A systematic review of interventions to promote HPV vaccination globally

Background Despite the human papillomavirus (HPV) vaccine being a safe, effective cancer prevention method, its uptake is suboptimal in the United States (U.S.). Previous research has found a variety of intervention strategies (environmental and behavioral) to increase its uptake. The purpose of the study is to systematically review the literature on interventions that promote HPV vaccination from 2015 to 2020. Methods We updated a systematic review of interventions to promote HPV vaccine uptake globally. We ran keyword searches in six bibliographic databases. Target audience, design, level of intervention, components and outcomes were abstracted from the full-text articles in Excel databases. Results Of the 79 articles, most were conducted in the U.S. (72.2%) and in clinical (40.5%) or school settings (32.9%), and were directed at a single level (76.3%) of the socio-ecological model. Related to the intervention type, most were informational (n = 25, 31.6%) or patient-targeted decision support (n = 23, 29.1%). About 24% were multi-level interventions, with 16 (88.9%) combining two levels. Twenty-seven (33.8%) reported using theory in intervention development. Of those reporting HPV vaccine outcomes, post-intervention vaccine initiation ranged from 5% to 99.2%, while series completion ranged from 6.8% to 93.0%. Facilitators to implementation were the use of patient navigators and user-friendly resources, while barriers included costs, time to implement and difficulties of integrating interventions into the organizational workflow. Conclusions There is a strong need to expand the implementation of HPV-vaccine promotion interventions beyond education alone and at a single level of intervention. Development and evaluation of effective strategies and multi-level interventions may increase the uptake of the HPV vaccine among adolescents and young adults. Supplementary Information The online version contains supplementary material available at 10.1186/s12889-023-15876-5.


Conclusions
There is a strong need to expand implementation of HPV-vaccine promotion interventions beyond education alone and at a single level of intervention. Development and evaluation of effective strategies and multi-level interventions may increase the uptake of the HPV vaccine among adolescents and young adults.

Background
The Human Papillomavirus (HPV) is the most common infection that can lead to cancer later in life. There are 570,000 incident cancer cases per year in females and 60,000 incident cancer cases in males attributable to HPV globally. 1 HPV can lead to cancers of the cervix, vagina, and vulva for females, penis cancer for males, and anus and oropharyngeal cancer for both. 1 The World Health Organization has a vison to eliminate HPV related cancers, particularly cervical cancer, globally by 2030. 2 Similarly, in the U.S., Healthy People 2030 has an objective to increase the proportion of adolescents who receive recommended doses of the HPV vaccine from a baseline of 48.0-80.0%. 3 HPV vaccination can prevent more than 90% of cancers due to HPV infections. 4,5 Vaccination starts at age 9 and catch up is through age 26 and can go up to age 45, with shared decision making between the patient and provider if not adequately vaccinated. 6 The HPV vaccine is recommended during routine vaccinations to children at ages 11-12. 7 Globally, an estimated 15% of girls are fully vaccinated for HPV. 8 In the U.S., about 58.5% of adolescents were up-to-date on HPV vaccination in 2020, with 61% of females being fully vaccinated versus 56% of males. 9 Public health efforts are needed to increase the global rates of HPV vaccination.
Globally, there have been several reviews of interventions to improve HPV vaccination rates. [10][11][12][13][14] Interventions to promote HPV vaccination have typically targeted parents, adolescents, young adults, and providers. HPV vaccination interventions have targeted various socio-ecological levels in uencing HPV vaccination to effect change. Some focus only on the individual level (e.g., via education such as informational text included with reminders), whereas others may include changes to policy (e.g., via formalized requirements, such as school mandates). Multi-level and multi-component interventions are increasingly used 11,12,14 and address health disparities. 15,16 Multi-level interventions target two or more levels of in uence at or around the same time; the approaches implemented at each level typically may vary in type (e.g., behavioral, health systems, or policy). 15,17 It is important to understand the wide range of levels that can be utilized in interventions from single level to multi-level and how those levels can impact the desired outcome of vaccination.
