Adolescent human papillomavirus vaccination in the United States: Opportunities for integrating pharmacies into the immunization neighborhood

ABSTRACT

Human Papillomavirus (HPV) vaccination faces several barriers, including a social stigma which carries religious and philosophical implications among parents of adolescents as well as young adults. Hundreds of immunization interventions and programs have been developed to address these factors and boost HPV vaccination rates in the United States. We sought to review the existing literature highlighting barriers to HPV immunization, as well as programs targeting increased HPV vaccine uptake in effort to develop novel vaccination initiatives. The most impactful barriers identified were parental stigma and low quality of provider recommendations for the vaccine. Despite the implementation of many HPV initiatives, outcomes of these programs are largely limited to modest improvements in vaccine uptake in small, homogeneous populations. We describe pharmacies as distinctly advantageous but underutilized resources within the immunization neighborhood and propose a novel concept to improve vaccination rates as well as reduce HPV-related disease burden in all demographics.

KEYWORDS:

• adolescent
• barriers
• HPV
• immunization
• initiatives
• pharmacy
• vaccination

Introduction

Human Papillomavirus (HPV) infection is a major public health issue in the United States (US) and throughout the world. As the most common sexually transmitted infection (STI) – HPV currently affects almost 80 million Americans with about 14 million new infections each year.¹ Despite having highly effective and readily available HPV vaccines in existence for over 10 years, recent estimates place HPV vaccination coverage among adolescents (age 13–17 years) in the US at 41.9% for girls and only 28.1% for boys (for completion of a full 3-dose series).² In 2010, the US Department of Health and Human Services launched Healthy People (HP) 2020 which outlined the nation's 10-year goals and objectives for preventive health and health promotion. HP 2020 set a national goal for HPV vaccination coverage at 80% for all adolescents aged 13–15 y.³ As a result, various healthcare professional and public health organizations have agreed to prioritize the improvement of HPV vaccination rates as a critical pillar for reducing HPV infection and related illnesses.⁴

There is an abundance of literature that describe existing barriers to immunizations in the United States including several articles highlighting barriers specific to HPV vaccination. There are also several published studies that analyze outcomes from initiatives and programs designed to improve HPV vaccination capture using multiple different strategies. We sought to review the current literature on barriers to HPV vaccination, as well as initiatives designed to improve immunization coverage for this disease. Our findings note that due to the increased number and complexity of barriers to HPV vaccination (in comparison to other vaccine-preventable diseases) – mixed levels of successes and major challenges have been identified in interventions targeting improved vaccination rates. More creative and targeted strategies are needed to address this major public health issue. We propose a team-based, multifaceted approach to HPV immunization provision using pharmacy-driven patient, family, and community engagement strategies. The formation and integration of this team concept has significant potential to improve HPV immunization rates through systematic breakdown of commonly encountered barriers to vaccination.

HPV: Virus and epidemiology

HPV is a double-stranded, non-enveloped, DNA virus, which infects squamous epithelial cells.⁵ HPV is most commonly transmitted through vaginal, anal, and/or oral sex, but can also be transmitted from mother to child during the perinatal period.⁶ Most sexually active men and women will contract the virus at some point in their lives.⁷ Most infections are asymptomatic, but clinical manifestations can include anogenital warts, recurrent respiratory papillomatosis, cervical intraepithelial neoplasias and cancers of the cervix, anus, vagina, vulva, penis, and oropharyngeal areas.¹ HPV acts as a carcinogen by containing viral sequences, integrated into the DNA of host cells, that can cause 103 malignant transformations by targeting regulatory molecules in the epithelial cells.⁸ There are currently more than 120 HPV types, with about 40 associated with cervical cancer. HPV types 6 and 11 are considered non-oncogenic (low-risk), and can typically cause genital warts and laryngeal papillomas. Oncogenic (high-risk) types such as 16 and 18, can cause cell abnormalities which can lead to cervical and anogenital cancers.¹ To assess the incidence of HPV-associated cancers, the United States Centers for Disease Control and Prevention (CDC) analyzed high-quality data from the National Program of Cancer Registries and the National Cancer Institute's Surveillance, Epidemiology, and End Results program from 2008–2012. During this time an average of over 38,000 HPV-associated cancers were diagnosed annually, with almost 25,000 cases attributable to high-risk types 16 and 18,⁹ demonstrating a significant disease burden in the United States.

