Introduction

Immunization is the most cost-effective public health intervention, and more than 20 diseases can currently be prevented with the recommended scheduled childhood and adolescent vaccines. In Latin America, since the inception of the Expanded Program on Immunization (EPI) 40 years ago, countries and territories in this region have made significant advances against vaccine preventable diseases. In fact, the Americas is the first world region to eradicate smallpox, eliminate polio, rubella and congenital rubella syndrome, and most recently eliminate endemic measles transmission.¹ Another opportunity presents itself to significantly reduce, if not begin to eliminate a disease-cervical cancer-with the availability of HPV vaccines. Cervical cancer is the second most common female cancer in Latin America, with approximately 64 000 new cases and 26 000 deaths each year.² HPV infection causes virtually all cervical cancers, in addition to being a risk factor for other cancer types (anal, vaginal, vulvar, oropharyngeal, and penile cancers).³

HPV vaccines were first licensed in 2006, and by early 2016 over 200 million doses of HPV vaccines had been applied around the world, with validating evidence of its safety.⁴ HPV vaccines in use around the world include a bivalent vaccine (Cervarix, GSK, Belgium) protecting against infection from HPV types 16/18; a quadrivalent vaccine (Gardasil, Merck, USA) protecting against infection from HPV types 6/11/16/18; and a recently approved nonavalent vaccine (Gardasil 9, Merck, USA) protecting against infection from HPV types 6/11/16/18/31/33/45/52/58).⁵

WHO recommends HPV vaccines to be introduced into national immunization programs if cervical cancer prevention is a public health priority, if it is programmatically feasible, has sustainable financing, and is cost-effective.⁶ For the Americas region, the Pan American Health Organization (PAHO) Technical Advisory Group on Vaccine Preventable Diseases recommended, in 2013, using 2- and 3-dose extended HPV immunization schedule for girls aged 9-13 years.⁷ Furthermore, the Regional Plan of Action on Immunization, endorsed by the Ministers of Health of the Americas during the 2015 PAHO Directing Council, calls for, among other things, strengthening platforms for universal vaccination, and monitoring the introduction of new vaccines including HPV vaccines.¹

Monitoring HPV vaccines, as is the case with other vaccines, includes monitoring coverage, safety, and impact. Because of the well established EPI programs in Latin America, immunization program performance, safety and coverage is routinely performed through organized information systems. Immunization coverage monitoring is routinely done using administrative data from immunization registries, vaccination cards and tally sheets, or surveys and records from health service providers, and reported annually through the PAHO/WHO/UNICEF Joint Reporting Form (JRF) for Immunization. Vaccine safety is routinely monitored through immunization program systems for adverse events. Vaccine impact monitoring is more commonly performed through surveillance and special studies. However, HPV vaccines, unlike other vaccines, involve a much more complex process for impact monitoring, as it requires robust clinical, laboratory, and surveillance infrastructure, including cancer registries. While establishing HPV vaccine monitoring processes is not a prerequisite for the initiation of an HPV vaccination program, monitoring coverage and safety are fundamental aspects for any immunization program.

In this article, we review the experiences in Latin American countries with HPV vaccine monitoring following its introduction in the region. We examine how HPV vaccines are currently being implemented and monitored, as well as the challenges and barriers to routinely monitor vaccine coverage and impact.

Materials and methods

Latin American countries were included in this analysis as follows: Mexico and Central America (Mexico, Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, and Panama); South America (Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Peru, Paraguay, Venezuela, and Uruguay); and Latin Caribbean (Cuba, Dominican Republic, Haiti, Martinique, and Puerto Rico).

We searched and retrieved published articles in peer reviewed journals, as well as official documents from government websites on information and reports related to national immunization programs and HPV vaccine monitoring, surveillance and evaluation from Latin American countries. PubMed, Science Direct and Google Scholar databases were searched from November to December 2016 using the following search terms: “human papillomavirus” OR “HPV” AND “vaccine” OR “immunization” AND “Latin America”. The search included English and Spanish language articles published after January 1, 2007. Websites from the World Health Organization, Pan American Health Organization, and Ministries of Health from Latin American countries were reviewed from November to December 2016 and reports on immunization programs and HPV vaccination were retrieved from these sites.

