Implementing interventions to start HPV vaccination at age 9: Using the evidence we have

ABSTRACT

Human papillomavirus (HPV) vaccination is routinely recommended for adolescents aged 11 or 12 years but can begin at age 9. On-time HPV vaccination by the thirteenth birthday has proven to be effective in preventing HPV cancer and pre-cancer. However, HPV coverage rates continue to lag behind other routinely recommended vaccinations for adolescents. A promising approach to improving coverage is to start HPV vaccination at age 9. This approach has been endorsed by the American Academy of Pediatrics and the American Cancer Society. Benefits of this approach include increased time to complete vaccination series by the thirteenth birthday, additional spacing of recommended vaccines, and a more concentrated focus on cancer prevention messaging. While promising, little is known about how and if existing evidence-based interventions and approaches can be used to promote starting HPV vaccination at age 9. Implementation science frameworks offer scientific direction in how to adapt current and develop new interventions to promote starting HPV vaccination at age 9 and accelerate dissemination and prevent HPV cancers.

KEYWORDS:

• Vaccination
• papillomavirus vaccines
• HPV vaccine
• HPV vaccination
• implementation science
• interventions

Human papillomavirus (HPV) vaccination prevents diseases caused by HPV, including six types of cancer (oral, cervical, anal, vaginal, vulvar, and penile), cervical precancer, genital warts, and recurrent respiratory papillomatosis. HPV vaccination is routinely recommended at age 11 or 12 years and can begin at age 9 up through age 26 in the United States (US). Recently, vaccinations have been recommended for some adults aged 27 to 45 years who were not vaccinated when they were younger, following a discussion with their health-care provider.^1–3 In the US, HPV vaccination coverage has reached nearly 77% of 13- to-17-year-old adolescents with one or more doses and nearly 62% completing the vaccination series.⁴ However, when compared to other routinely recommended vaccinations for adolescents, HPV vaccination continues to lag behind. Coverage for two other routinely recommended adolescent vaccines are more than 30% higher. Coverage rates for the quadrivalent meningococcal conjugate (MenACWY) vaccine is 89% and 90% for tetanus, diphtheria, and acellular pertussis (Tdap) vaccinenationally.⁴

Disparities in HPV vaccination coverage based on geographic region, rurality, and poverty persist.^4,5 Since the vaccine was first introduced in the US in 2006, HPV infections and cervical precancers have dropped significantly despite relatively slow uptake.⁵ However, the vaccine’s cancer prevention potential has not been realized due to a range of factors, including limited awareness and knowledge, lack of a strong health-care provider recommendation, and concerns related to safety and effectiveness. Recent studies^6–13 continue to validate the effectiveness of HPV vaccination for disease prevention, particularly on-time HPV vaccination by the thirteenth birthday.^14,15 Effective, scalable approaches that are widely implemented are urgently needed to improve on-time HPV vaccination to prevent related cancers and other HPV diseases.

A promising approach to improving coverage is starting HPV vaccination at age 9 as discussed in several published studies,^16–21 including those published in this special issue, which demonstrate the feasibility, value, and effectiveness of implementing HPV vaccination at age 9. The American Academy of Pediatrics²² and the American Cancer Society²³ have also strongly endorsed beginning the HPV vaccination series at age 9. In 2022, the Advisory Committee on Immunization Practices changed its statement to emphasize a recommendation to receive the vaccine at age 11 or 12, with the option to start at 9 years.²⁴ To ensure population benefits, it is important to reiterate that recommending and then administering HPV vaccination starting at age 9 may result in higher levels of initiation and on-time completion by the thirteenth birthday.

Beginning HPV vaccination at age 9 offers myriad benefits, such as increased time to complete the vaccination series by the thirteenth birthday, opportunities for additional spacing of recommending adolescent vaccinations, concerted focus on cancer prevention prior to first HPV exposure, lessened focus on sexual activity, and decreased emphasis on “required” vaccinations for school since HPV vaccination has school-entry requirements in only three US states at this time. However, evidence-based interventions to increase HPV vaccination have been largely based on bundled approaches with other routinely recommended adolescent vaccinations or for older populations, such as adults. Additionally, the evidence base for applying these approaches starting at age 9 is limited, leading to pressing questions: Can existing evidence-based approaches to support HPV vaccination be adapted to promote starting the series at age 9? How will we know if this is the case? To prompt attention to these questions, we offer an overview of the current evidence base related to promoting HPV vaccination, including gaps, and discuss the role of implementation science in guiding thoughtful adaptations to existing evidence.