HPV vaccine

Currently manufactured HPV vaccines use the HPV L1 major capsid protein of the virus as the non-infectious antigen.¹ Until recently, there were 2 HPV vaccines licensed for use in the United States.¹⁰ In 2006 the United States Food and Drug Administration (FDA) approved the quadrivalent (4vHPV) vaccine, Gardasil (Merck & Co., Kenilworth, NJ, United States), containing virus types 6, 11, 16, and 18.¹¹ In October 2009 a bivalent (2vHPV) vaccine, Cervarix (GlaxoSmithKline, Rixensart, Belgium) was approved, protecting against types 16 and 18.¹² Most recently, a 9-valent vaccine (9vHPV), Gardasil 9, (Merck & Co., Kenilworth, NJ, United States) was approved in December 2014, protecting against types 6, 11, 16, 18, 31, 33, 45, 52, and 58.¹³ As of late 2016, only 9vHPV is being distributed in the United States. The 9vHPV vaccine is approved for both males and females ages 9 through 26 y and contains inactive subunits allowing for vaccination of immunocompromised patients.^1,14

The safety and efficacy of the 2vHPV and 4vHPV vaccines are well documented.¹⁵ More recent studies have highlighted the safety and efficacy of 9vHPV. A phase III trial comparing efficacy of the 9vHPV series with the 4vHPV series in over 14,000 females aged 16–26 y displayed 96.7% efficacy of 9vHPV against disease caused by types 31, 33, 45, 52 or 58.¹⁶ Noninferior immunogenicity was found between 9vHPV and 4vHPV for types 6, 11, 16 and 18.^{16, 17} Similar efficacy data has been documented in 16–26 y old males, and 9–15 y olds of both sexes.¹⁴ The most common adverse effects of 9vHPV include injection-site pain (63.4–89.9%), erythema (20.7–34.1%), and swelling (20.2–40%), and headache (11.4–14.6%, in females only), with most rates comparable or slightly higher than that of 4vHPV.¹⁷

HPV vaccination: Current status in the United States

National coverage rates for the adolescent vaccines tetanus/diphtheria/acellular pertussis (Tdap), and meningococcal conjugate (MenACWY), have steadily increased over the past decade, with recent coverage rates reaching an estimated 86.4 and 81.3%, respectively.² Despite the fact that when age-appropriate, the CDC recommends the HPV vaccine to be given at the same time as those vaccines just mentioned,¹ coverage rates for HPV among adolescents fall severely short compared with Tdap and MenACWY. The necessity of 3 doses (before October 2016) to complete the vaccine series certainly has played a factor, but even national rates for only > 1 dose of HPV vaccine are still well below national goals, at 62.8% for girls and 49.8% for boys aged 13–17 y.²

Recently a pivotal open-label trial was conducted by Iversen et al. in over 1500 patients which studied the immunogenicity of a 2-dose 9vHPV vaccine series (given at 0 and 6 or 12 months) in males and females aged 9–14 y vs. the conventional 3-dose series (0, 2, and 6 months) in females ages 16–26 y. Sponsored and funded by Merck & Co., the study found at 4 weeks after series completion, antibody responses in patients who received the 2-dose series were noninferior to those responses in adolescent girls and young women who received the 3-dose series (p < 0.001 for each HPV type).¹⁸ These findings ultimately lead to the FDA approval of the 2-dose regimen (0, 6–12 months) for both boys and girls ages 9–14 y in October 2016¹⁹ which was subsequently supported by the Advisory Committee on Immunization Practices (ACIP).²⁰ It is important to note that immunocompromised patients and those initiating HPV vaccination after their 15^th birthday are still recommended to receive the 3-dose series (0, 1–2 and 6 months).^{14, 20} These new recommendations have significant implications for improved population coverage and cost-effectiveness, and provide a tremendous opportunity for immunization stakeholders to harness novel strategies to optimize HPV vaccination programs.

Methods

We searched the PubMed (US National Library of Medicine) online database from March 11, 2016 to January 20, 2017 using basic and Medical Subject Heading (MeSH) searches of the following terms: adolescent, barriers, community pharmacy, education, HPV, human papillomavirus vaccine, immunization, pharmacist, pharmacy, vaccine, and vaccination. Only articles written in English and published between April 2010 and December 2016 were included in the review. Pertinent articles included in the review were largely qualitative and/or quantitative descriptive studies of focus groups, interviews, survey/questionnaire analyses, or post-intervention data analyses with or without multivariable modeling (25), but also included invited commentaries/perspectives (3), randomized controlled trials (3), systematic reviews (3), one expert review and one prospective, controlled, parallel study.

Barriers to HPV vaccination

Improving HPV vaccine uptake cannot be accomplished without first understanding the key factors that prevent children, adolescents, and young adults from receiving age-appropriate vaccination. The provision of immunization against HPV is faced with arguably the most barriers of any vaccination, due to multiple factors. Adolescent vaccines in general can be hindered by socioeconomic factors, lack of accessibility, misinformation regarding vaccines, among several others.²¹ In addition, adolescents are a difficult group to reach regarding vaccinations due to less frequent contact with primary care providers for health maintenance.²² However, the nature of HPV as a STI poses an incremental challenge to vaccination, as it carries social, philosophical, and religious stigma among parents of young adolescents, as well as a hindrance on effective provider communications and recommendations.