For HPV vaccine coverage, we reviewed the WHO/UNICEF Joint Reporting Form database and the PAHO Immunization Annual Report. However, no data on HPV vaccine coverage were reported in these systems. Therefore, we consulted the HPV information database of the Catalan Institute of Oncology (ICO) and the International Agency for Research on Cancer (IARC), and extracted and updated relevant regional data from a previous global analysis of HPV vaccine coverage, for which the detailed methods were published elsewhere.⁸ Coverage data were identified through a systematic review of the literature and official government websites from Latin-American HPV national immunization programs, up to December 2016. We retrieved information on the year of introduction, the target ages, the schedule, implementation strategy (either primary or catchup) and approach (organized or opportunistic), and collected age-specific data on one, two and three-dose HPV vaccine coverage for each country. To estimate the coverage and number of vaccinated females, the retrieved coverage data were converted into birth-cohort specific coverages, with missing data imputed using an algorithm, and applied to global population estimates and cervical cancer projections by country and income level.

Results

Discussion

2017 marks ten years since the first preventative HPV vaccine was approved for use. The Latin American region has advanced more than any other World region, except Western Europe, with HPV vaccine introduction.⁴ This has resulted in an estimated 17 million vaccinated girls aged 10-14 years, and almost 100 000 averted deaths from cervical cancer in Latin America. Unfortunately, the nine countries that still lag behind with HPV vaccine introduction are among those with the highest rates of cervical cancer and have populations that can most benefit from this vaccine.¹² Cervical cancer disproportionately affects women in lower socioeconomic groups, mainly due to lack of access to health services for screening, early diagnosis and treatment; thus to prevent further inequities associated with cervical cancer HPV, vaccine introduction is urgently needed in these lagging countries.

National Immunization Technical Advisory Groups (NITAG) play a key role in decision-making for new vaccine introduction, but their resources and capacity vary across the region, including in the Latin American countries that have not yet introduced HPV vaccines.^13,14 Factors such as disease burden or cost-effectiveness have been considered, but the institutional and political context, as well as the legislative and regulatory environment, media coverage and advocacy, have influenced adoption decisions and prevented more rapid uptake of HPV vaccines into policy.¹⁴ The PAHO ProVac Initiative has strengthened national capacities and NITAG functions to make better informed, evidence-based decisions, by developing tools for economic analysis, and forming multidisciplinary teams to use these decision-making tools for new vaccines, including HPV vaccines.¹⁵

Yet, other obstacles persist for a wider adoption in the Region. First, together with the pneumococcal vaccine, the HPV vaccine remains the most expensive EPI vaccine. Despite its proven cost-effectiveness, the vaccine cost is perceived as unaffordable in the context of limited EPI budgets. Second, public health priorities in Latin America focus on childhood illnesses-pneumonia and diarrhea-and maternal mortality and, consequently, public investments are directed at their prevention. As a result, other new vaccines have been prioritized for introduction, and all countries in Latin America now have rotavirus vaccine and conjugate pneumococcal vaccine in their routine schedules.9 Finally, health professionals have limited understanding of HPV and cervical cancer and question its safety and efficacy, limiting wider adoption. For example, in Colombia general practitioners were noted to have very limited knowledge about HPV, cervical cancer and HPV vaccination, and in Argentina a study showed that 30% of specialized medical providers were not aware of the relationship between HPV and cervical cancer.^16,17

While cervical cancer prevention is the main objective, and females are the main target group of HPV vaccination programs in Latin America, equity issues have driven policy changes and boys are now included in HPV vaccine programs in three countries in the region and likely more in the near future. Although the expressed country specific reasons for these recent policy changes were not found in our search, reasons have been cited elsewhere and include protection against warts and HPV related cancer risk in boys, protection for high risk populations such as men who have sex with men, and effectiveness for other HPV related diseases.⁴ It is still too early to fully understand the programmatic implications of having gender neutral HPV vaccine programs, and whether it may challenge achieving high vaccine coverage, given the experiences to date with vaccinating girls only.

