearly a 57% reduction in HPV types 6, 11, 16, and 18, from 15.6% in unvaccinated women age 16–25 years to 6.8% in those who were vaccinated [13]. Similar reductions have been observed in Australia [36] post-introduction of HPV vaccine and the observed reductions in both studies from Argentina and Brazil correspond closely to findings from clinical trials [37]. As additional countries in the region gain more years of experience, thereby accumulating more years of vaccinated cohorts and data, it is anticipated that the Americas will serve as an important, continued source of evidence on the effectiveness and impact of HPV vaccination as a primary means to reducing and eventually eliminating the threat of cervical cancer.

7. Challenges and lessons learned

PAHO convened regional meetings with immunization program managers from national immunization programs, in 2017, and then specifically in the English-speaking Caribbean, in 2020. National program leaders and invited experts shared experiences regarding the introduction and monitoring of HPV vaccination, highlighting themes about coordination, evidence evaluation to inform decisions about schedules and target groups, demand generation and follow-up, communication, and financial sustainability [38,39]. Several lessons are learned from the challenges faced by countries in the Americas in the early years of HPV vaccine introduction into national immunization programs. Other lessons continue to emerge as countries build 5–10+ years of experience with their HPV vaccination programs.

7.1 Stakeholder engagement and coordination

One of the first key lessons learned with HPV vaccines in the region has been the critical importance of engaging and collaborating with a wide spectrum of stakeholders, spanning advocacy groups, scientific professional societies, clinicians, and policymakers with diverse focuses on adolescent health, non-communicable disease, cancer control, women’s empowerment, and immunization. The provision of scientific evidence on HPV vaccines, local data on burden of disease and cost-effectiveness of HPV vaccination were critical for these dialogs. National Immunization Technical Advisory Groups (NITAGs), and regional efforts like the one in the Caribbean, were involved in defining data gaps, reviewing evolving knowledge, and setting evidence-based policies and strategies [38,39]. Further, involving educators and education-sector decision makers was essential to establishing access to HPV vaccination for adolescent population through the school-based delivery of HPV vaccines. Coordination among these stakeholders was necessary to develop and plan for integrated approaches to mobilizing and implementing resources that crosscut many programs. Additionally, many countries in the region experienced setbacks when a relevant stakeholder across locally important political spectrums or community leaders were not engaged early in the process of planning for implementation of HPV vaccines. For example, prior to engaging, one Central American country faced challenges to mobilize sufficient resources to introduce HPV vaccines. Through a partnership with the ministry of education, the initial stock for HPV vaccine introduction was procured using budgetary resources outside the health sector []. Countries considered that an inter-programmatic or inter-sector planning committee aided substantially in the successful launch of HPV vaccination. By inviting relevant actors that generally have not played a role in delivering immunization programs, additional resources were mobilizedfor example, for educational campaigns and vaccine procurement, which otherwise would not have been identified.