HPV and parents

Many apprehensions to the HPV vaccine exist among parents of children and/or adolescents in the United States. According to the National Immunization Survey-Teen, United States, 2013, the top 5 reasons for parents choosing not to vaccinate their adolescent children against HPV were that the vaccine was not recommended (by a healthcare provider), lack of knowledge, felt the vaccine was not needed or necessary, concerns over vaccine safety/side effects, and the claim that their child was not sexually active.¹¹ A more recent review describes religious reasons, personal/philosophical beliefs, vaccine safety, and wanting for more information from healthcare providers as the 4 most prominent categories of overall vaccine refusal, delay, and/or hesitancy.²³ Most current research suggests that with regard to HPV specifically, vaccine education and misconceptions are among the top reasons for parental vaccine refusal.²⁴

Initially upon introduction of the HPV vaccine in the US immunization schedule for routine use in girls aged 11 or 12 y in 2006,²⁵ parents expressed concerns about the use of the vaccine as a tool for prevention of sexually transmitted infections.²⁶ In 2011, the HPV recommendations were expanded to include routine immunization of boys starting at ages 11 or 12 y.²⁵ In recent years, vaccine manufacturers and health organizations have shifted focus to education and advertisement for the vaccine as a method of preventing an infection which can lead to cervical cancer. Because of this, male children and adolescents become considerably neglected and often missed as targeted groups for HPV vaccination. One survey of 350 mothers of both male and female children in low-income families in the United States found that mothers were more likely to pursue HPV vaccine initiation and completion in their daughters compared with their sons.²⁷ As a result of these and other data²⁸ the CDC and other vaccine advocacy organizations have boosted their efforts in displaying educational material to appropriately inform parents of adolescent males and young men of their risk for HPV and related diseases, including genital warts, anogenital cancers, and laryngeal papillomas.¹

Another important parental barrier that has been well-documented is the fear that HPV vaccination may condone or lead to more promiscuous sexual behaviors in sons and daughters.²⁹ Though these thought processes present a significant challenge to immunizing clinicians, it should be noted and communicated to parents that there have been several studies which found no link between HPV vaccination and an increase in or risky sexual behavior,^30-33 and no evidence has been found to date which establishes any correlation.³⁴

Although parental barriers have been extremely well documented in the literature, the methodology of most studies designed to reveal these barriers still leave questions and gaps in the full picture of poor vaccine uptake. This is well-illustrated in a 2012 systematic review by Garcini, et al. which reviewed the methodology of 17 observational studies of HPV vaccine uptake from the perspective of parents. The authors found that most studies were cross-sectional, relied on parent self-report, focused on vaccine initiation instead of series completion, and surveyed parents of only females in all but one study included in the review.³⁵ This article demonstrated that studies using improved random sampling techniques, more diverse samples, and objective evidence of vaccine uptake and series completion (versus initiation) as outcomes³⁵ are needed to gain a more clear understanding of parental barriers to vaccination.

HPV and healthcare providers

In addition to addressing parental hesitancy, inadequate healthcare provider communications and recommendations are a major issue in HPV vaccine provision. The strength, quality, frequency, and most importantly, effectiveness, of HPV vaccine recommendations among primary care physicians, family practice clinicians, and other key stakeholders have been extensively studied.

A national survey of over 1500 family medicine, pediatric, and obstetrics and gynecology physicians was conducted by Vadaparampil, et al. in 2009 and 2011 to evaluate their HPV vaccination recommendations to females aged 11–26 y. The study was designed to determine whether the proportion of physicians who report ‘always’ recommending the HPV vaccine differed from 2009 (3 y post-vaccine licensure) to 2011 (5 y post-vaccine licensure). The study found only a slight increase in recommendations for girls aged 11–12 y (35% in 2009 vs. 40% in 2011, p = 0.03), with no change seen in patients 13–17 y (53% vs. 55%, p = 0.28) or 18–26 y (50% vs. 52%, p = 0.52).³⁶ Regardless of 2 additional years of post-vaccine licensure experience, less than half of physicians who are ideally positioned to immunize consistently recommended the vaccine to their adolescent female patients at the recommended age.

Another survey of over 700 family physicians and pediatricians performed by Gilkey et al. analyzed the quality of their recommendations for the HPV vaccine based on several factors. Results revealed that 27% of physicians in the study did not strongly endorse the vaccine. In addition, only 74% and 61% of physicians reported routinely recommending vaccination by the appropriate age to girls and boys, respectively. Furthermore, over half of physicians reported using a risk-based approach to recommending the vaccine instead of routine recommendation, and 49% reported delaying vaccination in 11–12 y olds vs. same-day recommendation and vaccination.³⁷

Several studies have also analyzed parental perception of provider recommendations for vaccination. For example, a cross-sectional survey of over 350 parents of children aged 9–14 y found that the HPV vaccine was less likely to have been “very strongly” recommended vs. other adolescent vaccines (39% vs. 45–59%, p < 0.05 in all comparisons). Those parents receiving a very strong recommendation were more likely to have their children vaccinated (71% vs. 39%, p < 0.001).³⁸ Another survey of 1,495 parents of adolescents aged 11–17 studied their experiences with HPV vaccination recommendations from providers in terms of strength of endorsement, urgency to vaccinate, preventative health and overall quality, and also analyzed the association between recommendation quality and vaccine initiation and completion.³⁹ An astonishing 48% of parents reported receiving no provider recommendation for the vaccine, 16% received low-quality recommendations and only 36% received high-quality recommendations. Parents receiving high-quality recommendations were significantly more likely to have had their child initiate (OR 9.31; 95% CI 7.1–12.22, vs. 4.13; 95% CI 2.99–5.70 for low-quality recommendations) and complete (OR 3.82; 95% CI 2.39–6.11, vs. 1.78; 95% CI 0.99–3.20) the HPV vaccine series.³⁹

