An Update on Human Papillomavirus Vaccination in the United States

Abstract

Cervical cancer remains a significant disease in the United States. While the human papillomavirus vaccine has been approved for those aged 9-26 and for some individuals up to age 45, there are many circumstances where health care professionals may not know if the vaccine should be recommended, such as patients previously infected, health care workers, and those older than age 26. This article highlights the evidence that the human papillomavirus vaccine is a safe and a highly effective way to prevent cervical cancer, with the strongest predictor of vaccine uptake being practitioner recommendation.

Precis:

An update on human papillomavirus vaccination with discussion on routine vaccination, previously infected patients, those older than 26 years old, number of doses, and health care workers.

Background: The HPV Vaccine

Human papillomavirus (HPV) remains the most common sexually transmitted infection in the United States (U.S.) in adults, with 45% of women and 40% of men tested being positive [1, 2]. Unfortunately, there has been sharp increase in the rate of HPV diagnosis in men over the last several years and this will likely eventually surpass the infection rate of women. While many HPV infections can be transient, 10-20% of infections can persist and eventually progress to various forms of cancer [3]. In 2018, there were 45,000 new cases of HPV-associated cancers diagnosed in the U.S. [4], and persistent HPV infection is responsible for approximately 90% of anal and cervical cancers, 70% of vaginal/vulvar cancers, 60% of penile cancers, and up to 70% of oropharyngeal cancers [5, 6].

The HPV vaccine provides primary prevention against over 90% of HPV infections and consequently prevents most HPV-associated cancers in a cost-effective manner [7, 8]. There are three types of HPV vaccine that have been licensed by the U.S. Food and Drug Adminitration (FDA) (Table 1). Since 2016, the 9-valent HPV vaccine (Gardasil 9) has been the primary vaccine administered in the United States. A study published in 2020 looking at over one million women in Sweden found that the quadrivalent HPV vaccine demonstrated a substantially reduced risk of invasive cervical cancer [8]. Furthermore, a model study based in Australia showed that with their extremely robust vaccination and screening rates, cervical cancer could be eliminated as a public health risk over the next 20 years [9].

Table 1.

Vaccine types

	Cervarix	Gardasil 4	Gardasil 9
Recommended age (years)	9-26	9-26	9-26, 26-45*
Avaliable for:	Females only	Males and females	Males and females
Targeted Types	16, 18	6,11, 16, 18	6,11, 16,18, 31,33, 45, 52, 58

^*Shared clinical decision making

The Centers for Disease Control and Prevention (CDC) and the Advisory Committee on Immunization Practices (ACIP) recommend that all adolescents get two doses of the vaccine between ages 11-12 years old and 3 doses if older than 15 years old (Table 2) [10]. Vaccination initiation can begin as early as 9 years old with catch-up through 26 years old if not previously adequately vaccinated. The vaccine has also been approved for individuals aged 27-45 for those not previously vaccinated based on discussions with their provider [11]. It is also recommended that individuals who are immunocompromized (i.e HIV, immunosuppresive/ immunomodulatory medications for autoimmune conditions, and post-transplant patients) be vaccinated with a 3-dose regimen [12].

Table 2.

HPV Vaccination Timeline

Age range (years)	9-14	15-26	27-45
Number of doses	2	3	3
Schedule	0 and 6-12 months	0, 1-2, and 6 months	0, 1-2, and 6 months

A recent press release from the WHO Strategic Advisory Group of Experts on Immunization (SAGE) evaluated the current scheduling regimens of the HPV vaccine. Previously, it was recommended that individuals get 2-3 immunizations based on age, however, the committee recently concluded that the single vaccine delivers enough protection when compared with the two-dose regimen in individuals less than 21 years old. They still recommend the two-dose regimen in those who are 21 years old and older [13]. Several factors that support the use of the single dose globally is its cost effectiveness, lower resources needed, and increased compliance. The CDC has not commented on this discussion yet, so individuals in the U.S. should continue to comply with CDC and ASCCP recommendations.

What is the current HPV vaccination upake in the U.S.?

The percentage of adolescents with up-to-date (UTD) HPV vaccination in the U.S. was around 59% in 2020 [14], but this remained below the Healthy People 2020 goal of having 80% of adolescents with an UTD HPV vaccine status [15]. UTD vaccination is currently defined as completing 2-3 shots in the vaccine series depending on age requirements. While this is the ultimate goal, there is recent debate with the WHO recommendations that do support the goal of a single vaccine, of which an estimated 75% of teens in the U.S have completed. Females tend to have the higher vaccination rate at 61% compared to 56% of their male counterparts [16].

There are many factors that play into low HPV vaccination uptake. These range from parent-specific to provider- and system-specific barriers. Parental-level barriers include: lack of education/knowledge, safety concerns, absence of provider recommendation, and apprehensions about promoting sexual behavior [17, 18]. Provider-level barriers include: lack of time to discuss the vaccine, knowledge gaps, vaccination access issues, and financial concerns [17, 18]. However, it has been consistently shown that a health care provider recommendation is the strongest predictor of HPV vaccination uptake [19, 20], even more so than other influencing variables such as access to care, race, belief system, or vaccine knowledge [21-23].