7.2 HPV vaccination schedules, target groups, and delivery strategies

The adoption of HPV vaccines into national immunization programs pose different challenges than traditional childhood vaccines for achieving and sustaining high immunization coverage. When HPV vaccines first became available in the region, three doses were recommended for adolescent girls between 9 and 14 years of age that required establishing three new vaccination encounters. Some countriesfor example, like Canada and later Mexico, opted for an extended schedule where adolescent girls received two doses and then were expected to receive a third dose after 5 years, which eventually was redefined as only a two-dose schedule [40]. Following updates to the evidence regarding the efficacy of a two-dose series, PAHO TAG revised its guidance to recommend only two doses of HPV vaccine with a 6-month minimal interval between doses for girls age 9–14 years while maintaining recommendations for three doses in girls 15 years and older or those who are immunocompromised [40]. In 2017, updated guidance from WHO suggested that intervals longer than the currently recommended upper limits (12–15 months) might lead to better sustained immune responses. One sub-national jurisdiction in the region, Quebec of Canada, has opted for a 5-year interval between doses administered in the two-dose HPV schedule and administers mixed schedules using a dose of the bivalent HPV vaccine after a dose of the nonavalent HPV vaccine [41]. Countries in the region, along with PAHO guidance, consider that the newly available evidence regarding the benefits of stronger, more durable protection may not outweigh the risks of girls being lost to follow-up over that period, potentially leading to even lower series completion. Recent studies have reenforced the benefits of establishing longer intervals between HPV vaccine doses. Other research continues to evolve about the efficacy of a single HPV vaccine dose strategy [42,43]. As of April 2022, on the basis of updated efficacy and effectiveness data, the SAGE endorsed optimizing HPV schedules with a one- or two-dose schedule, with at least 6 months between doses, and urged countries to use this flexibility to reach more numbers of individuals in their target population [29]. Following this update, the Regional TAG to PAHO and NITAGs will need to further evaluate the optimization of HPV vaccination schedules for countries in Latin America and the Caribbean, considering both the programmatic risks and health benefits at the population-level. Country experience in the region suggests that defining target groups for a newly adopted HPV vaccine must align with the overarching goals of the program. PAHO recommends that countries prioritize the use of HPV vaccines to reduce cervical cancer in the region, being that it is a leading cause of death and morbidity among women in Latin America and the Caribbean [28]. Nonetheless, HPV vaccines also have the potential to reduce other HPV-associated cancers and disease among men. The rationale for expanding the use of HPV vaccines beyond the primary target group of adolescent girls must be made scientifically and should align with local disease control priorities. Rationalizing that the expansion of HPV vaccine target groups to males will make vaccination overall appear more favorable, thereby improving acceptability of the program to the public, has had mixed results in the region []. Further, where evidence and priorities do not align with the definition of target groups, countries have experienced substantial challenges with efforts to effectively communicate the goals of the HPV vaccination program, leading to resistance and even disruption of support from political actors.

Clear definition of target groups that align with the overall public health priorities and goals of a country also leads to improved strategic planning for HPV vaccine delivery. There is wide-reaching consensus among immunization program managers in the region that a narrow goal of routinely vaccinating one age or school-grade cohort is a strategic use of resources. Catch-up campaigns may be considered at the launch of the HPV vaccination program, where resources permit the option. Leveraging school health programs or newly established relationships with the education sector, school-based delivery of HPV vaccination services has been shown to be highly effective [44]. Unlike childhood vaccination which generally relies on spontaneous demand tied to preexisting well child visits at health facilities, school-based vaccination programs take advantage of planned mass vaccination at school sites and side steps challenges associated with parental willingness or ability to bring their child to a health facility. School-based programs take the ‘opt-out’ approach where only adolescents and families who refuse vaccination are missed whereas facility-based programs function more as an ‘opt-in’ approach where adolescents and families must overcome hurdles of complacency and convenience in order to demand HPV vaccination and providers must have strategic plans in place to avoid missed opportunities for vaccination. As effective as they are, school-based programs are expensive; however, and they require substantial buy-in from teachers, school leadership, and parents even if their explicit written consent should not be a requirement. Advanced sensitization and coordination at the school-level translates into trust and acceptance once a vaccination campaign begins.

Facility-based and mobile clinic vaccination may be needed to supplement school-based delivery, where costs are too high or other concerns are present. For example, many countries noted that school absenteeism can interfere with initiating the HPV vaccine series or reaching high complete series coverage at the school sites and an organized follow-up needs to be in place to address the potential doses missed from occurring [38,39]. Schools have been instructed to redirect female students who missed doses to nearby health facilities or connecting the local health facilities to schools for follow-up. On the other hand, the pandemic related school closures and disruptions have posed serious challenges to using school-based delivery for initiating and completing HPV vaccination schedules in the past 2 years. Countries are finding that complimentary health-facility-based delivery is essential to ensuring that entire age cohorts are not missed by the HPV vaccination program. In the post-pandemic period when school vaccination resumes, this experience may prove important driver to reducing dropout and potentially increasing coverage.

7.3 Estimating and generating demand for HPV vaccination

According to the available regional data, countries in the Americas are off track for meeting the goal of achieving 90% coverage with two-doses of HPV vaccine of girls by age 15 years by 2030. Only 58% and 61% of girls 15 years of age were fully vaccinated against HPV in 2019 and 2020, respectively [33], which is only a few percentage point increases over that achieved by 2017 and by 2018. If the slow pace of increase in HPV vaccination coverage from 2017 to 2020 were maintained, the region would barely reach 80% full HPV vaccination coverage of 15 year old girls by 2030. However, this retrospective projection does not take into account the huge drop in coverage in 2020 and the likely drop in 2021, which may put the goal of reaching 90% coverage in the region even farther out of reach.

