Human papillomaviruses (HPV) are a diverse family of viruses composed of more than 100 types that can infect epithelial cells in oral mucosa, genital mucosa, and skin.1,2 HPV can be subdivided into mucosal types and cutaneous types. Cutaneous HPV types are commonly found on healthy skin as well as in skin lesions, such as benign skin warts, cutaneous papillomas, actinic keratosis, non-melanoma skin cancers, and keratoacanthomas.1 Mucosal HPV types include a subgroup of 12 high-risk HPV types (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) that are classified as carcinogenic to humans due to their association with cervical cancer, and 13 other HPV types that are classified as probably or possibly carcinogenic to humans.3 Transmission of mucosal HPV is primarily through sexual activity, including any genital contact, whereas cutaneous HPV occurs through skin-to-skin contact.
The Impact of Human Papillomavirus
HPV is the most common sexually transmitted infection in the United States. It is so common that nearly all men and women will get at least one type of HPV at some point in their lives. Current estimates indicate that there are about 14 million new infections each year, with nearly half of all new cases of HPV occurring in people age 15 to 24 years. Although most HPV infections are asymptomatic and self-limited, persistent infections with high-risk HPV types (eg, 16, 18) can cause cervical, vaginal, vulvar, penile, anal, and oropharyngeal cancers, whereas low-risk HPV types (eg, 6, 11) can lead to genital warts and respiratory recurrent papillomatosis.4 More than 44,000 new cases of HPV-associated cancers occur in the US each year. The incidence of oropharyngeal cancers (OPC) has tripled in the US over the past 10 years, with present data reflecting more cases of OPC than cervical cancers.5
Since the first vaccine against HPV was introduced in 2006, there have been three versions with differing levels of protection. The bivalent HPV vaccine included coverage for HPV types 16 and 18, which cause approximately 66% of cervical, 80% of anal, 60% of oropharyngeal, and 45% of penile cancers. The quadrivalent HPV vaccine added HPV types 6 and 11, which account for 90% of cases of genital warts. An HPV 9-valent vaccine (Gardasil 9, Merck & Co.) is the most recent HPV vaccine and the only one currently available in the US. It broadens coverage to also include 5 additional HPV types (31, 33, 45, 52, and 58) that cause 15% of cervical cancers.5 Multiple studies demonstrate the vaccine efficacy at 100% for cervical, vaginal, and vulvar cancer secondary to HPV types 6, 11, 16, 18, and 97% efficacy for HPV types 31, 33, 45, 52, and 58.6–8 With the introduction of the HPV vaccine, the prevalence of cervical intraepithelial neoplasia grades 2 and 3 and anogenital warts decreased significantly from 2007 to 2014 among young women age 15 to 19 years and women age 20 to 24 years. Similar declines in anogenital wart prevalence were noted among men age 20 to 24 years.9,10 Despite the benefits that the HPV vaccine provides, only two-thirds of adolescents between the ages of 13 and 17 years have initiated the HPV vaccine series, and only 50% have completed the series.11
As with other vaccines that are licensed for use in the US, the Centers for Disease Control and Prevention (CDC) monitors HPV vaccine safety primarily through three systems: the Vaccine Adverse Event Reporting System, the Vaccine Safety Datalink, and the Clinical Immunization Safety Assessment network. From June 2006 through December 2017, more than 100 million doses of HPV vaccines were given in the US, 28 million of which include Gardasil 9.12 Internationally, the World Health Organization Global Advisory Committee for Vaccine Safety (GACVS) routinely reviews evidence regarding the safety of HPV vaccines in other countries, including Australia, Japan, and other countries as concerns arise. Based on available evidence, GACVS did not note any safety concerns regarding the use of HPV vaccines. The most common side effects include injection site pain and fever. Less common systemic reactions are mild, including headache, dizziness, myalgia, arthralgia, nausea/vomiting, and abdominal pain. Studies thus far have not shown any association between HPV vaccine and autoimmune diseases, complex regional pain syndrome, or postural orthostatic tachycardia syndrome. Data also did not show any increased risk for Guillain-Barré syndrome or Bell's palsy.13 Post-vaccination syncope has been most commonly reported after adolescent vaccines (eg, Tdap, HPV, meningococcal conjugate vaccine), although it is unclear if it is secondary to the vaccines itself or the process of receiving multiple vaccines.14 For this reason, some clinics recommend that children receive the vaccines sitting or lying down and remain in that position for 15 minutes after receiving the vaccine.
