On surmounting the barriers to HPV vaccination: we can do better

Abstract

The major impediment to increased human papillomavirus (HPV) vaccination coverage in young males and females is lack of health care provider recommendation. Despite its efficacy in preventing cervical cancer, HPV vaccination in females (49.5%) and males (37.5%) ages 13 through 17 falls well below the Centers for Disease Control and Prevention’s (CDC) Healthy People 2020 target of 80% coverage. Parents’ willingness to vaccinate their child has been shown to be much higher when physicians share personal vaccination decisions for their own children as well as what other parents have done at that particular clinic. Furthermore, the vaccine must be presented presumptively as a “bundle” along with the rest of the standard adolescent vaccine panel. Multiple exemplars presented including in several European countries, low-income countries and Rwanda, demonstrate that school-based health care systems dramatically increase vaccination coverage. Finally, acceptability for vaccination of males must improve by increasing provider recommendation and by presenting the HPV vaccine as a penile, anal and oropharyngeal cancer prevention therapy in males and not merely a vaccine to prevent cervical cancers in females. Paediatricians, obstetrician/gynaecologists and primary care physicians should consider these data as a call-to-action.

Key messages

•   • Despite recent efforts in the US, only 49.5% of females and only 37.5% of males ages 13 through 17 have received all recommended HPV vaccine doses. These numbers fall well below the 80% target set forth by the Healthy People 2020 initiative.

•   • According to the CDC, if health care providers increase HPV vaccination rates in eligible recipients to 80%, it is estimated that an additional 53,000 cases of cervical cancer could be prevented during the lifetime of those younger than 12 years. Furthermore, for every year that the vaccination rate does not increase, an additional 4400 women will develop cervical cancer.

•   • First and foremost, healthcare providers (HCPs) must make a strong recommendation to vaccinate patients and these recommendations must become routine, including for males.

•   • It is clear that HPV vaccination rates improve significantly when vaccine administration occurs at designated, well-organized sites such as school-based vaccination programmes. Furthermore, HPV vaccination should be a high school requirement and offered in the standard adolescent vaccine panel as a bundle with Tdap and MenACWY vaccines in order to promote maximum adherence.

•   • Finally, research on immunogenicity and antibody titre longevity needs to be done in newborns. The HPV vaccine may be recommended in the newborn panel of vaccines to avoid any issues of sexualization and misplaced fears of sexual disinhibition, akin to the success of the Hepatitis B vaccine in the 1980s.

•   • The HPV vaccine is a vaccine against cancer and should be aggressively marketed as such. As healthcare providers, we need to make every effort to overcome barriers, real or perceived, to protecting our population from potential morbidity and mortality associated with this virus.

Keywords:

• Vaccine sexualization
• promiscuity
• vaccine acceptability
• sexual disinhibition
• risk compensation theory
• school-based health center (SBHC)

Introduction

Human papillomavirus (HPV) is the most common sexually transmitted infection (STI) and associated diseases have significant morbidity and mortality [1]. Most sexually active women and men will be infected at some point in their lives, with the peak occurring shortly after sexual debut. Divided into high and low-risk types depending on oncogenic potential, high-risk types of HPV cause virtually 100% of cervical cancers, 90% of anal, 70% of vaginal, 40% of vulvar, 50% of penile and 13–72% of oropharyngeal cancers [2,3]. HPV16 and HPV18 alone are responsible for ∼50% of high-grade cervical dysplasias and ∼70% of cases of cervical cancer. Worldwide, there are an estimated 530,000 new cases of cervical cancer annually representing 7.5% of all female cancer deaths [4,5]. Low-risk types (especially types 6 and 11) cause 90% of genital warts and recurrent respiratory papillomatosis (RRP, a rare but morbid disease in which tumours grow in the airways) [3,6].

Vaccines for HPV have been available since 2006. Previously, they included the bivalent (HPV 16/18) [7,8], and quadrivalent (HPV 16/18/6/11) [9,10] vaccines. Currently, only the nonavalent (HPV 16/18/6/11/31/33/45/52/58) [11] vaccine is available in the US. Greatest efficacy is contingent upon vaccination of young adolescent females and males prior to exposure via first sexual encounter.

In this article, we discuss current vaccination guidelines, barriers to vaccination, the roles of both patient and provider in achieving maximum adherence and present exemplars of excellent vaccination administration. Two of the most important barriers to optimal vaccination are lack of a strong recommendation from HCP and low male vaccination rates. Tackling these and other problems will undoubtedly increase vaccination broadly in the quest to eradicate HPV-associated diseases.

Vaccination guidelines

The Centres for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recommends that preteens (ages 11–12 years) receive HPV vaccine along with tetanus, diphtheria and acellular pertussis (Tdap) vaccine, and meningococcal conjugate (MenACWY) vaccine [12–14]. Recommendations by the American Academy of Paediatrics (AAP) and American College of Obstetrics and Gynaecology (ACOG) are similar to those of ACIP (see Table 1) [15,16]. The vaccination series can be started as young as 9 years of age but can be given to both genders through 26 years of age. For girls and boys, who receive their first dose of HPV vaccine before 15 years of age, only two doses are needed; if the first dose is given at 15 years of age or older, three doses are required [15,16]. Importantly, vaccination is recommended even if a patient is sexually active and may already be HPV DNA positive, since infection with all nine vaccine types is highly unlikely. Similarly, if a patient previously had an abnormal Pap test or history of genital warts, vaccination is still recommended [16].

Table 1. ACIP and AAP/ACOG guidelines for HPV vaccination series in selected cohorts.