The aim of this study was to conduct a systematic review of interventions to synthesize literature published from May 2015 to March 2020, to increase HPV vaccine uptake and/or completion. A previous systematic review and meta-analysis found that access-enhancing interventions were most effective. 10 Our review was intended to update this review of interventions for HPV vaccine promotion with more rigorous methodology, including exploration of sources of heterogeneity and quality assessment. Another purpose of the study was to improve understanding of multilevel interventions for HPV vaccine promotion. The review questions included: 1) What are the targeted audiences and levels of intervention for HPV vaccination interventions?, 2) What are common components of the interventions?, 3) What were facilitators and barriers to implementation of the vaccination interventions?, and 4) What are the study outcomes measured including the rates of HPV vaccination initiation and completion and their effectiveness? Our resulting study provides a strong contribution to the literature that can be used to inform future promotion efforts to increase HPV vaccine uptake.

Methods
We conducted a systematic review of the peer reviewed published literature, using methods following the PRISMA guidelines. 18 The team included cancer control researchers and Master's and doctoral students in public health and nursing.
Search strategy. The lead author, in collaboration with a health sciences librarian, created a search strategy using text and MeSH terms (Supplemental Table 1). We searched for relevant articles in six bibliographic databases, including Medline, CINAHL, Embase, Web of Science, Cochrane Reviews, and SCOPUS. An additional manual search was performed of the bibliographies of relevant studies identi ed from the database search. The team reviewed the articles found from the search and removed duplicates.
Inclusion criteria. To be included in the review, an article had to: a) aim to increase HPV vaccination through at least one intervention; b) report an outcome based on the intervention (e.g., increase knowledge of HPV, report on HPV vaccine outcomes determined either by self-report or medical records; c) be published between May 2015 through March 2020; and d) be published in English. Studies that tested single or multi-level interventions were included. Screening was conducted in two stages with the initial stage evaluating titles and abstracts, and a second stage screening full text articles independently reviewed by 3 authors (CE, CA, and MD) for full abstract review. Discrepancies were resolved through discussion at team meetings. Studies were excluded if they did not describe a primary intervention aimed to increase HPV vaccination, were systematic reviews or articles with just a program description, or had no study outcomes. Those that met eligibility through abstract review were included in the full-text review. After the full article review, the articles were examined further to see if they met the eligibility criteria, and 33 were excluded.
Data extraction. We retrieved the full text of eligible studies for review and abstraction. We then created a detailed codebook for data collection. Data extraction tables for the article and quality assessment were developed and maintained in an Excel database. They were modi ed following discussions between three reviewers prior to data extraction. Data extracted included study location, audiences, sample description, and setting; intervention details consisted of study design, description of intervention (e.g., control group components, if applicable), level(s) of intervention, delivery and barriers to implementation and vaccination, and outcomes of the study. We piloted the forms with ve studies and made re nements to the codebook and Excel database. We then conducted training for all data abstractors and had 15 reviewers (CA, CP, CE, MD, SS, CB, MF, AE, LS, ED, GR, KY, SL, TV, and PM). We invited cancer and implementation science researchers from the Cancer Prevention and Control Research Network 19 and doctoral and MPH students from the participating institutions. For quality control, we had 2 abstractors for each study, and we merged the data when consensus was reached for each article. The abstractors also performed study quality assessment for the articles they abstracted. The pair of abstractors came to an agreement if there were discrepancies. If there was a disagreement or question about a study quality answer, then the core team (CA, CP, and CE) had a discussion and came to an agreement on the study quality question.
Quality assessment. For this assessment, we employed the NCI Quality Rating assessment for Pre and Posttest Designs to conduct quality assessment of the included articles. 20 This assessment included 12 items; they are whether the objectives, intervention, and eligibility requirements were clearly stated, had a sample adequate for con dence in the data, had loss to follow-up of 20% or less, and measured changes in outcomes of interest before and after the intervention.