Where are some of the disparities in HPV vaccination?

Social determinants of health and race also play a large role in HPV vaccination. When compared with their White or Latinx counterparts, Black women were less likely to have heard about the vaccine (66% vs. 79%) [24]. HPV awareness also significantly varies between race, ethnicity, and gender. This knowledge gap is seen with women being more aware of the vaccine than men along with White patients being more likely to have heard of the vaccine compared to patients who are racial or ethnic minorities [25]. Moreover, Black and Latinx women are more likely to carry high-risk genotypes that are not covered by the HPV vaccine compared with White women [26].

Furthermore, there are vast differences in HPV vaccine rates depending on place of residence. For instance, Rhode Island has a nearly 80% vaccination rate in their teenage girls, whereas, Alabama only has around 35-50% [16, 27]. Adolescents who live at or above the poverty level outside a metropolitan statistical area (more rural) had lower vaccination rates compared with those who live in urban cities [28]. These disparities are thought to exist based on access to vaccine (more rural individuals may not have a local provider that offers it), state programs raising awareness, and health care professionals recommending vaccination.

While it has been shown that provider recommendation produces one of the highest rates of vaccine uptake [29], studies have demonstrated that Black women and other minorities are more likely to trust information (although effect on vaccine uptake is not fully known) coming from government health agencies, media sources, religious organizations, and family/friends rather than information from health care professionals [24, 30]. Therefore, it is important that health care professionals understand that the recommendation they give is important in vaccine uptake [23], but that it is also vital to provide accurate medical information from other trusted sources such as media outlets and public broadcasts [31].

The vaccine series can also be seen as tedious across all groups of individuals with only around 60% receiving the doses within 30 days of the recommended time schedules [32, 33]. However, when looking at all racial and ethnic minorities, there was a larger increase in vaccine initiation but greater disparities in completing the vaccine series [34]. In other words, minorities were more likely to start the vaccine series yet less likely to complete it [35]. Males aged 13-17 years old are also less likely to complete the vaccine series when compared with females of the same age (44.3% vs. 53.1%) [16]. When various studies have looked at using patient navigators, reminder systems, and improved communication delivery, vaccine completion rates in these populations have improved (one study specifically went from around 35% to 67%) [36, 37].

What is the role in vaccinating 27-45 year-old individuals?

In October 2018, the Food and Drug Administration (FDA) expanded the approved age for HPV vaccination with Gardasil 9 for all people ages 9-45 [38]. In 2019, The Advisory Committee on Immunization Practices (ACIP) HPV Vaccines Work Group released an evidence-based recommendation with unanimous support in favor of “catch-up” HPV vaccination for all persons through age 26 regardless of individual patient risk factors [10, 39]. Most HPV infections are acquired in this age group with a significant increasing prevalence with each year from age 14-24 years [10, 40]. Importantly, the HPV vaccine is most effective when administered before onset of sexual activity and exposure to the virus. Therefore, the vaccine confers the highest protective benefit in adolescents and young adults, which remains the primary focus for HPV prevention. In regard to adults aged 27-45 years, the ACIP did not recommend HPV vaccination across the board, but instead voted in favor of shared clinical decision-making regarding use of the HPV vaccine in this age group [39]. ACOG released a statement in June 2019 that supports this provisional recommendation by the ACIP and support of shared decision making between physician and patient regarding HPV vaccination for women aged 27-45 [41].

It is unclear how much HPV-related disease is related to new infections in this age group as the prevalence of HPV infection declines after 24 years and HPV vaccination is most beneficial in patients who have not yet been exposed to the virus [10, 40]. Though the HPV vaccine has been determined to be safe and effective in persons age 27-45, the population advantage of HPV vaccination in this group is expected to be limited [39]. Despite this, certain individuals at risk for acquiring a new HPV infection may benefit from the vaccine. There is also some data showing that women with high-grade CIN may have regression of disease after HPV vaccination [42]. The basis for recommendation of vaccination in this age group should be made based on a discussion between physician and patient regarding their sexual history and behaviors while acknowledging reduced benefit when compared to the younger, target population. While identifying 27–45 year-old patients who would benefit from HPV vaccination could be challenging for health care professionals, it is important to consider that a new sexual partner at any age is a risk factor for new HPV infection and that a sexually active adult may have been exposed to some but not all HPV types targeted with vaccination. In fact, clinical trials have demonstrated that HPV vaccines are protective against HPV infection and HPV-related disease from HPV types that patients were not already infected with prior to vaccination [39, 43]. Additionally, recommendations for HPV vaccination in this age group must consider that cost-effectiveness becomes much less advantageous with increasing age with limited additional public health benefit [39].

What is the role in vaccinating health care workers?