	Cohort	Guidelines
Advisory Committee on Immunization Practices (ACIP)	Males and females 9–14 years old	2 doses of HPV vaccine [12–14]
	Males and females 15–26 years old	3 doses of HPV vaccine [12–14]
	Females and males 9 years old	HPV vaccination series may begin (2 doses) [15,16]
	Females and males 11–12 years of age	Routine administration of any available HPV vaccine is recommended [15,16]
American Academy of Paediatrics (AAP)/American College of Obstetrics and Gynaecology (ACOG)	Females and males <15 years of age	2 doses of HPV vaccine administered at 0 (baseline) and at 6–12 months If the interval between 1st and 2nd dose is <5 months, a 3rd dose is recommended [15,16]
	Females and males ≥15 years of age	3 doses of HPV vaccine administered at 0 (baseline), 1–2 months after first dose, and 6 months after first dose [15,16]
	Females and males ≥26 years of age	Absence of HPV vaccine recommendation at this age

To monitor vaccination coverage among teens aged 13–17 years, the CDC analyzed data from the National Immunization Survey of Teens (NIS-Teen). From 2015 to 2016, coverage increased for ≥1 Tdap vaccine dose (from 86.4 to 88.0%), ≥1 MenACWY vaccine dose (from 81.3 to 82.2%) and, among males, ≥1 HPV vaccine dose (from 49.8 to 56.0%). Among females, vaccination coverage estimates for each HPV vaccine series dose rose from 62.8 to 65.1% for ≥1 dose. In 2016, 43.4% of adolescents (49.5% of females and 37.5% of males) were up to date with the HPV vaccination series [17]. Disparities in coverage for adolescents indicate that substantial missed opportunities remain for vaccinating teens, especially against HPV [18].

Barriers to vaccination

Most health barriers are associated with a variety of social, psychological, economic, environmental and logistical challenges. Perceived barriers are an important construct of most major health behaviour theories [19–24]. Greater perceived barriers are associated with a reduced likelihood of behaviour change across a wide range of health behaviours [25]. Gerend et al. propose that perceived barriers are multidimensional and they make the distinction between practical and global barriers in the setting of perceived barriers to HPV vaccination among young women. They propose that people who have decided to enact a particular health behaviour are likely to focus on practical barriers (e.g. time constraints, cost and logistical barriers) while those who elect not to pursue certain behaviours demonstrate more abstract thinking and barriers related to whether or not the behaviour (e.g. vaccination) is relevant or safe [26].

Parents and caregivers

Receiving a physician’s recommendation or discussing the HPV vaccine with a physician is associated with vaccine acceptance and initiation in numerous studies; in fact, parents frequently cited not having a physician’s recommendation as the reason for not vaccinating their child [27–30]. Although most parents were aware of the vaccine, they cited lack of knowledge as a barrier to vaccinating their child [27,28,30–37]. One study found that only 56% of physicians and 50% of family physicians strongly recommended vaccination for girls 11–12 years of age [38]. Another study found 60% of individuals who declined vaccination reported lack of a provider recommendation [39]. In a study by Kester et al., strength of provider recommendation was significantly correlated with higher rates of vaccination completion. Individuals whose providers “strongly recommended” vaccination had higher rates of completion [29].

Physician attitudes play a major role in these parent-caregiver vaccine discussions. Qualitative studies have found that health care professionals think the decision to vaccinate is beyond their control and cite parental attitudes and concerns as a barrier [40–44]. Notably, paediatricians reported lower levels of job satisfaction as a result of needing to discuss childhood vaccinations – in particular, the time it takes and competing demands of primary care [44]. The two most effective communication practices in convincing skeptical parents to vaccinate their children were personal statements by physicians about what they would do for their own children and their personal experiences with vaccine safety among their patients [44]. Ultimately, care givers need to initiate vaccine discussions with parents early and often as lack of these discussions present a clear and present barrier to higher HPV vaccination rates in the US.

Acceptability of HPV vaccine for men

In 2011, ACIP recommended routine HPV vaccination for males aged 9–26 years old [14] and that the vaccine be covered by the Vaccines for Children (VFC) programme for males 18 years of age and younger. However, the recommendation was “permissive” rather than the stronger “routine” recommendation made for women [45]. Only 37.5% of males age 13–17 years have received all recommended HPV vaccine doses [17]. Although several other countries such as New Zealand and Australia have licensed the quadrivalent vaccine for boys, it is typically not covered by insurance plans [46].

Parents and healthcare providers typically view female vaccination as a higher priority than vaccinating males [47,48]. Although many parents report being willing to vaccinate their adolescent sons against HPV, they describe logistical barriers – most commonly, lack of recommendation from health care provider [49]. One study found that adding men to HPV vaccination programmes is less cost-effective than vaccinating women only [47]. However, under circumstances of low female HPV vaccination rates, as in the US, adding male vaccination becomes cost-effective [50,51]. A study by Reiter et al. suggested that cost played a large role in parental acceptability: among mothers, 47% were definitely or probably willing to vaccinate their sons with a free vaccine compared to only 11% for a $400/series vaccination [52]. Mothers who were knowledgeable about HPV vaccine had higher acceptability as did mothers who had vaccinated their daughters. Interestingly, acceptability was also associated with the belief that HPV vaccine may protect their son’s future female partners from HPV-related disease.

McRee et al. found that more respondents were willing to get vaccinated when the vaccine was presented as preventing genital warts and anal, oral or penile cancer than when framed as preventing genital warts alone [53]. Another study confirmed the reduction of the health and economic burden of HPV-related outcomes in men who have sex with men (MSM), who bear a particularly heavy burden of HPV-related disease [54]. The most cost-effective scenario would be to vaccinate at age 12 before exposure to HPV, but vaccination up to age 26 was still cost-effective [54].

On desexualization of HPV vaccine

HPV vaccination programmes are aimed at preventing cancer (mainly cervical cancer) by reducing the spread of a highly contagious STI and are thus targeted at adolescents prior to their sexual debut [55]. Herd immunity is achieved much faster by vaccinating both sexes and as both men and women can transmit HPV, a sex-neutral approach equalizes the burden of vaccination across the sexes. Unfortunately, HPV vaccination has remained highly sexualized [56]. Profiling of young male vaccination mainly as a means for protecting girls against cancer appears to be a poor incentive for parents to vaccinate their sons [57].