Synthesis of the results. We compiled all article abstractions into one database. We ran descriptive statistics and created summary scores for study setting and program component descriptions. The Community Guide categories (education, technology, vaccine access, incentive, provider eduation, health system change, community wide campaign, and policy) were used to organize the interventions into informational; behavioral change for participants, providers or both; or environmental (small or large policy). These categories also were applied in the Walling et al systematic review. 11 We also created summary tables for study characteristics, outcomes, and quality ratings. The primary outcome was HPV vaccine initiation and/or completion, although we reported on other outcomes related to HPV vaccination (i.e., HPV vaccine determinants). We examined the range of HPV vaccine initiation and completion for adolescents and/or young adults.

Results
The search identi ed 1,201 studies after removing duplicates. As a result of the title and abstract screen, 1,045 studies were excluded due to not being an intervention study or not reporting outcomes. The full-text of the remaining 152 articles were reviewed, leading to the exclusion of an additional 72 articles that did not have descriptions of the intervention or outcome data. This resulted in 79 articles included in the review for data extraction (Fig. 1). Table 1  Audiences. Intervention settings included clinics (32, 40.5%), schools (26, 32.9%), communities (10, 12.7%), an organization (1, 1.3%), a health insurance system, and online (10, 11.4%). Study samples ranged from 36 to 8,062.
Of the 79 studies, most interventions targeted adolescents only (39 studies, 49%), 21 79 and clinicians, adolescents, and young adults (1 study). 48 Only three studies included only male adolescents or young adult study populations (2 were adolescents only, and the last one was both adolescents and young adults).
Twenty-seven interventions (33.8%) reported the use of theory in intervention development. 25 Community Guide Intervention Categorization.
We report on categorization of the interventions based on the Community Guide's categorization of health-related evidencebased interventions. 11 The most common type of HPV vaccination interventions were informational interventions (25,31 23,52,53,58,65,79,84,98 were both patient and provider targeted interventions. Only 2 (2.5%) 24,45 were related to environmental interventions related to small policies (Fig. 3).

Discussion
We conducted a systematic review to assess interventions for HPV vaccine promotion. Our goal was to better describe common target populations of HPV vaccine interventions, common intervention levels and components, barriers and facilitators to intervention implementation, and the relationship between types of interventions and HPV-vaccine related outcomes. Previous systematic reviews have identi ed the breadth of intervention designs and contributed to our understanding of relative effectiveness of different intervention types; 11,13,101 however, given the advances in HPV vaccination research over the last several years, an update to these reviews was warranted. In our update to these reviews, we found that while intervention components were described thoroughly to contribute to our knowledge of types of interventions being implemented, fewer details about barriers and facilitators and HPV vaccine-related outcomes (particularly vaccination rates) were included. There were few patterns to be discerned in which types of interventions were found to be most effective, and in fact, among those that did report, only 20.3% reported signi cant increases in either initiation or completion or both. Despite this, our ndings offer six key insights into the types of interventions being implemented that makes effective interventions.
From intervention research, we know that there are certain "components" that can help to promote successful intervention implementation and outcomes. For HPV vaccination speci cally, we know that working with healthcare providers is an effective strategy. 10 More broadly, literature suggests that interventions are more effective when they focus on implementing at multiple levels 84 and use theory in intervention development. 102 However, in our review, we found that overall, many of the interventions identi ed did not adhere to these best practices; only 23% of the interventions were multi-level (18 total) and 34% employed theory (27 total).