Current Vaccine Recommendations
The American Academy of Pediatrics (AAP) and the Advisory Committee on Immunization Practices (ACIP) of the CDC updated recommendations in 2016 based on studies that demonstrated significantly higher immunogenicity in persons age 9 to 14 years who received 2 doses as compared to 3 doses in older patients.15 The vaccine is most effective when given prior to any HPV exposure through sexual activity. Studies have also indicated that HPV infection typically occurs within 2 to 3 years of first sexual activity. As such, HPV vaccine effectiveness is lower in older age groups because of previous infections.16 The summary of current vaccine recommendations are listed in Table 1.
Current Vaccine Recommendations for HPV
The only true contraindication is a severe allergic reaction (eg, anaphylaxis) after a previous dose or to a vaccine component, including yeast. HPV vaccines are not recommended for use during pregnancy, although additional pregnancy testing prior to vaccination is not necessary. ACIP does recommend routine HPV vaccination beginning at age 9 years for children who have a history of sexual abuse or assault. For people who have primary or secondary immunocompromising medical conditions that reduce cell-mediated or humoral immunity (eg, B or T lymphocyte deficiencies, HIV, immunosuppressive therapy), ACIP recommends 3 doses of HPV due to a reduced immune response.15
Addressing HPV Vaccine Hesitancy through Effective Recommendations
Most literature directed toward vaccine hesitancy and improving vaccination rates has found that strong provider recommendations lead to higher rates of vaccination initiation as compared to those who do not.17,18 With HPV vaccine, physicians may differ in the strength of their recommendations, comfort level in discussing HPV with patients, or consistency in delivering recommendations secondary to time constraints during a visit. In considering effective HPV vaccine communication practices, recommendations should emphasize the importance of HPV vaccination and cancer prevention, advise same-day HPV vaccination for all children by age 12 years, recommend HPV at the same time and in the same way as other adolescent vaccines, and focus on “routine” immunization schedule versus what is required for school entry.17
Brief presumptive announcements versus participatory conversations were found to be more effective in increasing HPV vaccination initiation rates.19 An example would be, “Now that your son is 11, he is due for his 11-year-old vaccines that help protect him against whooping cough, HPV cancers, and meningitis. We will give them today at the end of this visit.” This recommendation emphasizes timeliness, cancer prevention, and bundling adolescent vaccinations as they are all important. The announcement approach leads to higher parental acceptance, provides more efficiency during the clinic visit, and allows time to discuss parental concerns if there are any.17–19
Although most families will plan to vaccinate their child that day, some may still be hesitant and have additional questions. Research-tested messages for addressing these concerns (eg, “This really isn't about sex. The HPV vaccine is about preventing cancer” or “The HPV vaccine is safe, just like other vaccines given at this age”) can be found in the article by Shah et al.20
For those parents who initially decline the HPV vaccine, continue to offer it at later visits because approximately 70% of parents will eventually accept the vaccine.21 Secondary acceptance was associated with receiving follow-up counseling about HPV immunization from a health care provider, although only 50% of parents report receiving such counseling.21 The way that the clinic communicates about HPV immunizations, from the front desk scheduling visits to the clinical staff rooming patients to the providers recommending vaccines, can all affect vaccination rates.
Practical Actions to Improve Vaccination Rates
In addition to provider recommendations, broader initiatives may be implemented to improve HPV immunization rates. Quality improvement projects have the added advantage of being useful in quantifying impact as well as qualifying for Maintenance of Certification Part 4 credit. One project may be identifying missed opportunities for vaccination. This refers to any patient who has contact with health services and is due for vaccination but does not receive the vaccines for which the person is eligible. Ways to address missed opportunities include (1) chart review the previous day to identify adolescent patients who may be due for vaccines, regardless if it is a health maintenance visit; (2) daily “huddles” in which clinical teams are reminded of adolescent patients who are in clinic and due for vaccines; and (3) electronic medical records prompts to alert clinical staff and providers about patients who are due for vaccines.