In a recent report, Velan and Yadgar propose that desexualization of vaccines against STDs, in general, can be achieved by limiting information regarding sexual transmission and distancing the age of vaccination from the age of sexual debut [56]. Withholding all information related to the sexual nature of HPV infection is inappropriate but distancing the age of vaccination from the age of sexual debut represents an attractive approach to higher rates of vaccination. For example inclusion of Hepatitis B vaccine in the newborn vaccination series in the late 80s facilitated its portrayal as a “routine” vaccine rather than a vaccine to prevent an STI [58]. However, the same cannot be true for the HPV vaccine – there is no recommendation to vaccinate infants or young children against HPV. Studies have documented neutralizing antibody at 12 years after vaccination, but data beyond that point is lacking [59–61]. Furthermore, vaccine immunogenicity and duration of protection in younger children and newborns is unknown. Since achieving maximum efficacy is contingent upon beginning vaccination prior to sexual activity, policy-makers targeted HPV vaccination to boys and girls between the ages of 9–13 years [62]. Vaccinating at 9 years of age promotes desexualization of the vaccine and is preferable to vaccination of pre-pubertal 13-year olds, which affirms sexual context of the vaccination programme as a coming-of-age process.

Concerns about promiscuity

One concern about the HPV vaccine is the fear that adolescents will respond to vaccination with sexual risk compensation (also referred to as sexual disinhibition), initiating sexual activity at a younger age and/or reducing self-protective sexual behaviours [63]. Parental concern about disinhibition has been found to be associated with lower HPV vaccine acceptability [64]. However, several studies strongly suggest that risk compensation is not a post-vaccination problem [48,65–71]. In a study of 14–17-year-old girls, 75 of whom were recruited after HPV vaccine licensure compared to 150 who were recruited prior to licensure, no difference was found in the rates of gonorrhoea, chlamydia and trichomonas infections [68]. In fact, the pre-licensure group had more instances of unprotected sex than the post-licensure group, the opposite of what would be predicted by risk compensation theory. Another large study with a cohort of 260,493 Canadian girls found no evidence that HPV vaccination increased the risk of teen pregnancy or STD infections [72]. These and other studies should assuage parents’ fears regarding promiscuity post-vaccination.

Vaccine financing

There are multiple sources of private and public funding that assure that nearly all children and young adults in the US are covered for the cost of the HPV vaccine, as per ACIP recommendations. The Affordable Care Act requires private insurance plans to cover recommended preventive services without beneficiary cost-sharing [73]. Plans must cover the HPV vaccine for the recommended age groups of males and females, Pap tests and HPV testing for women. Individuals who obtain insurance through the ACA marketplace are also covered by the HPV vaccine, Pap tests, and HPV DNA testing without cost-sharing. Public financing options are also available. The VFC programme pays for vaccinations for all children through age 18 who are either Medicaid-eligible, uninsured, American Indian or Alaska Native, or underinsured. The ACIP recommended VFC coverage for Gardasil 9 in February 2015 for males and females ages 9 through 18 [74]. Children’s Health Insurance Program (CHIP) is separate from Medicaid programmes and must cover ACIP-recommended vaccines for beneficiaries since they are not eligible for coverage under the federal VFC [75].

With regard to cost of the HPV vaccine, findings were mixed with some studies identifying cost as a barrier while others indicating it was not a barrier [29,31,36,76]. These considerations were especially important in parents deciding whether or not to vaccinate young boys, as mentioned previously. Thus, despite the resources available to overcome financial challenges, the barriers related to vaccine cost should not be ignored. It has been suggested that healthcare professionals increase their participation in the VFC programme as a potential strategy for reducing these barriers [77].

Lack of awareness

Improved parental awareness of HPV vaccines has the potential to increase vaccine uptake earlier in life, thereby reducing adolescents’ later risk for HPV infection and cervical cancer. One study conducted by Wisk et al. examined the data from 5735 parents of preadolescents and adolescents aged 8–17 years from the 2010 National Health Interview Survey. Parents were asked if they had ever heard of HPV vaccines or shots and while most US parents (62.6%) heard of HPV vaccines, these parents were most likely to have had a child who was female, was privately insured, had a usual source of care and had a well-child checkup in the last 12 months [78]. Not surprisingly, female parents and parents of female children had statistically significantly higher odds of having heard of HPV vaccines than did male parents and parents of male children (2.40x and 1.86x, respectively). Because HPV-associated cancers are more common overall in females than males, due primarily to cancer site (i.e. cervix, vulva and vagina), providers, patients and parents may be more aware of HPV vaccination because of perceived greater benefits for females than males [79–81]. However, the incidence rate of HPV-associated cancers in sex-neutral sites (i.e. anus and oropharynx) is more than twice as high for males than females, underscoring the critical importance of vaccine awareness and administration in boys [78].

Several studies have indicated that racial and ethnic minorities are less likely to have heard of HPV vaccines, as are women born outside the US [82–84]. Importantly, racial and ethnic minorities are more likely to experience HPV-related disease burden [85]. It has been suggested that low acculturation or English-language proficiency may contribute substantially to these disparities. Language, in particular, may moderate how individuals obtain HPV vaccine information, and thus providing culturally sensitive information and information in multiple languages may improve vaccine awareness in vulnerable populations [78].

Finally, differences in parental awareness varied by parental education and family income, two important components of socioeconomic statuses (SES) that may be contributing to vaccine uptake disparities [78]. Efforts to increase parental awareness should thus target low-SES groups. A one-time, education-based intervention led by a community health educator at a public school is one strategy that has been proven effective for increasing HPV vaccine knowledge among parents of school-age children [86]. This strategy offers the benefit of wide-spread dissemination of information while participation is not insurance-dependent nor requires a fee.