We used the Community Guide and the Walling et al. systematic review classi tion of interventions such as informational, behavioral, and environmental to categorize and rank interventions. 10 Firstly, our review revealed the most commonly implemented interventions were not the types of interventions that had previously been shown to have the greatest impact. For example, while the success of behavioral provider and clinic focused interventions (particularly ones that promote changes to systems like utilizing reminder-recall and encouraging strong recommendations) is well-documented, 10 in our study we found other types of interventions were more often used. For example, information-providing interventions (used to increase knowledge of HPV, HPV-associated cancers and the HPV vaccine 10 ) were most common (31.7%) followed by patient decision support interventions (29.1%). Among these intervention categories, the intensity of the activities ranged widely. For example, in our study among information-providing interventions some studies employed a passive approach by offering pamphlets and educational materials 41 whereas others were more active and included live presentations. 46,67 Yet, educational, or information-giving interventions have been found to be less effective in increasing uptake or completion. 103 The interventions being implemented are not the types that have been shown to be most effective is consistent with other research that has identi ed a discrepancy between implementation of interventions or strategies that are most effective compared to interventions that may be deemed "easiest" to implement. 104,105 Secondly, despite extensive research showing increased effectiveness of multi-level interventions, 84 there were limited interventions included in this review that were multi-level (23%). For example, The Community Guide has found insu cient evidence for provider or patient education alone for vaccination, but has found that using education in combination with provider-focused interventions (i.e. provider reminders; assessment and feedback) has been successful. 106 In this review, 75% of the interventions reported intervening on only a single level, most commonly in clinical or school-based settings focused on individuals or providers. Future interventions to promote HPV vaccination should prioritize intervening at multiple levels to more effectively improve vaccine outcomes and discern which combination of levels result in higher vaccination.
Thirdly, using theory is well-documented as a best practice in intervention development and implementation; 102,107 however only one-third of the interventions in this review reported on the use of theory in the design of their program strategies. It is highly possible that some of these interventions did in fact use theory or theoretical constructs to guide their research, but did not report it explicitly. The Health Belief Model, Theory of Planned Behavior, Social Cognitive Theory and the Elaboration Likelihood Model were the most commonly utilized; this is consistent with a recent systematic review exploring use of theory in HPV vaccine interventions. 108 Using theory allows for understanding why speci c interventions may be effective (or not effective) and for comparison across multiple studies. Thus, future HPV vaccine interventions should report more broadly on use of theory in their intervention development and how constructs are employed in their design of intervention components or assessed in evaluation.
Fourthly, the effectiveness of these interventions was di cult to discern due to heterogeneity in measurement, outcomes, and study designs. Unfortunately, it is di cult to speak to what types of interventions were most effective as only about half reported on vaccine initiation (48%) and less than a third (32%) reported on vaccine series completion. Other commonly assessed outcomes included parental knowledge, 54,55,59,75 self-e cacy, 28,34,39,49,52,80,81,84,86,87 attitudes/beliefs, 25,34,36,39,46,49,52,59,60,66,68,73,84,86,94 and acceptability. 27,31,35,49,56,63,69,76,82 There is mixed evidence, however, on whether these outcomes are associated with uptake. For example, one meta-analysis found that parents' beliefs, attitudes and intentions were positively associated with HPV vaccine uptake, 109 while other studies have found intention to be unrelated to uptake, particularly in multivariable models, other factors seem to attenuate the effect of intention. 110 Moreover, many of the studies included in this review were quasi-or non-experimental, making it di cult to draw inferences about the effectiveness of any of the outcomes reported, almost half had multiple components, and only about half focused on vaccine series initiation and completion. There are promising ndings that a proportion of the interventions that reported signi cant changes in vaccination uptake or completion are multi-level and multi-component. Future intervention studies should focus on using rigorous methods to assess effectiveness for different types of interventions, including vaccination outcomes of series initiation or completion, and have longer term follow-up to be able to assess longer-term outcomes. In addition, evaluation of multi-level interventions for promotion of HPV vaccination should be conducted to contribute to their evidence of effectiveness.