Several reasons have been proposed for healthcare provider hesitancy and ineffectiveness in recommending the HPV vaccine. Many revolve around lack of clarity in the most effective method of communication (i.e., direct vs. open-ended, comprehensive vs. targeted disease prevention, etc…), while others point to the perception of parents (of young adolescents) as unreceptive to discussions regarding the vaccine.³⁷

Regardless, outcomes of all of the above studies are concerning and target a major reason for poor vaccine uptake. The combination of lackluster provider recommendations coupled with parental apprehension and other barriers to vaccines in general, poses a significant challenge to meeting national HPV immunization goals set by HP 2020.

Tackling the barriers: HPV immunization initiatives

We sought to review and summarize the literature on recently conducted HPV vaccination initiatives and/or programs and describe their outcomes. The major initiatives included in this review focus on 3 strategies: technology-based interventions, school-entry requirements for vaccination and health-system initiatives. Strategies using vaccine manufacturer support for low-income families, alternative settings for vaccination, health plan and public health initiatives, are also discussed.

Technology-based interventions

In an effort to promote self-persuasion of adolescent HPV vaccination, Baldwin et al. developed a tablet-based application designed to stimulate self-persuasion for HPV vaccination among parents of adolescent patients. The application was designed to elicit self-persuasion through the presentation of a short informational video followed by a question-prompt program which led parents to brainstorm and summarize vaccination rationales that are important to them. The authors piloted the application in 45 parents of adolescents attending safety-net clinics in the US. After completing the self-persuasion tasks of the application, 27 of 33 (82%) parents of unvaccinated adolescents reported the decision to vaccinate their children against HPV.⁴⁰ This study showed that self-persuasion strategies conducted through a technology-based intervention can be easily implemented and has a significant impact on parental HPV vaccination intentions.

Another tech-based intervention studied the efficacy of phone vs. text message reminders for HPV vaccination series completion in 369 parents of 11–17 y olds in a parallel randomized controlled trial. After controlling for several variables, text intervention resulted in a significantly higher proportion of adolescent series completion (49% vs. 30% in control group, p = 0.001), whereas phone intervention resulted in a non-significant difference (48% vs. 40% in control group, p = 0.34).⁴¹

Several other studies have shown variable measures of success with phone, text, or other e-based interventions.^42-45 Despite the abundance of data on technologic interventions, more studies are needed to test whether these types of interventions are effective in affluent populations, and whether they can elicit series initiation in unvaccinated patients, vs. just series completion in those who already started the series.

School-entry requirements for vaccination

School-entry requirements for childhood and adolescent vaccinations have been implemented by state lawmakers for both public schools and day care facilities (in all 50 states and the District of Columbia), as well as private schools in the United States.⁴⁶ Currently only 3 jurisdictions (District of Columbia, Rhode Island, and Virginia) mandate HPV vaccination specifically,⁴⁷ but these states do allow exemptions for medical, religious, and/or philosophical (Virginia only) reasons.⁴⁸

Overall physician support for school-entry requirements for HPV vaccination has been shown to be modest at best and dependent on several individual provider factors. A survey of 775 primary care providers in 2014 found that 74% supported school-entry requirements, but only 47% were in support when opt-out provisions were not specified.⁴⁹ Those who agreed with requirements without exemption options were those with more years of practice experience, reported providing higher quality HPV vaccine recommendations, and believed HPV vaccination was equally or more important than other adolescent vaccines.⁴⁹ Parental viewpoints have been shown to be quite similar, as one survey of over 1,500 parents of 11–17 y olds found that including exemption provisions nearly tripled parental support of HPV vaccination school-entry requirements, shifting support from 21% to 57%.⁵⁰ Interestingly, those indicating Hispanic race were more likely to agree with requirements without opt-out provisions (OR 1.53, 95% CI 1.05–2.22) in comparison to non-Hispanic whites in multivariable analysis. Parents who were less likely to support school-entry requirements included residents in Midwest states and those who believed drug companies were supporting such mandates for financial gain.⁵⁰

Though school-based mandates have been shown to improve vaccine capture of several other vaccines (Tdap, MenACWY, hepatitis B, measles, mumps, and rubella, etc.),⁵¹ unassertive provider and parental support in addition to generous exemption provisions have derailed efforts of school-based HPV requirements. Two recent studies were conducted using the CDC's National Immunization Survey – Teen data, looking at the impact of school-entry mandates on HPV vaccine coverage.^52,53 One study of data from almost 100,000 adolescents from 2008–2012 indicated that HPV vaccine coverage was only 0.4% higher in states with HPV vaccine requirements vs. states without (47.7% vs. 47.3%, p < 0.05 after multivariable analyses).⁵² The other study used multiple logistic regression models to compare HPV vaccination rates for 13–17 year-old females residing in jurisdictions with vs. without HPV vaccine mandates, using data from 2009–2013. After adjustment for known covariates – no significant difference was found in rates of vaccine series initiation or completion for any year.⁵³ The authors explicitly stated that “liberal opt-out language” is one of the most crucial hindrances to current school mandates.