Vaccine safety, anti-vaccination movement and religion

Analysis of the National Immunization Survey of Teens, 2008–2010 by Darden et al. demonstrated the alarming rise in safety/side effect concerns of the HPV vaccine in parents from 4.5% in 2008 to 7.7% in 2009 to 16.4% in 2010, approaching the most common reason for vaccine refusal, which was “Not Needed or Not Necessary” at 17.4% [87]. This increase in safety concerns, which coincided with a decreased incidence of “Not Recommended” as a reason not to get the vaccine may imply decreased parental reliance on clinician recommendations. The decrease in “Not Recommended” as a reason for not vaccinating was not seen with concomitant childhood vaccines such as Tdap/Td and MCV4, for which this reason was consistently two to three times as common for the HPV vaccine. Moreover, those parents that had private insurance and a family income greater than or equal to 200% of the federal poverty limit were more likely to worry about vaccine safety than their counterparts [88]. While long-term efficacy studies have yet to be done as of 2017 (the vaccine has only been available for about 10 years), this issue has been the target of several studies [17,59–61,89–94]. There have been 22,000 Vaccine Adverse Event Reporting System (VAERS) reports following vaccination. Ninety-two percent were reports of events considered to be non-serious (e.g. fainting, pain and swelling at the injection site (arm), headache, nausea and fever), and about 8% were considered to be serious (headache, nausea, vomiting and fever being the most frequently reported symptoms) [94]. Using the nationwide healthcare database in France, Miranda et al. conducted a cohort study of over 2 million young girls finding no significant increase in autoimmune diseases consequent to HPV vaccine administration [92]. In a recent study of the bivalent HPV vaccine, both HPV 16 and HPV 18 antibodies remained elevated several-fold above natural infection levels up to 9.4 years after vaccination [90], while other studies show immunogenicity and clinical efficacy of the quadrivalent vaccine after 10 and 12 years [60,61]. Finally, the nonavalent HPV vaccine efficacy was sustained for up to 6 years with similar immunogenicity profile to the quadrivalent vaccine and potential to prevent infection, cytological abnormalities, high-grade lesions and cervical procedures related to HPV 31, 33, 45, 52 and 58 [93]. Appropriate dissemination of this evidence-based information is critical for achieving patient autonomy and thus, informed decision-making. The role of the provider cannot be emphasized enough in these circumstances.

Anti-vaccine sentiments have negatively impacted HPV vaccination rates [95,96]. Despite strong evidence of the vaccine’s safety and efficacy [60,61], HPV vaccine coverage among American adolescents is low compared to other recommended adolescent vaccines. Fowler et al. found that real-world politicization is indeed associated with decreases in support for HPV vaccine requirements, state immunization programmes and confidence in doctors and in government. Moreover, they found that among those less likely to have encountered real-world politicization, there is marginal evidence that exposure to political conflict decreases support for state immunization programmes and clear evidence that politicization reduces confidence in doctors [96]. Because HPV is not an airborne virus, some believe that one parent’s choice to refuse the vaccine will have little, if any, impact on public health. However, herd immunity is still critical to combat HPV. HPV is indeed a communicable disease in that it can be spread through skin-to-skin contact during vaginal, anal, and oral sex; it can also be spread from mother to child during the birth process [14]. Lowering the age of consent has been proposed as a solution to recalcitrant parents in light of a willing child. HPV vaccination or similar vaccination in general may join the ranks of issues, such as pregnancy, abortion, alcohol and drug treatment, as well as infectious/communicable diseases such as STIs, for which a minor is allowed to give consent in several states [95]. Above all, it is the provider’s responsibility to dispel misinformation and to promote vaccine adherence through provision of evidence-based materials.

Research has shown that specific religious beliefs or teachings may influence vaccine decisions [97–101]. For example parents who file vaccine exemptions on the basis of religious or personal beliefs are able to delay or refuse childhood immunizations that are mandated for school entry. Currently, 48 out of 50 states allow some form of religious exemption for mandatory vaccinations [99]. Compared with parents who reported no religious affiliation, Catholic parents were more than three times likely to have vaccinated their daughters (vs. being undecided) [97]. Parents from Protestant and other Christian religions reported more negative beliefs about HPV vaccinations. Specifically, Protestant parents were more likely than other parents to express opposition to HPV vaccination, and other Christian parents were more likely to prefer that HPV vaccination occurs at older ages (19 + years) [97]. Studies have reported lower HPV vaccine acceptance and more negative attitudes among parents who strongly identify with religious views that prohibit sex before marriage or adhere to beliefs of monogamy and abstinence [97,102–104]. Taken together, these data demonstrate a clear need for sensitivity on behalf of the provider when it comes to religious considerations. While religious beliefs may not always be in favour of modern medicine, it is important to take an approach that is understanding rather than dismissive.

Underserved, minority and geographic considerations

Patients who are medically underserved generally have lower household incomes, lack health insurance, are of minority status and have lower HPV vaccine coverage rates. Differences in HPV vaccine acceptance, initiation and series completion have been noted across racial/ethnic groups [27,28,50,88,105]. Data from NIS-Teen indicates that Black and Hispanic adolescents are less likely to complete the HPV vaccine series compared with Whites [27,51,105]. Several other studies found that adolescents who racially identified as Black were less likely than those who identified as White to complete the vaccine series, even when they had higher rates of series initiation [27,106–110].

In the US, incidence rates for HPV-associated cancers were highest among women living in neighbourhoods where at least 20% of the population lives below the poverty line compared with neighbourhoods in which <5% of the population is below the poverty line [111]. In addition to provider and individual-level factors, geographic or neighbourhood factors like area-based socioeconomic status (SES) may independently influence vaccination uptake [112]. Geographic factors, such as area-based SES, racial-ethnic composition and rural versus urban residence have been shown to influence health status and health behaviours independent of an individual’s SES or other individual factors such as health insurance [113–117]. Similarly, area-based SES and geographic factors can influence vaccination uptake via material resources of the neighbourhood, availability and ease of health care access and social capital or networks [118–120].