Fifthly, related to the lack of reporting on intervention outcomes was a lack of reporting on implementation barriers and facilitators. Less than 20% of studies reported on facilitators and less than 30% reported on barriers. This is a similar nding to the review conducted by Smulian et al. (2016), who also reported a lack of reporting on barriers and facilitators. 10 This kind of information is critical in understanding program implementation, adaptation and tailoring for different settings. 47,61,72 Recently, the use of hybrid trials, which can be used to assess both effectiveness and implementation outcomes, is emerging among implementation research. 111,112 In the future, researchers could prioritize conducting these hybrid trials so that we can not only identify those interventions that are most effective, but also important implementation determinants that can inform sustainability and scalability in multiple types of healthcare settings.
Finally, it is important to note that it is a critical time, in the era of COVID-19 pandemic to disseminate effective cancer prevention interventions. HPV vaccination rates have fallen during the pandemic 113,114 and competing priorities have led to less time for clinics to devote to vaccine promotion. 115 Coupled with recent data suggesting that concerns about HPV vaccine safety are rising, 116 this is indicative of a need to identify what works and how to implement it to prevent future generations from being susceptible to HPV-associated cancers. Overall, increased reporting of both vaccine outcomes as well as barriers and facilitators will move the eld forward and provide data to help researchers determine which types of interventions to prioritize.

Strengths and Limitations
Our study was strengthened by the inclusion of interventions globally and our focus on understanding multi-level intervention strategies. By categorizing interventions at different levels (e.g., individual, interpersonal, clinical) we have added to the growing literature on multi-level interventions. Additionally, almost 30% of the studies included were conducted outside of the United States. This nding helps to add to growing global literature on HPV vaccine interventions and allows for comparability between the U.S. and other countries that continue to struggle with low HPV vaccination rates. 2 However, this should simultaneously be recognized as a potential limitation, as results may not be generalizable across all global geographies. While studies from North and South America, Europe, Africa, Asia, and Australia were included, there were only several from each continent (other than North America) which limits generalizability of results. Similarly, less than 15% of studies included parents or children from diverse racial and ethnic identities (de ned ≥ 50% other races than White). This makes it hard to assess the impact of interventions for HPV vaccination on racially and ethnically diverse populations.
Future HPV vaccination research should focus on these populations to test intervention effectiveness. We also were limited by only reporting on articles written in English and may be missing HPV vaccination interventions written in other langauges.
Another key limitation is the lack of reporting vaccine-related outcomes in studies. Just over 50% reported either initiation and/or completion outcomes. This fact with varying study designs makes it di cult to collectively assess intervention effectiveness through a data synthesis. Moreover, 40% of the studies were rated as "fair" or "poor" quality in our quality assessment, primarily due to studies not including multiple time points for outcome measures, not blinding participants in intervention studies, and for group-level studies not reporting on individual level data to determine group level effects. These limitations identify key gaps in the literature and that future research should focus on including more diverse populations in interventions, employing more rigorous study designs, and including vaccine initiation and completion rates.

Conclusions
In 2020, the World Health Organization adopted a Global Strategy to eliminate cervical cancer, aiming for 90% of girls to be fully vaccinated by age 15. 2 Given that males can suffer from HPV-associated cancers as well, many countries have expanded their vaccination programs to include males as well. However, worldwide, most countries fall far short of this 90% goal. Therefore, there is a strong need to expand implementation of HPV-vaccine promotion interventions beyond education alone and at a single level and use rigorous intervention designs. Inclusion of longer term evaluations focusing on vaccine initiation and/or completion to truly understand what is most effective in improving HPV vaccination rates. Many of the interventions included in this review did not report vaccine uptake data; relied on strategies found to be less effective (e.g., education alone); did not use or not report on use of theory; did not report on barriers and facilitors to implementation; or addressed a single level for intervnetion. Improving on the design and evaluation of HPV vaccination interventions is particularly critical at this moment as many adolescents missed vaccinations during the COVID-19 pandemic and vaccine hesitancy is growing. Improving our understanding of which interventions to prioritize for implementation will be important to ensure future generations of adolescents are protected against HPV-associated cancers.