No specific regional targets have been set for HPV vaccination coverage. However, the Global Vaccine Action Plan 2011-2020 calls for a 90% national coverage and 80% in every district for all vaccines in national programs.¹⁸ This may be an ambitious target for Latin America for HPV vaccines based on the results illustrated in this analysis, and a separate global HPV vaccine coverage analysis showing an average of 71% coverage for Latin America and the Caribbean region.⁸ Challenges to achieving a higher coverage, especially in low and middle income countries, have been noted and include: difficulties with covering multiple age groups, requirements for multiple dose vaccine, reaching an adolescent population, and concerns about safety, efficacy and perceptions of association with increased sexual activity.^19,20 The ongoing media stories questioning the safety of the HPV vaccine may also have affected coverage rates, as have been documented elsewhere.²¹ However, school-based delivery strategies, which are predominantly used in Latin America, have been cited as a more effective strategy to reach high vaccine coverage in this age group.²² In addition, Vaccination Week in the Americas, an annual immunization campaign coordinated by PAHO, has strengthened national immunization programs to reach populations with little access to regular health services, and provides an opportunity to increase HPV vaccination coverage.²³

Perhaps more challenging, as noted by the scant information found for our analysis, is to mount and sustain surveillance systems for monitoring and evaluation of HPV vaccines, in order to accurately monitor coverage, safety and impact, using the indicators previously described. Monitoring and evaluation of vaccines requires adequate program databases and information systems, and ability to capture and link data. Here is where the challenges lie, because although EPI programs are well established with monitoring systems, they still need to be adapted to integrate issues specific to HPV vaccines, such as capturing data for multiple age groups, school settings as well as health clinics. Only two Latin American countries have more than seven years of HPV vaccine implementation experience, and can be expected to have robust and comprehensive monitoring systems. All other countries have about 2-3 years of implementation experience and it may still be relatively early to monitor complete coverage and impact.

Monitoring coverage for HPV vaccines is unlike doing it for other vaccines, given the multiple age groups, multiple doses and multiple delivery strategies through school-based programs and health facilities. There is clearly a need for standardization of coverage monitoring procedures, notably in standardizing the denominators used to calculate coverage, to allow for more accurate comparability between country data. There is also a need for more consistent and regular annual reporting of coverage data for this vaccine, through the PAHO/WHO/UNICEF Joint reporting form. But there are opportunities to improve coverage data through the use of electronic immunization registers, which are in the process of being established throughout Latin America and, once in place, will facilitate more accurate and timely coverage monitoring and reporting.

Monitoring HPV vaccine impact is not necessary for HPV vaccine introduction. It is a complex and resource intense process that requires HPV testing and HPV laboratory capacities, cervical cancer screening capacity and cancer registries.¹⁰ Genital warts, which develop relatively soon after HPV infection, can be monitored within a short period of time but it does not demonstrate vaccine impact on precursors to cervical cancer. Also it is only appropriate for the quadrivalent vaccine. In limited resource settings, the priority should be on developing surveillance systems to monitor cervical cancer impact, by monitoring changes in HPV genotype prevalence over the short term and changes in precancerous cervical lesions over the medium term.

Monitoring HPV genotype in sexually active population, possible after 5-10 years of vaccine introduction, can provide an early indicator of vaccine effectiveness, but it does require considerable resource commitment and is likely feasible in a few limited sites (e.g., sentinel surveillance). No reports from Latin America were found on changes in HPV genotype prevalence post HPV vaccination. But experiences from other countries indicate there are reductions. For example, prevalence of HPV infection for types 6/11/16/18 decreased by 86% after three doses among Australian women and by 89% after one or more dose in women in the USA within six years.²⁴

Monitoring precancerous cervical lesions, which develop many years after HPV infection, involves screening women and diagnosing those with cervical intraepithelial neoplasia (CIN), a precursor to cervical cancer and acceptable surrogate for measuring vaccine efficacy. However, this requires health service capacity, organized population-based cervical cancer screening programs and laboratory infrastructure, which are resource intensive. Furthermore, changes in screening practices could improve rates of detection of pre-cancerous lesions and may give misleading conclusions about vaccine impact. However, results from HPV vaccine impact monitoring studies from developed countries illustrate the promising impact that may be possible in Latin America. CIN (grade 2 or higher) has been reported to decline in cohorts of vaccinated females within five years by 75% in studies in Sweden, 73% in Denmark, 69% in Canada, and 57% in Queensland, Australia.²⁴

Monitoring reduction in cervical cancer is a much longer term undertaking, requiring 20 years or more. At this point in time, no studies are available on reductions in cervical cancer rates as a result of HPV vaccination, given that it has only been available for 10 years.

In conclusion, HPV vaccine introduction has been successful in Latin America, although challenges persist with achieving a high vaccination, as well as screening coverage, establishing monitoring and evaluation systems, and reporting on HPV vaccine coverage and effectiveness.