Overall, the odds of vaccine initiation in light of individual and community-level geographic factors among teen girls were highest among older girls, girls with CHIP or Medicaid health insurance, girls with younger mothers, and those whose mothers had lower levels of education and incomes below the federal poverty level [112]. Yet again, receipt of a provider recommendation was one of the factors most strongly associated with HPV vaccination initiation.

Exemplars of successful vaccination protocol

Despite the benefits of HPV vaccines, only 49.5% of girls and only 37.5% of males age 13–17 years have completed the vaccination series [17]. Compared with many other countries, HPV vaccination rates in the US are unacceptably low and national and state vaccination coverage fall well below the 80% target set forth by the Healthy People 2020 initiative [121]. The following exemplars of successful vaccination programmes illustrate effective methods at achieving optimal vaccination.

Australia and Europe

Australia was one of the first countries to implement a fully government-funded HPV vaccination programme. It began in 2007 as school-based programme with a three-dose course of the quadrivalent vaccine, targeting females in the first year of high school (age 12–13 years), with a catch-up for those ages 12–26 years until December 2009 [122]. In 2013, the Australian government extended the programme to include 12–13-year-old males, including a 2-year catch-up vaccination programme for those ages 14–15 years. The highest rates of vaccination were achieved in these school-based cohorts with about 70% of all young girls and boys receiving all three doses [2,123,124]. The greatest decline in vaccine-type HPV prevalence was found in the 18–24-year-old age group, which had the highest vaccine coverage [59,125,126]. However, even the unvaccinated eligible female population and males benefitted as a result of herd immunity [125,127].

Scotland has a national school-based programme targeting 12–13-year-old girls with a 3-year catch-up from 2008 to 2011 for 13–17-year olds. Coverage for the bivalent vaccine is up to 90% and reported declines in vaccine-related infections went from 29.8 to 13.6% [128]. The United Kingdom also has a national childhood immunization programme wherein vaccines are administered in schools. Over the 6 years that the three-dose HPV vaccine series was recommended, vaccine coverage for at least one dose has been 91.1% and all three doses ∼86.7%. This has resulted in a reduction in vaccine-type HPV prevalence from 19.1 to 6.5% in 16–18-year olds, for whom the vaccine is recommended [129]. Finally, Denmark’s national screening programme for girls aged 12–17 years old offers free vaccination. Coverage is ∼82% for all three doses of HPV vaccine and 90% for at least one dose [130]. The trend is clear: a national, government-supported screening and vaccination effort, particularly school-based programmes, is highly effective in promoting increased rates of vaccine coverage.

Denver health paradigm

Denver Health is an integrated urban safety net health system serving >17,000 adolescents, more than one-half of the uninsured and Medicaid population, 43% of the Hispanic community, and 33% of the African American community in Denver, Colorado. Adolescent vaccines are administered at eight federally qualified health centres, 16 school-based health centres (SBHCs), and the Denver Public Health immunization clinic, utilizing a vaccine registry, standing orders for vaccination, presenting vaccines in a standard “bundle” of the three adolescent vaccinations (Tdap, MenACWY and HPV) and SBHCs which also offer periodic vaccination drives [131]. The process begins with the use of the Denver Health internally-developed immunization registry, VaxTrax, which has a recommendation feature, vaccine inventory, and historical information storage functionality.

In 2013, HPV vaccine coverage for at least one dose in females was 89.8% and in males, 89.3% compared with national rates of 57.3 and 34.6%, respectively. Rates improved further in 2014 where coverage (at least 1 dose) was 90.4% for girls and 89.7% for boys vs. national HPV coverage of ≥1 dose of 60.0% for girls and 41.7% for boys. HPV coverage of ≥3 doses in 2014 was 66.8% for girls and 59.9% for boys in the Denver Health system compared to national rates of 41.9% for girls and 28.1% for boys [131]. Important to note is that Denver Health is an urban safety-net hospital and as such, most of the barriers to HPV vaccination in the patient population are not due to refusal but more traditional reasons that low-income families do not get vaccinated, such as transportation issues, access to care, and inability to take time off from work to take children to medical appointments. Insurance coverage is also less of a barrier because in this population, the majority of patients are covered by public insurance and thus have vaccine coverage by the federally funded VFC programme [131]. The Denver Health paradigm is a powerful prognosticator of what vaccination coverage might look like if similar practices are adopted nationwide.

The Carolina framework for cervical cancer

Cervical cancer mortality in the US has dropped from 7.9 per 100,000 women in 1950 to 2.4 per 100,000 in 2008, likely due to the introduction of and widespread use of Pap screening [132]. Similarly, within 6 years of vaccine introduction from the pre-vaccine era (2003–2006) to the post-vaccine era (2009–2012) there was a 64% decrease in 4vHPV type prevalence among females aged 14–19 years and a 34% decrease among those aged 20–24 years [133]. However, over 4000 women still die of this preventable cancer each year [134]. Disparities in cervical cancer mortality include higher rates among African American, Hispanic, low-income women and rural-dwelling women, especially in Appalachia and on the US-Mexico border [132,134–141]. Additionally, states within the US demonstrate wide variation in cervical cancer mortality, ranging from 1.2 per 100,000 women in Utah to 3.8 per 100,000 women in Mississippi [132]. To address these issues, Cervical Cancer-Free North Carolina, a state-wide initiative to reduce the cancer burden, developed the Carolina Framework for Cervical Cancer Prevention. The Carolina Framework guides prevention by identifying and addressing four main causes of cervical cancer: HPV infection, lack of cervical cancer screening, screening errors and not receiving follow-up care.

Moss et al. used the Carolina Framework to identify counties in North Carolina with higher cervical cancer prevention need and showed striking geographic disparities, with two high-need clusters of counties in the north eastern and south-central regions of the state [132]. Causes of higher need are likely complex; however, identified counties were remarkable for being in regions that have lower population density, higher poverty and higher percentages of African American residents. This pattern suggests that access to care, as well as broader social determinants of health, play a role in cervical cancer prevention in North Carolina. To this end, the authors made several recommendations to improve cervical cancer prevention, such as: reduce missed opportunities for HPV vaccination among eligible adolescents; increase provision of adolescent vaccines in alternative settings, including pharmacies and schools; increase funding to establish universal coverage of all CDC-recommended vaccines, including HPV vaccine, to children up to age 18; improve recruitment of women rarely- or never-screened for cervical cancer; and reduce missed opportunities for cervical cancer screening.