The “occupational risk” of health care workers’ exposure to the HPV virus has recently been raised and remains investigational. While available data on the significance of occupational exposure to the virus and subsequent risk for HPV-associated disease is limited, several studies have demonstrated HPV DNA in surgical smoke generated during gynecologic procedures [43-46]. Furthermore, one study detected HPV DNA in nasal samples of clinicians after performing these procedures that corresponded to the HPV type in the cervical samples [46]. Additionally, several case reports identify laser surgeons and an operating room nurse who developed HPV-associated disease, including oropharyngeal cancer [47, 48]. These findings, although limited, suggest a plausible risk to clinicians treating HPV related disease in the surgical setting and warrant consideration of HPV vaccination for these individuals in addition to continued risk reduction including efficient smoke evacuation, room ventilation, and compliance with personal protective equipment, especially N95 respirators.

In 2020, the ASCCP released a statement recommending HPV vaccination for clinicians aged 27-45 years old exposed to the virus routinely in their practice [49]. Given the HPV vaccine is safe and effective, vaccination should be considered by previously unvaccinated physicians, nurse practitioners, nurses, residents and fellows, office staff, and operating room staff involved in treating HPV-related diseases and who are otherwise approved to receive it.

Should we still vaccinate if a patient has had an abnormal pap test or is HPV positive?

As previously discussed, the HPV vaccine is most effective at preventing all types of HPV-related dysplasia in patients with no prior exposure to HPV. However, it is not necessary to screen patients for HPV prior to their vaccination [50]. The vaccine is still efficacious against other targeted HPV types even if an individual is positive for a different type of HPV at time of vaccination [51]. This highlights the importance of health care professionals counseling their patients on the utility of the HPV vaccine even if they have had prior infection with HPV. It has also been noted that a person can clear an infection with a specific type and still be reinfected with that same type, but the effect of the vaccine on a previously cleared type is unknown [52, 53]. While the recommendation is that individuals who are 27-45 years old should discuss whether vaccination is appropriate, it is important to discuss if getting the HPV vaccine will help protect against new exposure to HPV types (sexual activity level, new sexual partner, health care worker, etc) [10]. It has been proposed that it is not cost-effective to vaccinate all individuals that are >30 years old which brings up the importance of health care professionals having discussions and recommending it to higher risk populations even if they are already HPV positive [54].

Should we still vaccinate after an individual has been treated with an excisional procedure (i.e. cold knife conization, loop excisional procedure, etc.)?

This then leads to the question, should women who have high-grade squamous intraepithelial lesions (HSIL or CIN 2-3), undergo an excisional procedure also be vaccinated for HPV? Up to 15% of women with CIN2+ will experience persistent or recurrent disease [55]. Therefore, these women are at an increased risk of cervical cancer compared with the general population even though they have had adequate treatment [56]. While these women are at the highest risk for having residual disease, it has also been shown that women who have already developed CIN2+ are at a higher risk for developing a new HPV-associated lesion [57]. Several studies have evaluated the utility of vaccinating women with CIN2+ with the HPV vaccine and found that it may provide a significant reduction in the persistent and recurrent lesions in this patient population [51, 58, 59]. A more recent study demonstrated a 4.5-fold decrease in the risk of persistent or recurrent CIN2+ when women were given the HPV vaccine after an excisional procedure [60].

What is the future of the HPV vaccine?

While the WHO has announced their stance on the potential use of a single-dose regimen for HPV vaccination, the CDC and ASCCP have not supported this statement yet in the U.S. However, currently there is an on-going trial that will potentially help further move the pendulum towards a single-dose regimen. The ESCUDDO study is a randomized, controlled, double-blinded, non-inferiority trial to evaluate one-dose versus two-dose regimens [61]. A similar study was just published that evaluated women in Kenya aged 15-20 who received a single dose nonvalent or bivalent vaccine compared with a control non-HPV vaccine. Women were followed 18 months, and those who received the single-dose regimen were found to be sufficiently protected against HPV infection [62]. However, the ESCUDDO study has all the strengths of an RCT with a control group that receives routine vaccination [63]. If found to be non-inferior, the results of this RCT will likely push for a single-dose regimen in appropriately-aged individuals to be the standard of care.

Conclusion

Cervical cancer remains a significant global and national health issue. A few of the most important things regarding the HPV vaccine are: 1. The HPV vaccine is a safe and a highly effective way to prevent cervical cancer [8]; 2. The strongest predictor of vaccine uptake is provider recommendation; and 3. Patients with prior infection or excision should still be offered the vaccine. While this discussion primarily reflects the status of HPV vaccination in the U.S., it is important to remember that additional considerations and methods should be considered to determine guidelines in other countries based on their resources and evidence. While there are national guidelines on vaccination for individuals 9-26 years old, there are also other individuals who may benefit from the vaccine including certain individuals over 26 years old and some high-risk health care workers. Furthermore, the vaccine regimen can be seen as tedious, and many individuals do not complete the whole series. Some research has indicated that a one-dose regimen is sufficient at protecting against high-risk HPV, and the results are pending to see if a large RCT confirms this. Most importantly, health care professionals need to continue to educate their patients about HPV in general and then also strongly recommend the HPV vaccine to the appropriate individuals.