Health-system initiatives

Health-systems and health plans have also advocated for and trialed creative strategies to facilitate HPV vaccination with considerable success. In Colorado, Denver Health – an urban safety net health system which serves over 17,000 adolescents annually – developed a process for improving immunization which focused on “bundling” 3 adolescent vaccines (Tdap, MCV4, and HPV) through several strategies, including routine use of an internal immunization registry (VaxTrax) at every patient visit, standing orders for appropriate vaccines, provider education of the “bundling” strategy, and provider feedback through regular review of immunization metrics, among several others.⁵⁴ Compared to national data, patients in the Denver Health system reported substantially higher rates for at least one dose of HPV vaccine (89.8% vs. 57.3% in females, 89.3% vs. 34.6% in males) as well as series completion (66.0% vs. 37.6% in females, 52.5% vs. 13.9% in males) in 2013. As expected, coverage rates for Tdap and MCV4 were also considerably higher than the national average.⁵⁴

Another highly regarded health-system program worth noting is the 4 Pillars™ Practice Transformation Program – “a multi-faceted, cloud-based quality improvement (QI) platform that provides health care organizations with a library of up-to-date, evidence-based QI programs from leading medical practice innovators.”⁵⁵ Created by researchers at the University of Pittsburgh, this program has been used by over 50 primary care offices and focuses on 4 domains: convenience, communication, facilitation, and motivation.⁵⁶ In 2013, the inventors of program partnered with the Immunization Action Coalition (IAC) and conducted a randomized, cluster trial of 20 primary care practices with at least 50 11–17 y old patients. After 9 months of program implementation at intervention sites, HPV series initiation rates increased 10.2 percentage points vs. 7.3 in control sites (p < 0.001 for difference). Unfortunately, no difference was found in series completion rates between groups.⁵⁶

Other strategies

Vaccine advocates, public health officials, clinicians and research have trialed many different initiatives, in addition to those aforementioned. For example, alternative settings (typically defined as outside of the traditional primary care, family medicine, or medical home setting) have been suggested as strategies to increase HPV vaccine capture. A recent study found that 50% of parents and 37% of their adolescent sons would be comfortable with receiving the HPV vaccine at a school or pharmacy – suggesting an increase in vaccine uptake of more than 10% in boys who had not recently seen a healthcare provider.⁵⁷ Other capable alternative settings proposed include in-school health centers and specialty clinics, but those settings would need to substantially increase in number through grant funding or other avenues to have a significant impact on HPV vaccination rates.⁵⁸

The outreach of health plans to large populations is another promising strategy. Among several high-performing health plans, the use of strategies to “normalize” the HPV vaccine (by recommending it as part of routine immunizations), educate and provide reminders to patients and providers, provide feedback to providers using data transparency, and enhancing access to registry data, were described as the key factors in facilitating HPV vaccination among their beneficiaries and network providers.⁵⁹ Public health organizations also continue to support providers by developing unique programs (such as the CDC's AFIX Program – Assessment, Feedback, Incentives, and eXchange) designed to raise immunization awareness and coverage rates, with varying levels of success and ongoing data collection and analysis.⁶⁰

Of note, a few authors have analyzed multiple program outcomes via systematic review. For example, a recent meta-analysis of 23 studies on adolescent immunization intervention program efficacy by Das, et al. found moderate-quality evidence of an overall increase in vaccination coverage of 78% (RR 1.78, 95% CI: 1.41–2.23), and that programs using reminders and school-based requirements, as well as the CDC/ACIP national recommendation for vaccination of males in 2009,⁶¹ were of most potential to improve vaccine uptake.⁵¹ Perhaps the most comprehensive systematic review to date, performed by Walling et al., was recently published in Pediatrics. Conducted using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, this review identified 51 intervention studies outlining post-intervention HPV vaccination rates, classified them in 3 district categories (informational, behavioral, and environmental), and compared their relative efficacy.⁶² The authors support many of the reviewed interventions and also highlight key successes and challenges faced by each approach. A summary of these findings can be seen in Table 1 and can be used as a key tool for future application.

Table 1. Summary of findings from Walling et al. (2016).⁶²

Intervention Classification	Intervention Type (no.)	Advantages	Disadvantages/Challenges
Informational	• Education targeting low-income parents (1)	• Improved vaccine uptake during intervention period	• Limited sustainability
	• Media information campaign (1)
Behavioral	• Patient-targeted decision support (5)	• Reminder strategies highly successful	• Require large amount of effort and resources
	• Patient-targeted Reminders (7)	• Combined patient- and provider-targeted interventions improve both initiation and series	• Inconsistent results among non-reminder strategy interventions
	• Provider-targeted (4)
	• Combined patient- and provider-targeted (2)	completion	• Implementation barriers poorly reported in studies
Environmental	• Small policy: school- and/or clinic-based (12) • Big policy: national	• ↑ access	• School-based: low participation
		• Can impact large and diverse populations
	or local government involvement (19)	• School-based: can be effective in series completion	• Community support is key to success
Key Discussion Points:
• Peer group endorsement highly influential on patient behavior
• Provider-targeted interventions most effective for series initiation
• Patient-targeted interventions most effective for series completion