These estimated protection levels by age 15 for girls do not reflect the success of programs with new HPV vaccine introductions. Moreover, these data may reflect early challenges to accurately recording and reporting the number of HPV vaccine doses administered and the denominator for the vaccine eligible target population. For this reason, countries regionwide also monitor the year-to-year coverage achievements in their locally defined target groups, which may vary in age or gender between and even within countries. Where possible, countries are also collecting information that would allow for equity analysis, looking at poverty, race/ethnicity, healthcare access. Determining the factors that motivate adolescents and their parents or teachers to help them start and complete a HPV vaccination series can help identify and define strategies for successfully targeting messaging, outreach, and ultimately vaccination services, as several countries have tried to do so [45–48].

To improve data quality and monitoring, countries in the region recognize the need to collect HPV vaccine administration data by age, gender, and dose, at a minimum [28]. Immunization programs regionwide have invested in developing nominal information registry systems that allow for tracking individual vaccination status. While relevant to all vaccines, this is crucially important for HPV vaccination because there is a longer interval between doses than the traditional childhood vaccination schedules and individual follow-up is critical to ensuring complete schedules. Additionally, there is a need to have an accurate historical record of vaccination status because the type of vaccine and scheduled completed may be an important criterion for future HPV-associated cancer screening decisions [25].

Despite the availability of HPV vaccines in most national immunization programs in the Americas, issues of access to services, successful follow-up, and use of sustainable delivery approaches remain in the region. For example, drastic declines in HPV vaccination coverage have occurred at times – in Brazil, according to the Ministry of Health, HPV complete series vaccination coverage reached 97% of the target population in 2017, using a massive vaccination drive campaign in the first year of the program, but otherwise has oscillated between 62% and 72% [33] Similar trends have been observed in other countries with longstanding HPV vaccination programs such as those in Mexico and Colombia. Dropout between recommended doses is substantial regionwide (Table 2). These challenges have been further exacerbated in the wake of the 2019 SARS-CoV-2 pandemic. Quick, strategic shifts in delivery modes have helped confront the risk of access barriers or pandemic-related disruptions in demand. Some countries have offered drive-up vaccination sites for child and adolescent vaccination, where school-based delivery has been interrupted. Others have developed plans for catch-up campaigns once community transmission of SARS-CoV-2 begins to slow. As students return to schools and the toll of the pandemic begins to dissipate, immunization programs in the region foresee the promotion of HPV vaccination as a mechanism for restoring confidence in immunization more generally through outreach activities and a sustained messaging campaign. Recuperating the lost progress of recent years toward increasing the reach of HPV vaccination programs in the region is critical to avoiding the loss of health benefits over time [49].

7.4 Communication

Another aspect of HPV vaccine programs that represent a departure from prior experiences for national immunization programs is the critical importance of strategic communication. Due to the diverse sources of opposition to HPV vaccination, national immunization programs have learned to proactively develop communication plans that tailor messages to differing needs across diverse communities and sets of stakeholders. Secondly, unlike most routine immunization services, HPV vaccines have been met with more resistance in religious communities and some other sectors of society in the Americas. Following public resistance, countries have learned to develop crisis response and mitigation plans that leverage the voices of key influencers in the community and fact-based messaging campaigns. Before, during, and after introduction of HPV vaccines, these plans must be continuously evaluated and updated, keeping in mind the relevant actors who might facilitate or impede acceptance of HPV vaccines. A sustained period of sensitization and public education is needed, even when the first few years of experience with HPV vaccines have been successful. Experiences in Peru [38], Colombia [50] and Brazil [38], where HPV vaccine coverage fell dramatically following media reports on adverse events following immunization (AEFI), later evidenced to be not causally linked to vaccination, illustrate the need for a risk communication plan to be in place for HPV vaccines and to counter the sensationalization that has been associated with this vaccine.