Implementation science offers us a path forward to ensure high rigor with adaptation of existing evidence-based interventions and can also inform conceptualization, development, and testing of newly developed interventions to improve HPV vaccination coverage. Implementation science is defined as “the scientific study of methods to promote the systematic uptake of research findings and other evidence-based practices into routine practice, and, hence, to improve the quality and effectiveness of health services”²⁵ and as “the study of methods to promote the adoption and integration of evidence-based practices, interventions, and policies into routine health care and public health settings to improve the impact on population health”.²⁶

The first step in assessing adaptation opportunities is to examine the available research evidence. The National Cancer Institute Evidence-based Cancer Control Programs (EBCCP) is an important repository of evidence-based interventions (or programs) for various cancer prevention and control topic areas.^27,28 The repository includes interventions tested in a research study with published results in a peer-reviewed journal. The EBCCP website is searchable and includes HPV vaccination interventions. As of November 2022, there were six HPV vaccination interventions included in the EBCCP (Table 1).^29–34 The interventions largely focused on education and training. The time period for publication of the primary outcome (HPV vaccination initiation and/or completion) ranged from 2011 to 2016, which precedes the availability of Gardasil9 in the US and also prior to the latest ACIP guidelines published in 2019.^1,2 Only two of the interventions included address HPV vaccination among both females and males;^30,33 four interventions are female-only.^29,31,32,34 The majority of these evidence-based interventions – five out of six – did not include 9–10-year-olds.^29–33 There are efforts underway to update the EBCCP repository for HPV vaccination programs and also many interventional research studies underway to determine effectiveness.

Table 1. Overview of evidence-based cancer control programs for HPV vaccination.

Intervention Name	Year of Primary Outcome Publication	Brief Description	Age*	Sex
1-2-3 Pap: Easy Steps to Prevent Cervical Cancer^Citation29	2013	Educating 18–26-year-old women in rural communities using a DVD and fact sheet, scheduling follow-up appointments, conducting scripted reminder calls, and providing appointment reminder cards.	19–39 years	Female
DOSE HPV: Development of Systems and Education for HPV Vaccination^Citation30	2015	Educating medical providers on HPV vaccination and effective communication with parents and also providing medical providers with vaccination data for real-time monitoring.	11–18 years, 19–39 years	Female, Male
Give Teens Vaccines^Citation31	2013	Clinician-focused component (electronic health record alerts, video, and quarterly reports on rates) and family-based component (automated reminder call) to increase HPV vaccination among girls.	11–18 years	Female
HPV Vaccine Decision Narratives: Encouraging Informed HPV Vaccine Decision-making^Citation32	2011	Educating college women using a video with decision narratives to encourage vaccination.	19–39 years	Female
Making Effective HPV Vaccine Recommendations^Citation33	2016	Training health-care providers to more effectively recommend HPV vaccination using the “announcement” strategy.	11–18 years	Female, Male
Promoting HPV Vaccination among American Indian Girls^Citation34	2016	Educating mothers of 9–12-year-old daughters through a social activity and educational activities for the mothers and daughters.	0–10 years, 11–18 years, 19–39 years, or 40–65 years	Female

*Age categories are 0–10 years, 11–18, 19–39, or 40–65, which do not align with HPV vaccination recommendations, and were self-selected by developer(s)

Another commonly used source of evidence-based interventions is The Guide to Community Preventive Services (The Community Guide), which is a collection of the evidence-based findings of the Community Preventive Services Task Force.³⁵ The Community Guide provides information on community preventive services, programs, and policies that have been shown to work and how they may fit the needs of a community. The Community Guide does not include specific interventions for HPV vaccination but does include recommended approaches for vaccinations overall. Unlike EBCCP, The Community Guide recommends interventions that are less packaged programs and more approaches or strategies. For vaccinations, interventions that are recommended based on strong evidence include interventions to enhance access to vaccination services, increase community demand for vaccinations, and increase provider- or system-based interventions. However, it is unclear which of these interventions, recommended based on strong evidence, are relevant for HPV vaccination and which may be appropriate for starting at age 9.