Opportunity for pharmacy-driven programs

The need for more successful HPV vaccination programs is evidenced by an astounding projection of the potential HPV disease burden. Studies have estimated that the lifetime probability of acquiring HPV ranges from 50% to nearly 100% in unimmunized sexually active men and women.^63-65 Additional cohort studies demonstrate high disease prevalence even after short follow-up periods at levels exceeding 40% over 3 y.^66-68 The corresponding economic burden that follows a highly-prevalent disease is equally impressive. Recent data estimates the total lifetime direct medical cost of HPV infection in the United States at $1.7 [$0.8–2.9] billion, a cost second highest only to HIV among STIs.⁶⁹ Several studies demonstrate substantial cost-effectiveness and savings through application of vaccination and screening programs that used mixed prevention strategies encompassing cancer screening, HPV testing and gender/age targeting across different settings including ambulatory care sites.^70-75

The SK&A National Pharmacy Market Summary states that as of 2016 – 34,973 pharmacies and 76,627 pharmacists make up the 25 largest pharmacy chains in the United States.⁷⁶ Meanwhile, the National Community Pharmacy Association represents 22,000 independent community pharmacies that dispense nearly half the United States’ prescription medications.⁷⁷ This pharmacy workforce is perhaps the most accessible existing healthcare resource in the United States, with almost 95% of Americans living within 5 miles of a pharmacy.⁷⁸ The expanse of community integration also encompasses low economic areas that are devoid of general health care clinics and offices, and the depth of community integration includes already expanding immunization programs. While in recent years pharmacies have become more regularly associated with influenza vaccine provision, it should be noted that most US pharmacies carry and administer a full spectrum of vaccines, including travel vaccines. Pharmacy services may also include a broad range of medication therapy management services and point-of-care testing programs (e.g., diabetes, lipidemia, hypertension, infectious diseases), depending on location.

Community pharmacies represent an underutilized and cost-effective resource that already exists in our global health care force. Without the need for appointments (and office resources, administrative costs, staff support), individuals can receive vaccinations, education, and point-of-care services at their neighborhood pharmacy when they shop for groceries or home supplies. Important to note, the majority of retail pharmacies have extensive business hours, with many servicing patients 24 hours a day, alleviating the need for parents to schedule additional physician appointments for vaccines which may interfere with occupational requirements. In fact, a large study showed that over 30% of vaccinations administered by a large pharmacy chain from August 2011-July 2012 were provided during off-clinic hours,⁷⁹ meeting the needs of working-class citizens. In addition to convenience, direct access to the patient, access to medication and demographic information, and integrated physician communication, pharmacies are well-suited to facilitate completion of the 2- or 3-dose HPV vaccine series, in addition to identifying new vaccine recipients. With about a 20% differential loss between series initiation and completion in both boys and girls,^2,11 there is much potential for pragmatic capture of vaccine recipients in their residential areas. The importance of a follow-up intervention is magnified by the accessibility of community pharmacies and their access to patient demographics including their primary care providers.

Pharmacists are also uniquely equipped to support an integrated, multifaceted vaccine program. There are over 280,000 pharmacists trained in immunization provision through national certificate programs⁸⁰ with extensive emphasis on effective patient communication and recommendation for vaccines. In addition, all Doctor of Pharmacy professional degree programs have formal sterile drug compounding and preparation competencies that focus on aseptic technique. Many community pharmacists further specialize in medication therapy management, focused on disease state management which includes recommendations for age and disease-appropriate vaccinations. Furthermore, pharmacy-based immunization training features combined motivational and educational strategies to address vaccine misinformation – a critical obstacle to overcoming perceptions and fears that inhibit vaccinations.⁸¹

Pharmacy integration: Evidence and support

Pharmacies’ early success in immunization provision came with influenza and continues to grow. According to the CDC, pharmacists vaccinated approximately 10% of all adults who received the influenza A subtype H1N1-specific vaccine in 2009,⁸² and currently about 1 in 4 adults are vaccinated from influenza by pharmacists.⁸⁰

Early success with influenza led to expansion of pharmacy-based immunization programs to include provision of many routine and travel vaccinations. A recent systematic review by Burson, et al. showed that pharmacy-based immunization programs are widely accepted by patients, improve accessibility, and are able to improve vaccination rates.⁸³ In fact, a simple, 1-minute pharmacist personal selling intervention, designed to educate patients about herpes zoster risk and vaccine efficacy was found to increase patient commitment to receive the vaccine 10-fold.⁸⁴ This dramatic effect can be expected considering pharmacists are second behind only nurses as the most honest and ethical professionals in the United States, according to a recent Gallup survey.⁸⁵