Lessons from Rwanda

Cervical cancer is the most common cancer among women in Rwanda, an East African country with around 11 million citizens [142]. In 2010, Rwanda partnered with Merck to begin an HPV vaccination rollout. In so doing, Rwanda became the world’s first low-income country to provide universal access to the HPV vaccine. Before 2011, neither cervical cancer screening nor HPV vaccination was available in public health facilities – only a few private clinics and nongovernmental organizations offered screening services. Rwanda’s National Strategic Plan for the Prevention, Control, and Management of Cervical Lesions and Cancer includes screening and vaccination programmes for women between 35 and 45 years of age and a memorandum of understanding with Merck that guaranteed Rwanda three years of vaccinations at no cost and concessional prices for future doses. In April 2011, 93,888 Rwandan girls in primary grade six received their first shot of Gardasil (quadrivalent vaccine). The programme’s first round achieved 95.04% coverage, the second 93.90% and the third 93.23% [142].

Introduction of the HPV vaccine might have increased the public’s awareness of, and demand for, cervical cancer screening services. However, due to the limited scale of the existing pilot screening sites, it was unclear whether this translated into increased service utilization [143]. The Ministry of Health has plans in place to roll out more extensive screening services over the coming years [144]. The availability of routine vaccination services did not appear to have changed in most facilities (24/27), 5 years later [143]. The cost of delivering the HPV vaccine has been estimated at $5.77 per girl fully immunized by a recent study in Tanzania, which is above external support from the Vaccine Alliance (Gavi) of $2.40 per girl fully immunized [145]. The economic cost in Tanzania was estimated at $12.40, a much higher level reflecting staff and material costs. Although costs are lower in Rwanda, the HPV vaccine remains a significant investment for a lower income African country [143].

A successful nationwide HPV vaccination programme requires a well-established vaccine delivery system with adequate cold chain transportation, human resources and monitoring capacity. Collaboration between public and private institutions within the framework of strong national ownership is critical for long-term sustainability. Three early decisions were crucial to Rwanda’s HPV vaccine rollout success. First, the Ministry of Health widened its technical group on vaccinations to include the Ministry of Education, the Ministry of Gender and Family Promotion and the Center for Treatment and Research on AIDS, Tuberculosis, Malaria and other Epidemics. Multidisciplinary subcommittees were tasked with identifying cold chain requirements, numbers of girls in and out of school, nurse and community health worker training capacity, procurement and distribution logistics, a budget for implementation, etc. A nationwide desensitization campaign was planned in advance of vaccination in order to assuage fears and skepticism. The second key to success was to adopt a school-based strategy to deliver the three-dose series, since 98% of Rwandan girls attend primary school. Third, a multi-phased vaccination strategy spanning three years beginning in primary grade six was undertaken. During the programme’s second and third years, a “catch-up” phase targeting girls in the third year of secondary school ensured complete coverage of all adolescent girls. Programmes like these offer a paradigm solution to vaccination in developing countries, but also offer valuable insight for improvement of western programmes.

Lowest income countries

In 2008, there were 275,000 deaths from cervical cancer worldwide with 88% occurring in developing countries [146]. In an effort to address these concerning numbers, Axios Healthcare Development managed the Gardasil Access Program (GAP), wherein Merck pledged to donate at least 3 million doses of Gardasil for administration in seven low-income countries. The intent of GAP was to capture the experiences and lessons learned by participating programmes and institutions and leverage this knowledge to improve HPV vaccine access and child/adolescent immunization models. A total of eight programmes were implemented in seven countries including: Bhutan, Bolivia, Cambodia, Cameroon, Haiti, Lesotho and Nepal. Using three different vaccination delivery models, programme coverage and adherence between doses 1 and 3 were recorded. The health facility model (hospitals and mobile clinics) had a lower rate of coverage (77.1%) than programmes using a mixed model (93.8%) or a school model (93.0%). Programme adherence was highest in the mixed model (96.6%), intermediate for the school model (88.6%) and the health facility model was least effective (79.7%) [146]. Once again, school-based vaccination delivery methods were most effective at reaching girls within the WHO-recommended age range. This system may draw its success from ease of follow-up, whereas other models lack a robust follow-up system to ensure that participants visit the clinic for each of the three scheduled doses. Interestingly, there was a trend toward increased rates of programme coverage and programme adherence with an increased number of vaccine administration sites. An analysis of HPV vaccine acceptability in Botswana found 74% of study participants would have their daughters vaccinated against HPV at school if the vaccine was available [147]. An important key to the success of the GAP campaign was sensitization and training of school teachers to assist in recruitment and follow-up of girls for the study. In fact, such training was deemed an essential component of the success of a school-based HPV vaccine programme in Peru [148]. Additionally, effective use of schools as venues for HPV vaccine programmes is an important factor in successful adoption of HPV vaccine in low-resource settings [149].

Discussion

HPV vaccine coverage among US adolescents has steadily increased since vaccine licensure but remains well below the 80% target set forth by the Healthy People 2020 initiative [121]. A number of barriers have hindered increased coverage including: lack of a strong recommendation to vaccinate from HCPs, low acceptability of vaccination of males, presumptive versus participatory recommendation, sexualization of HPV vaccine and non-uniform timeline for vaccination administration (see Table 2).

Table 2. Barriers to HPV vaccination coverage and proposed solutions.