7.5 The PAHO Revolving Fund: Sustainability, supply, and financing

The successful launch of HPV vaccination in the Americas and elsewhere in the world has led to levels of demand that currently outpace the available global supply. For this reason, countries in Latin America and the Caribbean have learned the critical importance of developing accurate demand forecasting plans and working with the PAHO Revolving Fund in continued efforts to pool demand, leveraging a stronger purchasing power to negotiate lower prices. The PAHO Revolving Fund has negotiated on behalf of participating countries to reduce the price of procuring HPV vaccine from >US$ 120 per dose in 2007 to under US$ 10 per dose by 2010, resulting in the low cost of delivering the HPV vaccine of approximately US$ 20 per girl vaccinated [51]. In 2020, PAHO revolving fund procured 1.8 million doses of HPV on behalf of PAHO Member State countries, which finance the purchase and provide the vaccines free-of-charge to the public. These prices are much lower than other low, middle, and even upper-middle-income countries are able to access outside of the PAHO region and have been critically important for the introduction of HPV vaccines in small population countries and territories in the Caribbean [52]. The long-term financial sustainability is directly linked to self-financing structures that have legal and institutional support. Additionally, countries have learned that extending the policies that provide vaccination for free to children into adolescence is an important mechanism for achieving predictable demand.

8. Expert opinion

The Americas region has the potential to be the first World region to eliminate cervical cancer, building on the strong immunization programs that exist in countries in the region; the historical achievements in eliminating polio, smallpox among others; and the established cervical cancer screening programs and commitment to cervical cancer elimination. This will, however, largely depend on ensuring that almost all girls, at least 90%, are vaccinated against HPV by the time they reach 15 years of age, and that women are screened with HPV tests and treated for pre-cancer and invasive cancer accordingly. Achieving such a high HPV vaccine coverage has proven to be a challenge in all countries, after over 10 years of introduction of HPV vaccines. While the costs of HPV vaccines may have been the initial hurdle, overcome through the provision of evidence and cost-effectiveness data as well as regional procurement through the PAHO Revolving Fund; the new challenge has been to reach a sufficient level of the adolescent population using school-based delivery, amidst backlash and criticisms and widespread media reports that undermine public confidence in this vaccine. In countries, such as Colombia, where HPV vaccine coverage dramatically fell following events of mass psychogenic illness [50], lessons are revealed in the importance of using media, in particular social media, to provide evidence-based information on HPV vaccine effectiveness, safety and to counter propagated myths about this vaccine. And now, with the prioritization of the COVID-19 vaccine, which adds an additional vaccine into the immunization schedule and to health budgets, efforts will need to be re-doubled to ensure that HPV vaccine implementation continues to be a priority, as part of national immunization programs with routine monitoring and reporting. The PAHO regional plan of action and global strategy for cervical cancer elimination certainly provides the framework and a forum to bring together the multi-sector collaboration that will be needed to maintain a focus on increasing HPV vaccine coverage, while at the same time introducing HPV testing and increasing coverage of screening and treatment, to put countries on the path toward elimination.

9. Conclusion

HPV vaccine availability and access has increased substantially since initial market launch in the late-2000s in Latin America and the Caribbean. Improving uptake at the population-level, specifically among adolescent girls and other vulnerable populations, will be crucial to achieving the regional and global targets for cervical cancer control by reducing the number of new cases and deaths by one-third by 2030. The actions put into place today can still make a difference for the region.

Article highlights

• Since 2006, 44 countries in the Americas have adopted the HPV vaccine as an important component to programs for the prevention and control of cervical cancer

• Substantial experience piloting and evaluating HPV vaccine delivery strategies suggest that there is no one-size-fits-all in the region

• Several obstacles remain to improving HPV vaccination coverage among girls in the Americas

• However, there is high-level commitment throughout the region to prioritize equitable access to HPV vaccines and motivate demand in order to reach the 2030 cervical cancer elimination goals

• Throughout the past decade or more, countries and territories in the region have accumulated important lessons learned to inform programmatic decisions and policies in the region and elsewhere going forward

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or mending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Disclaimer

The authors LHO and SL are staff member of the Pan American Health Organization. The authors alone are responsible for the views expressed in this publication, and they do not necessarily represent the decisions or policies of the Pan American Health Organization

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

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Funding

This paper was not funded.