In addition, a few collaborative pharmacist-driven models for immunization provision have demonstrated promising results, particularly in the medically underserved. In 2012, a prospective, controlled, parallel study by Higginbotham, et al. analyzed the impact of a pharmacist-immunizer embedded in a primary care center serving primarily indigent patients. At the conclusion of the study, the availability of a pharmacist-immunizer significantly increased the number of patients current on all immunizations (χ² = 15.8, df = 1, p< 0.001) compared with a control group.⁸⁶ Another recent systematic review and meta-analysis of 36 studies performed by Isenor, et al. found that involving pharmacists in the immunization process in multiple different capacities (as educators, facilitators, or vaccine administrators) resulted in improved vaccine uptake, when compared with conventional immunization provision without pharmacist involvement.⁸⁷

Though much success has been seen with pharmacy-based immunizations in adult vaccines, the literature is scarce on programs specifically targeting adolescent vaccines such as HPV. HPV may present the most significant challenge to pharmacies publicly, as a recent survey showed that only 29% of parents would be willing to have their children vaccinated for HPV at a pharmacy, vs. 62% for influenza and 41% for Tdap.⁸⁸ In our search we discovered only one pharmacy-based, HPV-focused program, which was conducted by Navarrete et al. and targeted underinsured college students through a university-based Student Health Clinic Pharmacy – partnered with the Merck vaccine prescription assistance program (MVPAP) – in effort to increase uptake of HPV vaccination in that population. Over a period of 2 years, 89 underinsured patients (81% female) were approved for the MVPAP with assistance from pharmacy personnel. All of these patients received the first HPV dose and 43 (48.3%) individuals completed the full 3-dose series.⁸⁹ This result speaks volumes as this rate is slightly higher than national average and was accomplished in a population that would otherwise have little to no access to the vaccine.

Despite some success demonstrated by studies of pharmacy and pharmacist-based models, their accomplishments are not without limitations. As stated above, several pharmacy-based initiatives have been shown to increase adult immunization uptake, but models that specifically target adolescent vaccination appear to be few and far between in the literature, especially in comparison to health system- and public health-driven models for adult vaccines. As indicated above, the only pharmacy-driven adolescent program that we found in our literature search did result in a positive outcome for HPV vaccination, but this was in a small, homogeneous population.

In addition, it should be noted that pharmacies themselves are not without both commonly encountered and unique barriers to immunization provision. For example, in the intervention by Navarrete, et al. over half of patients initiating the series did not complete it, with loss of follow-up being the most common reason for incompletion (72%).⁸⁹

Since 1994, the CDC's Vaccines for Children (VFC) program has provided federal funding for the free provision of child and adolescent vaccines (including HPV) for qualified federally-insured, uninsured, underinsured, American Indian, and Alaska Native patients.⁹⁰ However, there are only about 100 pharmacies across the nation designated as VFC providers compared with 44,000 total providers.⁹¹ This is largely because accomplishing and maintaining VFC status poses major pragmatic challenges to chain pharmacies, such as the necessity to maintain a completely separate vaccine inventory, onerous ordering, storage, and handling requirements, and perhaps most notably, program training for hundreds to thousands of pharmacy personnel. It should also be noted that health plan recognition and reimbursement for pharmacy-based immunizations is improving, but such efforts have focused mostly on influenza (covered at pharmacies under Medicare Part B and most commercial plans), pneumococcal (covered at pharmacies under Medicare Part B and some commercial plans), and herpes zoster (covered at pharmacies under Medicare Part D with variable co-payments) vaccinations. Pharmacy benefit coverage for adolescent vaccines has made less headway, and can be a significant barrier for the majority of pharmacies that are not VFC providers and/or those who serve largely non-VFC populations.

Proposed multifaceted immunization concept

A comprehensive, multifaceted approach to breaking down barriers and improving vaccination rates is greatly needed. Considering both shared and unique challenges faced by multiple vaccine providers, a tri-pronged vaccination ‘team’ – featuring novel, pharmacy-based patient and family engagement strategies, could be a plausible strategy to tackle this significant and complex public health concern. We propose the following model (Fig. 1) which is described in further detail below.

Figure 1. Proposed multifaceted immunization concept.

In this approach, a vaccination team, created by a partnership between a group of primary care, family medicine, and/or OBGYN providers, a pharmacy or pharmacy group, and local, state, and/or national public health department(s), is integrated into the Immunization Neighborhood – a term originally coined by the American Pharmacists Association to describe “collaboration, coordination, and communication among immunization stakeholders, with the goal of meeting the immunization needs of patients and protecting the community from vaccine-preventable diseases.”⁹²

The vaccination team should consist of physician groups, ideally VFC providers, and a group of pharmacies with significant footprint in the community. Health departments are the third prong and designed to support providers and pharmacists through promotion and education of the public, and in many cases are VFC providers themselves. A shared electronic health record (EHR) is ideal, but often difficult to achieve. In that case, state registries (available in all 50 United States as well as US Territories) are well-capable of maintaining patient information pertinent to vaccines in secure systems accessible to qualified vaccine providers.⁹³

Team affiliation with a university could serve as a distinct advantage. A university with colleges of medicine, pharmacy, public health, and/or social work is most ideal. Team support from college faculty (through provision of clinical staffing, application for grant funding, etc.) and students (administrative and clinical support, public outreach, and age-correlation to target population) can provide incremental support and can also be mutually beneficial for the university. Health plans should also be notified and invited into the “Neighborhood” and should offer provider tools for communication as well as performance feedback using registry and/or claims data.