Barrier to HPV vaccination coverage	Proposed solutions
Lack of a strong recommendation from health care provider	1.Offer HPV vaccination administration at multiple venues such as at health clinics or school-based systems with strong provider recommendations at each site [2,122]. 2.Health insurance companies should adopt the practice of using high rates of HPV vaccination as a metric for successful provision of health care to incentivize physicians to recommend the HPV vaccine. 3.Health care provider might share with parents what he/she would do if it was his/her child up for vaccination. He/she may also tell the parents about what other parents in the clinic have done with their children in a similar situation. Persistence on vaccination recommendation to parents is also warranted [44].
Low acceptability for vaccination of males	1.A strong recommendation for vaccination in males must be made by the patient’s health care provider [48–52]. 2.Change ACIP guidelines for male vaccination from “permissive” to “routine” [45]. 3.Advertise HPV vaccination in males as a primary preventive therapy against penile, anal, and oropharyngeal cancers and not merely as a prevention strategy for cervical cancers in women [54,58].
Vaccine sexualization	1.Label or characterize the HPV vaccine as a cancer prevention therapy rather than as an STD vaccine [59]. 2.Present vaccine presumptively and as routine rather than engaging in a collaborative discussion [150–152]. 3.Administer HPV vaccine along with Tdap and MenACWY adolescent vaccines a routine “bundle” [131]. 4.Begin research on vaccine immunogenicity in newborns [60]. 5.Establish a routine timeline for vaccine administration, e.g. strongly recommend vaccine at first gynaecological visit.

Lack of a strong provider recommendation is the primary reason for parents’ failure to vaccinate their children. Similarly, lack of a strong recommendation for males in the target age group contributes to very low vaccination rates in males and females. A shift of thinking in the field must be made toward HPV as a cancer therapy both in males and in females and to distance the image of HPV vaccine as an STD therapy.

Lack of a strong recommendation from HCP

Throughout this article, we have demonstrated multiple situations in which lack of a strong recommendation to vaccinate by HCP is cited as a major barrier in the decision to vaccinate. HCPs may not recommend vaccination at the appropriate times due to issues, such as time constraints, lack of perceived necessity at the patient’s age, availability of insurance coverage, safety and/or efficacy concerns and discomfort with discussion of sexuality and information needs [63,153]. Vaccine risk communication, in general, is a challenge for HCPs [154]. Some providers feel that discussion of vaccine risks and benefits (including issues of sex with HPV transmission in particular) might alarm rather than reassure patients and take up too much time. Many HCPs report feeling uncomfortable engaging in discussions regarding sexuality with their adolescent patients [155,156].

Provider endorsement is a key determinant of HPV vaccine acceptance by parents and potential vaccine recipients. Providers need to know how and why the vaccine is important and to understand the vaccine’s limitations. Thus, preliminary provisions for provider education should include a mandatory training for all employees that come with each new lot of vaccine, perhaps providing the most up-to-date research and newsworthy coverage of the vaccine to be shared with patients, if inquired. Similarly, Continuing Education credit can be offered for completion of immunization courses as is done currently by the CDC. However, these can be made mandatory and on an institutional basis (rather than on a federal website) in light of the constantly evolving data on the HPV vaccine. Another approach might be to have insurance companies declare practice guidelines with high rates of HPV vaccination as a metric for successful provision of health care. This may incentivize providers to overcome their fears of alarming their patients and to increase their comfort with discussing such matters. Additionally, ACOG/ACIP/AAP guidelines should coincide with regard to first mention of the vaccine, setting a hard date rather than keeping a broad window. For example on the ninth birthday or first visit thereafter, all providers should be urged to initiate conversations with parents about HPV vaccination.

To overcome some of the problems caused by reliance on HCP recommendation, different venues for vaccination, such as schools or pharmacies may be utilized as we have learned from the exemplars presented above in Australia, UK, Denmark and Scotland [2,122]. Currently, the HPV vaccine is not a national requirement for entry into the secondary school system. Only Virginia and Washington, DC require HPV vaccination of girls entering the sixth grade [157] and Rhode Island requires both boys and girls to be vaccinated by the seventh grade. Thus, the school system represents an excellent opportunity for vaccination introduction and education. As HPV is a highly communicable disease and a growing public health concern, it is imperative to use the school system as a venue for raising awareness. Currently, the US and New Zealand are the only two countries that are allowed to participate in direct-to-consumer advertisement. While HPV vaccine commercials have been met with some success, school requirements will undoubtedly increase vaccine prevalence. Finally, and quite important, is to frame the HPV vaccine as routine and/or as a cancer prevention vaccine instead of a vaccine for a sexually transmitted disease. This point is of critical importance and again serves to circumvent HCP reluctance to discuss sexuality with patients. Simultaneously, parents are more likely to oblige vaccination when it is framed in such fashion. These and other strategies are necessary to integrate a strong recommendation from provider amidst a backdrop of supportive knowledge and positive influence.

Low acceptability for vaccination of males

The NIS-Teen data indicate that completion of the HPV vaccine series is much lower among male adolescents than female adolescents [17,87]. HCPs are more likely to recommend the vaccine to females than males [28,42]. One qualitative study found that some health care professionals did not think vaccinating males was worth the cost or effort, were unaware of serious HPV-related disease in males or thought that parents would not be interested in vaccinating their sons [42]. Results from other studies indicated that parents were unclear about the need to vaccinate males [37,76] perceived the consequences of HPV infection as less severe for males [36], or were unaware that the vaccine could be given to males [36,52,158]. HPV infection causes cancer at several anatomical sites, including the cervix, vagina and vulva in women but also the oropharynx and anus in both sexes as well as the penis in men. Between 2008 and 2012, 38,793 cases of HPV-related cancer were reported in the US, 23,000 (59%) in women and 15,793 (41%) in men [159]. The most common cancer among these cases was oropharyngeal squamous cell carcinoma (OPSCC), of which there were 3100 cases in women and 12,638 in men [159]. The incidence of HPV-related OPSCC among women plateaued from 2002 to 2012, rising only 0.57% annually, which failed to reach statistical significance. In contrast, the incidence among men (7.8 per 100,000) increased dramatically (∼2.89% per year) and has already surpassed the incidence of cervical cancer in women (7.4 per 100,000) [160]. Mounting evidence suggests that prophylactic HPV vaccination protects against infection of oral HPV types associated with OPSCC (particularly type 16) and thus serves to reduce the OPSCC incidence and overall viral burden in the long term [17,81,161,162]. However, the low uptake of the vaccine among males remains a barrier to achieving this necessary advancement in public health. Thinking in the field needs to change as males represent 50% of the viral burden in the form of carriers, but more importantly, they are themselves susceptible to manifestations of HPV infections including genital warts, anal, oral and penile cancer.