In addition to these two evidence-based repositories, there are numerous other published interventions that have been shown to successfully improve HPV vaccination initiation and/or completion.^36,37 We have highlighted a few examples here. There is growing evidence about the value of designing multilevel interventions to target different levels (e.g., individual, interpersonal, clinical, and community).^38,39 Quality improvement^40–43 and learning collaboratives^44–47 have shown promise by aligning activities with usual clinical workflows and also by including approaches recommended in The Community Guide. School-based interventions have not been as commonplace in the US as in other countries but have shown promise in certain geographic regions.⁴⁸ To date, these interventions have not yet been indexed in EBCCP or clearly outlined in The Community Guide. Nonetheless, with few exceptions, most of these have focused on the routine recommendation age of 11–12 years. Additionally, the existing evidence base does not reflect the diversity of populations who may benefit from HPV vaccination at age 9 and the range of public health and clinical settings that serve them.

Across the research literature, the absence of empirically tested interventions to improve HPV vaccination initiation and completion among 9–10-year-olds is noticeable and presents an ideal opportunity to explore how existing evidence-based interventions can be adapted and tested to ensure the key components of these interventions remain effective at earlier ages. Previous studies have estimated that translation of research evidence into practice takes 17 years.^49–51 Drivers of these lags are quite diverse, ranging from attributes of the intervention (e.g., complexity and appropriateness for the setting) to attributes of organizational and social context (e.g., resource availability and characteristics of service recipients).^52,53 There are other depictions as well, such as bridging the discovery-delivery disconnect⁵⁴ that accounts for gaps that emerge during the traditional research process, notably the final gap in dissemination that characterizes the pitfalls of “if you build it, they will come” and emphasizes the importance of engagement throughout the research enterprise. A recent publication by Khan, Chambers, and Neta⁵³ showed that the landmark publication of HPV vaccination was in 2002 with US Food and Drug Administration (FDA) approval in 2006. The 50% threshold in HPV vaccination was achieved in 2016. This resulted in a 4-year gap between landmark publication and FDA approval and an additional 10-year gap to achieving the tipping point indicator. To prevent HPV cancers in the future, a more accelerated approach to ensuring good fit with existing evidence-based interventions and starting at age 9 for HPV vaccination is needed. With already slow uptake of HPV vaccination, especially among certain populations, acting now to improve vaccination rates is essential.

Implementation science offers systematic approaches to adapting and testing evidence-based interventions and approaches developed for older adolescents and even for adults to determine if they still yield meaningful impacts on vaccination rates for programs encouraging vaccination starting at age 9. In addition to developmental differences, the context change related to starting at age 9 may require altered implementation strategies to attend to relevant determinants. Adaptation has been defined as a process of thoughtful and deliberate alteration to the design or delivery of an evidence-based intervention to improve its fit or effectiveness in a given context or for a specific population.⁵⁵

Adaptations to evidence-based interventions must support a balance between making changes to maximize desired outcomes while retaining fidelity to fundamental elements of the evidence-based intervention.⁵⁶ This is often easier said than done, given that it is not always clear which elements of an intervention are critical versus exchangeable. One useful way to consider the balance is to focus on preserving the “function” rather than the”form” of the intervention.⁵⁵ This allows for utilization of the core principles of an intervention, without being tied to every detail of delivery. For example, some of the HPV interventions in the repositories emphasize use of digital video discs, commonly called DVDs, and were developed too soon to include social media or mobile phone applications. Appropriate adaptations can preserve this type of engagement and messaging strategy while using dramatically different delivery channels.

When making and testing adaptations, it is critical to capture and report these changes using systematic procedures, to support the development of a rich evidence base around adaptation. A few of the frameworks and approaches to guide the adaptation process are summarized here. These frameworks and approaches offer a rigorous manner to track inputs, processes, and outputs due to planned and unplanned adaptations to focus on starting HPV vaccination at age 9. Future research is needed in studying the type and nature of adaptations so as not to reduce intervention effectiveness.