Adolescents tend to visit the physician's office less often than other age groups and do so more often for acute care visits than preventive care visits.22 As such, every encounter with adolescents should be seen as an opportunity to provide preventive care services.
Other ideas to increase vaccination rates include the implementation of standing orders that decrease barriers to receiving vaccines by allowing nurses or medical assistants to assess need and administer vaccines to patients. Reminder/recall systems involving telephone call, postal mail, text messaging, and email are also effective in boosting adolescent vaccination rates.23–25 Many additional resources are available through the CDC, American Academy of Pediatrics, and National HPV Vaccination Roundtable.
The HPV vaccine continues to be underused in the US despite its proven safety profile and efficacy in cancer prevention. Physicians should feel comfortable talking to families about the vaccine as well as its disease burden. How health care providers communicate about this vaccine matters, and it is the single most important predictor of HPV vaccination,26 so ensure that your recommendations are strong, consistent, and timely.
- Bzhalava D, Guan P, Franceschi S, Dillner J, Clifford G. A systematic review of the prevalence of mucosal and cutaneous human papillomavirus types. Virology. 2013;445(1–2):224–231. doi:10.1016/j.virol.2013.07.015 [CrossRef] PMID:23928291
- Gheit TInfections and Cancer Biology Group, International Agency for Research on Cancer. Mucosal and cutaneous human papillomavirus infections and cancer biology. Front Oncol. 2019;9:355. doi:10.3389/fonc.2019.00355 [CrossRef] PMID:31134154
- International Agency for Research on Cancer. Human papillomaviruses. In: Biological Agents: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol 100B. International Agency for Research on Cancer; 2012: 255–313.
- US Centers for Disease Control and Prevention. Human papillomavirus (HPV) infection. https://www.cdc.gov/std/tg2015/hpv.htm. Accessed May 11, 2020.
- US Centers for Disease Control and Prevention. Cancers associated with human papillomavirus, United States – 2012–2016. https://www.cdc.gov/cancer/uscs/about/data-briefs/no10-hpv-assoc-cancers-UnitedStates-2012-2016.htm. Accessed May 11, 2020.
- De Vincenzo R, Conte C, Ricci C, Scambia G, Capelli G. Long-term efficacy and safety of human papillomavirus vaccination. Int J Womens Health. 2014;6:999–1010. doi:10.2147/IJWH.S50365 [CrossRef] PMID:25587221
- Cutts FT, Franceschi S, Goldie S, et al. Human papillomavirus and HPV vaccines: a review. Bull World Health Organ. 2007;85(9):719–726. doi:10.2471/BLT.06.038414PMID:18026629 [CrossRef]
- Huh WK, Joura EA, Giuliano AR, et al. Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16–26 years: a randomised, double-blind trial. Lancet. 2017;390(10108):2143–2159. doi:10.1016/S0140-6736(17)31821-4PMID:28886907 [CrossRef]
- Flagg EW, Torrone EA, Weinstock H. Ecological association of human papillomavirus vaccination with cervical dysplasia prevalence in the United States, 2007–2014. Am J Public Health. 2016;106(12):2211–2218. doi:10.2105/AJPH.2016.303472 [CrossRef] PMID:27736208
- Centers for Disease Control and Prevention. Sexually transmitted disease surveillance 2017. https://www.cdc.gov/std/stats17/2017-STD-Surveillance-Report_CDC-clearance-9.10.18.pdf. Accessed May 20, 2020.
- Walker TY, Elam-Evans LD, Yankey D, et al. National, regional, state, and selected local area vaccination coverage among adolescents aged 13–17 years - United States, 2017. MMWR Morb Mortal Wkly Rep. 2018;67(33):909–917. doi:10.15585/mmwr.mm6733a1 [CrossRef] PMID:30138305
- US Centers for Disease Control and Prevention. Questions about HPV vaccine safety. https://www.cdc.gov/vaccinesafety/vaccines/hpv/hpv-safety-faqs.html. Accessed May 11, 2020.