Presumptive versus participatory recommendation

How providers initiate their vaccine recommendations to parents of patients is an important determinant of the dynamics of parental acceptance versus resistance. In one study, use of participatory formats (those involving discussions with parents) making vaccine recommendations was associated with increased odds of parental resistance [150]. This highlights that instead of presenting the vaccine as an option, it must be considered presumptively and routine. This can be achieved by bundling the HPV vaccine with other vaccines of adolescence such as Tdap and meningococcal conjugate.

Collaborative communication and shared decision-making in the context of childhood vaccines need to be carefully considered. Although a participatory approach may be aligned with expectations parents have of providers in vaccine discussions [151,152], use of this approach may need to be reconsidered if it leads to fewer children being fully vaccinated. Shared decision-making is typically not indicated when there is only one medically acceptable choice [163]. This is precisely the case with HPV vaccination. Finally, of note, if providers continue to pursue their original recommendation after encountering parental resistance many parents eventually agree to vaccination [150]. Thus, initiation of HPV vaccine discussion needs to be presumptive and aimed at routine administration as a vaccine against cancer rather than an optional, supplemental and necessitating a discussion.

Vaccine sexualization

The most common mode of transmission of HPV is through sexual contact. As such, vaccination against this cancer-causing agent has become tethered to sexual behaviour and concerns about promiscuity. One solution might be to recommend the vaccine be administered earlier in childhood. However, the immunity developed by HPV vaccination needs to be robust for several decades to ensure that infection does not occur when young people become sexually active and beyond. Vaccine-elicited antibody responses appear to be long-lasting, with relatively low titres adequate for protection [164]. Studies have shown antibody persistence up to 12 years after vaccination and studies remain ongoing in Nordic countries [59–61]. Importantly, immune response in younger adolescents is at least as strong as in older adolescents and young adults [165]. If needed, a booster dose of vaccine may be administered years after the initial series to sustain efficacy [166]. Desexualization of the HPV vaccine thus may be advantageous from the public health standpoint, especially in cases where parents believe that HPV vaccination leads to promiscuity, that protection against STD is not relevant to their children and for those who are not comfortable discussing the sexuality of their children.

Non-uniform timeline for vaccine administration

Since HPV vaccine initiation is recommended for girls and boys between ages 9 and 13 years, it is often the child’s paediatrician who recommends vaccination. As noted earlier, many HCPs report, feeling uncomfortable engaging in discussions regarding sexuality with their adolescent patients [155,156]. As such, they may not initiate vaccine discussions with their patient or patient’s parents and thus, this represents a missed opportunity for vaccination. One suggestion might be to make it standard practice to recommend HPV vaccination at the adolescent’s first gynaecological visit which typically occurs around age 15. Although not optimal, it does provide a uniform way to reach those who were not vaccinated at the recommended age. Health care providers should take every opportunity to address adolescents’ vaccination needs during health care visits, including those for acute care and sports physicals, as adolescents are less likely to attend preventive health care visits than younger children [167,168].

The need for three doses of the HPV vaccine creates additional challenges [169], which is why giving the vaccine at the recommended age(s) 11–12 improves compliance since it involves completion of only a two-dose series of the nonavalent vaccine. Adolescents generally encounter the health care system less frequently than any other age group and often seek only acute care or physical examinations for athletics [170,171]. Using reminder and recall systems may facilitate vaccine series completion [172]. Innovative, communications-based interventions, including e-mail, text message reminders and electronic medical records, may also increase series completion. However, these programmes should take into account the specific populations that they serve and consider that certain methods may not be effective for reaching the underserved population [167,173]. Whether the HCP is a paediatrician, obstetrician/gynaecologist, or family medicine doctor, it is important that each specialty has not only a standard set of guidelines, but also a standard timeline for vaccine recommendation.

Conclusions and implications

Despite recent efforts in the US, only 49.5% of females and only 37.5% of males ages 13 through 17 have received all recommended HPV vaccine doses [17]. These numbers fall well below the 80% target set forth by the Healthy People 2020 initiative. According to the CDC, if health care providers increase HPV vaccination rates in eligible recipients to 80%, it is estimated that an additional 53,000 cases of cervical cancer could be prevented during the lifetime of those younger than 12 years [18]. Furthermore, for every year that the vaccination rate does not increase, an additional 4400 women will develop cervical cancer.

In this article, we presented various exemplars of successful HPV vaccination programmes, from which valuable conclusions can be drawn. First and foremost, HCPs must make a strong recommendation to vaccinate patients and these recommendations must become routine, including for males. It is clear that HPV vaccination rates improve significantly when vaccine administration occurs at designated, well-organized sites such as school-based vaccination programmes. Furthermore, HPV vaccination should be a high school requirement and offered in the standard adolescent vaccine panel as a bundle with Tdap and MenACWY vaccines in order to promote maximum adherence. Finally, research on immunogenicity and antibody titre longevity needs to be done in newborns. The HPV vaccine may be recommended in the newborn panel of vaccines to avoid any issues of sexualization and misplaced fears of sexual disinhibition, akin to the success of the Hepatitis B vaccine in the 1980s. The HPV vaccine is a vaccine against cancer and should be aggressively marketed as such. As healthcare providers, we need to make every effort to overcome barriers, real or perceived, to protecting our population from potential morbidity and mortality associated with this virus.

Disclosure statement

The authors report no declarations of interest.