As previously mentioned, the integration of pharmacies maximizes patient accessibility and convenience, and reaches massive populations. However, each pharmacy in the program must adopt novel and tailored patient and family engagement strategies to break through communication barriers, provide high-quality and frequent recommendations, and aggressively follow-up for patient retention and series completion (see Fig. 1 for strategies). Community engagement by the pharmacy within the Immunization Neighborhood is also of paramount importance, and in fact has been displayed as an untapped resource with needs that the vaccination ‘team’ (especially those with university affiliation) are well-positioned to assist with.⁹⁴

Of note, this approach assimilates patients and families representing those with pro- and anti-vaccine viewpoints, as well as those who are vaccine hesitant. Strategically, their proposed ‘paths’ in this concept are less divergent than one would initially think. Those desiring HPV vaccination may receive all doses from the vaccine provider that is most convenient and accessible for them. Specific pharmacy-based engagement strategies as well as integrated Neighborhood initiatives (see Fig. 1) are designed to provide consistent follow-up to maximize probability of series completion. Prior to program implementation, key stakeholders will be identified as “motivational specialists” (representing the team) or “community champions” (representing the Neighborhood). Those undecided on vaccination will be referred to a motivational specialist extensively trained in motivational interviewing, communication, and factual scientific vaccine knowledge. Those who refuse vaccination will be referred to a community champion. This concept has been implemented in other interventions, but we strongly feel the key to effective immunization champions are as follows. First, these people must be community based and ideally trusted, non-medically associated individuals such as a faith-based organization leaders, local politicians, or school teachers. Second, they must be trained and ready to address the challenging environment of vaccine science communication, a concept highlighting the “failure of compelling scientific evidence to resolve public dispute over risks and similar facts.”⁸¹

In an era marked by the rapid dissemination of vaccine misinformation from highly polarizing figures, it takes more than just scientific facts to dispel harmful misconceptions about immunizations. Community champions in this program will be trained to address this “risky” environment by 1) garnering support from peers, most strategically those who have been burdened by some form of HPV or related cancer(s), and 2) effectively promoting the beliefs of those few polarizing figures (local celebrities, political leaders, social media/internet stars, business and industry leaders, etc.) with pro-vaccine views. Though promising, it should be noted that this community champion concept is plausible to implement but quite challenging to refer opposed patients. A process of vaccine information sharing, starting from the community champion and disseminating among citizens of the Neighborhood, may be the most effective method of swaying immunization naysayers. Lastly, it is important to note that although this model has been proposed to address the unique challenges and barriers to HPV vaccination, it can be adapted and effectively applied to address other vaccine-preventable diseases as well.

Some vaccine stakeholders feel that adolescent vaccination efforts should be solely focused on parents and young adults who are open to vaccination but are hesitant or encounter barriers. The proposed thought is that those who oppose immunizations due to personal or philosophical beliefs are essentially immovable.²¹ We argue that to take major steps toward national immunization goals, a long-term initiative focusing on new methods of community engagement and altering vaccine science communication – has significant potential to make an impact on those subset populations with philosophical or personal hesitancy. As history shows us – the fact that something has not yet been accomplished does not render it impossible.

Conclusion: Next steps and future research

Despite the efforts of hundreds of programs and subsequent outcome analyses, HPV vaccination rates remain well below national goals. This can be largely explained by the difficulty faced by vaccine stakeholders in developing initiatives that are effective in a wide range of socioeconomic and demographic groups, simultaneously address multiple vaccination barriers, and are scalable and replicable in larger populations. These difficulties represent a significant gap which must be bridged to substantially increase vaccination rates and reduce HPV disease burden.

The integration of pharmacies into the Immunization Neighborhood is one approach that warrants further support and research. As seen in Fig. 1, we propose a complex but plausible immunization practice model to be implemented in southeast Michigan. The vaccination team has been formed and shares a parallel vision for methodology to improve series initiation and completion. Local community organizations with track records of support for public health and immunizations have joined the Neighborhood. Peer groups will be identified and compensated for their work in support of vaccination for those who experience barriers. Program support will be necessary and grant funding is being pursued for the initiation of a pilot designed to be scaled for implementation in larger populations. We advocate for the implementation of programs similar to ours, with interventions designed to effectively engage the community and tackle both patient- and provider-based barriers.

In conclusion, with an abundance of heterogeneous HPV immunization programs all with mixed success and challenges, it can be extraordinarily difficult to determine an approach that will be most impactful and sustainable. The development and support of novel, multi-disciplinary, team-based, and community-focused strategies for future research in HPV immunization programs is desperately needed, and we advocate for a pharmacy-driven approach designed to enhance interdisciplinary healthcare and community engagement, and also to guide future resource allocations and health policy. This approach has significant potential to maximize vaccine accessibility and recipient retention, and reduce overall HPV disease burden in both small communities and large populations alike.

Disclosure of potential conflicts of interest

The authors report no conflict of interest.