- World Health Organization. Human papillomavirus vaccines: WHO position paper, May 2017. Weekly Epidemiological Record. 2017;92(19):241–268.
- Meissner HC. What do data show regarding safety of HPV vaccine? https://www.aappublications.org/news/2018/08/29/idsnapshot082918. Accessed May 20, 2020.
- Meites E, Kempe A, Markowitz LE. Use of a 2-dose schedule for human papillomavirus vaccination – updated recommendations of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep. 2016;65(49):1405–1408. doi:10.15585/mmwr.mm6549a5 [CrossRef] PMID:27977643
- Meites E, Szilagyi PG, Chesson HW, Unger ER, Romero JR, Markowitz LE. Human papillomavirus vaccination for adults: updated recommendations of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep. 2019;68(32):698–702. doi:10.15585/mmwr.mm6832a3 [CrossRef] PMID:31415491
- Gilkey MB, McRee AL. Provider communication about HPV vaccination: a systematic review. Hum Vaccin Immunother. 2016;12(6):1454–1468. doi:10.1080/21645515.2015.1129090 [CrossRef] PMID:26838681
- Dempsey AF, Pyrzanowski J, Lockhart S, Campagna E, Barnard J, O'Leary ST. Parents' perceptions of provider communication regarding adolescent vaccines. Hum Vaccin Immunother. 2016;12(6):1469–1475. doi:10.1080/21645515.2016.1147636 [CrossRef] PMID:27078515
- Brewer NT, Hall ME, Malo TL, Gilkey MB, Quinn B, Lathren C. Announcements versus conversations to improve HPV vaccination coverage: a randomized trial. Pediatrics. 2017;139(1):1–9. doi:10.1542/peds.2016-1764 [CrossRef] PMID:27940512
- Shah PD, Calo WA, Gilkey MB, et al. Questions and concerns about HPV vaccine: a communication experiment. Pediatrics. 2019;143(2):1–10. doi:10.1542/peds.2018-1872 [CrossRef] PMID:30670584
- Kornides ML, McRee AL, Gilkey MB. Parents who decline HPV vaccination: who later accepts and why?Acad Pediatr. 2018;18(2S):S37–S43. doi:10.1016/j.acap.2017.06.008 [CrossRef] PMID:29502636
- Nordin JD, Solberg LI, Parker ED. Adolescent primary care visit patterns. Ann Fam Med. 2010;8(6):511–516. doi:10.1370/afm.1188 [CrossRef] PMID:21060121
- Bernstein HH, Bocchini JA Jr, Committee on Infectious Diseases. Practical approaches to optimize adolescent immunization. Pediatrics. 2017;139(3):e1–e14.
- Jacobson Vann JC, Jacobson RM, Coyne-Beasley T, Asafu-Adjei JK, Szilagyi PG. Patient reminder and recall interventions to improve immunization rates. Cochrane Database Syst Rev. 2018;1:CD003941. doi:10.1002/14651858.CD003941.pub3 [CrossRef] PMID:29342498
- Morris J, Wang W, Wang L, Peddecord KM, Sawyer MH. Comparison of reminder methods in selected adolescents with records in an immunization registry. J Adolesc Health. 2015;56(5)(suppl):S27–S32. doi:10.1016/j.jadohealth.2015.01.010 [CrossRef] PMID:25863551
- Ylitalo KR, Lee H, Mehta NK. Health care provider recommendation, human papillomavirus vaccination, and race/ethnicity in the US National Immunization Survey. Am J Public Health. 2013;103(1):164–169. doi:10.2105/AJPH.2011.300600 [CrossRef] PMID:22698055
Current Vaccine Recommendations for HPV
Routine HPV vaccination should be given to all children at age 11 or 12 years
HPV vaccination can be given starting at age 9 years through age 26 years
For people younger than age 15 years, a 2-dose series should be given on a 0-, 6-, 12-month schedule.
For people age 15 years and older, a 3- dose series should be given on a 0-, 1- or 2-, 6-month schedule.
Persons receiving vaccination with HPV 9-valent, 4-valent, or 2-valent at the current recommended dosing schedule are considered adequately vaccinated, and no ACIP recommendations have been made regarding additional vaccination with 9vHPV