Early publications on adaptations identified potential sources of intervention adaptations, such as to the setting, target audience, mode of delivery, cultural, and core components, and have informed evolving frameworks to guide adaptations.⁵⁷ The Framework for Modification and Adaptations was developed to document modifications to evidence-based interventions.⁵⁸ This framework assesses and documents by whom modifications are made, what is modified, at what level of delivery (for whom or what modifications made), which context modifications are made, and what is the nature of the content modifications. The Framework for Reporting Adaptations and Modifications-Expanded (FRAME) built on the original model to include when and how changes happened, whether changes were planned or unplanned, relationship to fidelity, and reasons and goals for the changes.^59,60 An additional model, FRAME-Implementation Strategies (FRAME-IS), offers a more intentional focus on the strategies used to support integration of evidence-based interventions into practice settings.⁶¹

Other frameworks and approaches for adaptation also exist. Intervention mapping⁶² is a commonly used intervention development framework, which also has relevance for adaptation. Intervention Mapping-Adapt (IM-Adapt) has emerged as an essential guide to apply principles of intervention mapping to adapting evidence-based interventions.^63,64 IM-Adapt focuses on understanding needs and capacity and planning and evaluating adaptations based on these assessments.^63,64 ADAPT was developed to guide specific adaptations to evidence-based interventions to account for new contexts.^64–66 The multi-step development process of ADAPT resulted in a series of questions for adaptation that can ensure the process includes the right people (adaptation team), clear rationale for adaptations, planning for and undertaking adaptations, and ensuring that interventions can be implemented and maintained at an appropriate scale.⁶⁶ Finally, assessing the impact of adaptations may require additional guidance to ensure complexities are considered. For example, Iterative Decision-making for Evaluation of Adaptations (IDEA) offers a series of decisions to balance adaptations to evidence-based intervention.⁶⁷ Those making adaptations are prompted to consider core elements of the intervention, opportunities for piloting, and whether or not potential costs of adaptations are acceptable.

A search of the peer-reviewed published literature revealed no published studies explicitly using one of the aforementioned frameworks and approaches to adapt HPV vaccination interventions for age 9. However, there were articles describing various approaches to adapt interventions – or components of interventions – for different populations and different channels.^68–72 This included reference to commonly used implementations of science theories, models, and frameworks, as well as needed cultural adaptation. Gilkey and colleagues,⁷³ examined the challenge with bringing evidence-based HPV vaccination interventions to scale in real-world settings. Of note, the authors acknowledge the importance of future implementation research in examining the role of contextual factors in supporting scale-up and leveraging assets to enhance sustainability.⁷³ These challenges noted by Gilkey are addressable using adaptation frameworks to track and monitor necessary modifications and to assess the impact of such modifications on overall process and outcome measures.⁷³

There are other considerations when exploring adaptations of existing evidence-based interventions for starting HPV vaccination at age 9. As noted, there are differences in HPV vaccination coverage depending on geographic location, rurality, and population characteristics that have persisted. Therefore, equity is a critical consideration when determining the necessary adaptations to evidence-based interventions for success with starting at age 9.^74,75 There may be instances where an evidence-based intervention requires adaptations to meet the needs of a new target population in which the context may differ so drastically from the original source of the evidence base that enough adaptations would be needed that one could not consider the program evidence-based any longer. In this case, starting at age 9 may elucidate altered determinants or implementation strategies due to the modified context. Partnerships with those most affected (e.g., young people and their caregivers), those delivering care (e.g., pediatricians and school clinic nurses), and those who can impact the process (e.g., policymakers) can offer insight into the types of adaptations required for success. This will inform decisions around adapting to existing interventions or beginning anew.⁷⁶ Similar considerations are also highlighted in calls to use methods of transcreation^77,78 to co-create and co-produce interventions (while drawing on the evidence base) in pursuit of addressing health inequities. In addition to noted major considerations regarding adaptations, the economics of adaptation is an important element to track, monitor, and consider.⁷⁹ The planned and unplanned adaptations made to an intervention may alter the required resources necessary for effective implementation of core components. Increasing recognition of research-to-practice gaps has called for rapid research informed by rigorous models, which predated the pandemics, such as the Framework to Assess Speed of Translation (FAST),⁸⁰ Designed for Accelerated Translation (DART),⁸¹ and designing for dissemination.^82,83 Additionally, such efforts must consider a focus on sustainability, if we are to continue achieving population benefit.⁸⁴ Table 2 provides potential adaptations of The Community Guide recommended interventions and approaches guided by FRAME and FRAME-IS to illustrate possible application in practice.

Table 2. Potential adaptations to the community guide interventions and approaches.

Key interventions and approaches recommended by The Community Guide	Potential adaptations guided by FRAME and FRAME-IS to increase uptake of HPV vaccinations starting at age 9
Enhance access to vaccination services: home visits to increase vaccination rates, reducing client out-of-pocket costs, vaccination programs in schools and organized childcare centers, vaccination programs in WIC settings.	Content modifications for home visits interventions that incorporate children at the age of 9 for their target populations Contextual modifications to incorporate a starting age 9 in the delivery of HPV vaccinations in schools and organized child care programs Content modifications to ensuring vaccines for children at age 9 are covered to reduce out-of-pocket costs. Content modifications related to HPV-vaccine eligibility with vaccines for children program providers
Increase community demand for vaccinations: client reminder and recall systems, community-based interventions implemented in combination, vaccination requirements for childcare, school and college attendance.	Content modifications that include changes in reminder/recall systems that incorporate starting age at 9 years Content modifications that include changes in vaccine registry forecasting tools that incorporate starting age at 9 years Content modifications to incorporate HPV vaccination starting at age 9 years, within community-based educational and training materials Contextual modifications in how the schools and childcare implement HPV vaccination requirements that include children age 9
Provider- or system-based interventions: health care system-based interventions implemented in combination, immunization information systems, provider assessment and feedback, provider reminders, standing orders.	Update immunization information systems and health-care systems to capture data for HPV vaccination starting at age 9 Train health-care organizations, providers, and staff and modifications in trainings and for health-care organizational staff and providers to incorporate a focus on age 9 as the starting age for HPV vaccinations Modifications to evaluations for provider- or clinic-level vaccination rates so that children starting at age 9 are considered

We do not have 17 years to wait for newly developed evidence-based interventions to promote the start of HPV vaccination at age 9.⁸⁵ With growing evidence around the success of HPV vaccinations globally, it is imperative that we leverage implementation science to reduce the research-to-practice gap for evidence-based interventions and use tools today to see if what we know works now can be adapted for additional populations and contexts. Current approaches to HPV vaccination have worked for many – but not for all. We fall short of the Healthy People 2030 goal of 80% of 13–15-year-olds vaccinated in the US, especially in some regions of the country and among some populations. Starting vaccinations at age 9 has the potential to increase HPV vaccination rates. However, many evidence-based interventions and strategies have not been specifically tested and/or incorporated with a focus on vaccine initiation for 9-year-olds. Implementation science and specifically the study of adaptations, can help to ensure that we can modify existing interventions and strategies to be applicable to 9-year-olds while simultaneously documenting the key determinants and drivers for implementing interventions to be maximally effective. We require additional information on intervention implementation in a constantly changing healthcare environment to understand how to adapt appropriately. In addition to using what we have now that has been shown to work for 11–12-year-old children, we must also consider novel approaches that may be needed with populations that have had consistently lower coverage, such as rural and/or more conservative communities in the US. What we have available now is not working for all and adaptation of existing evidence-based interventions may or may not bring the needed results. The longer we wait to meet the Healthy People 2030 goal, which was the same as our Healthy People 2020 goal, hundreds of thousands of children will miss out on this safe, effective cancer prevention vaccine.

Disclosure statement

The authors declare the following: Dr. Brandt: Nothing to disclose. Dr. Footman: Nothing to disclose. Dr. Adsul: Nothing to disclose. Dr. Ramanadhan: Nothing to disclose. Dr. Kepka: Dr. Kepka is a co-investigator on an HPV vaccination study at the University of Utah. In this study, a small portion of her salary was supported by the American Cancer Society, who received funding from Merck, for the purpose of the “Mission: HPV Cancer Free Quality Improvement Initiative.” This project will end on December 31, 2022. Dr. Kepka has also assisted Merck as an expert consultant.

Additional information

Funding

This publication was supported by the American Lebanese and Syrian Associated Charities (ALSAC) of St. Jude Children’s Research Hospital. Additional funding sources include the National Cancer Institute [U54CA156732]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. No commercial support was obtained.]