Pediatric Annals

Special Issue Article 

HPV Vaccine in Adolescents

Paula K. Braverman, MD

Abstract

Human papillomavirus (HPV), the most common sexually transmitted viral infection worldwide, is the causative agent for cervical cancer and attributed to anogenital cancers as well as oropharyngeal cancer. Three effective, safe, prophylactic HPV vaccines have been licensed, and studies have demonstrated decreases in HPV prevalence and HPV-related disease endpoints without evidence of waning protection to date. In the United States, only the 9-valent vaccine, which covers 90% of the cancers attributed to HPV in US registries, is available. Because higher titers are found at younger ages, two rather than three doses are needed if the first dose is given prior to age 15 years. HPV vaccination rates in the US lag compared to tetanus-diptheria-acellular pertussis and meningococcal conjugate vaccines. Current efforts are aimed at improving vaccination rates through delivering strong and consistent clinician recommendations at the same time as discussing other adolescent vaccines and preventing missed opportunities for vaccination. [Pediatr Ann. 2019;48(2):e71–e77.]

Abstract

Human papillomavirus (HPV), the most common sexually transmitted viral infection worldwide, is the causative agent for cervical cancer and attributed to anogenital cancers as well as oropharyngeal cancer. Three effective, safe, prophylactic HPV vaccines have been licensed, and studies have demonstrated decreases in HPV prevalence and HPV-related disease endpoints without evidence of waning protection to date. In the United States, only the 9-valent vaccine, which covers 90% of the cancers attributed to HPV in US registries, is available. Because higher titers are found at younger ages, two rather than three doses are needed if the first dose is given prior to age 15 years. HPV vaccination rates in the US lag compared to tetanus-diptheria-acellular pertussis and meningococcal conjugate vaccines. Current efforts are aimed at improving vaccination rates through delivering strong and consistent clinician recommendations at the same time as discussing other adolescent vaccines and preventing missed opportunities for vaccination. [Pediatr Ann. 2019;48(2):e71–e77.]

Human papillomavirus (HPV), a DNA virus in the Papillomaviridae family, is the most common reproductive tract virus worldwide1 and the most common sexually transmitted infection (STI) in adolescents and young adults in the United States.2 HPV causes anogenital and oropharyngeal cancers, genital warts, and recurrent respiratory papillomatosis resulting in significant morbidity and mortality. Although prophylactic vaccines containing some of the most common HPV types causing these diseases are currently available, uptake has been variable. The World Health Organization (WHO) has recognized HPV-related diseases as a global public health problem and recommends inclusion of HPV vaccination in a national immunization program.1

Epidemiology

The primary route of HPV transmission is sexual behavior including genital-genital and oral-genital contact causing infection of skin and mucous membranes. Intrapartum (ie, mother-to-infant) transmission is also possible; nonsexual transmission is less common.1,2 Prevalence is primarily related to the number of sexual partners and the sexual behavior of the partner(s).2 Transmission from females to males is more common than from males to females.2 HPV is rapidly acquired with the onset of sexual activity, making it a top concern for providers caring for adolescents who may be experiencing coitarche.2

There are more than 150 HPV types that have been identified, with approximately 40 types infecting the genital area including the cervix, vulva, vagina, anus, and penis.2 Twelve types are labeled as high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) because of their association with cancers in the anogenital and oropharyngeal areas (tonsils, base of tongue, soft palate, walls of the pharynx).1,2 Other types, including types 6 and 11, are considered low-risk types because they usually result in noncancerous lesions such as genital warts and recurrent respiratory papillomatosis (RRP).2 Although they are benign lesions, genital warts have been associated with negative psychosocial consequences including anxiety and depression.2 Juvenile onset of RRP is thought to be from vertical transmission to an infant at the time of delivery.2 It presents at a median age of 3 years with recurrence of warts in the upper respiratory tract and larynx affecting the airway and frequently requiring multiple treatments over a prolonged period of time.2 Adult-onset RRP is usually seen in the third decade of life and is believed to be from horizontal transmission during sexual activity.1

The majority of new HPV infections are asymptomatic with a median duration of 8 months.2 New cervical infections are cleared by 70% of people in 1 year and by 90% in 2 years.2 Persistence of infection is related to development of cancer. Of the high-risk types, HPV 16 is most likely to persist. Being immunocompromised, such as having HIV, increases the likelihood of acquiring HPV and disease progression.2 Genital warts are also more difficult to treat in immunocompromised patients.2 In general, it takes about 20 years to go from HPV acquisition to invasive cervical cancer, but more rapid progression is possible.1 In the case of cervical cancer, in addition to immune status, risk factors for progression include coinfection with other STIs, young age at first pregnancy, parity, and smoking tobacco.1

In the US, approximately 79 million people age 15 to 59 years are infected with HPV.2 Roughly one-half of the 14 million new annual infections in the US are seen in the 15- to 24-year-old age group.2 It is estimated that by age 45 years, more than 80% of men and women in the US are infected with HPV.3 The latest data from the US include analysis of the cancer registries covering 97.8% of the population in 2015. When comparing 1999 to 2015, there has been a decrease in rates of cervical carcinoma and vaginal squamous cell carcinoma (SCC) with an increase in vulvar SCC as well as oropharyngeal and anal SCC in both males and females. Rates of penile cancer have been stable.4 Based on previous studies in the US, HPV DNA has been detected in 91% of cervical and anal cancers, 75% of vaginal, 70% of oropharyngeal, 69% of vulvar, and 63% of penile cancers.4 Approximately 79% of HPV-associated cancers are attributable to HPV5 (Table 1).

Estimated Number of Cancer Cases Associated with and Attributable to HPV Annually in the United States: 2011–2015

Table 1.

Estimated Number of Cancer Cases Associated with and Attributable to HPV Annually in the United States: 2011–2015

The number of new oropharyngeal cancers has exceeded cervical cancers 5 years ahead of the original predicted date of 2020, with 4.5 times more cases in men than women.4,6 Overall, anal cancers are twice as common in women as compared to men, although men who have sex with men and those with HIV infection are at high risk.4 These trends are explained by screening programs for cervical cancer that effectively reduce cervical cancer rates; sexual risk factors of unprotected oral and anal receptive sex; and a decrease in smoking rates, which contributes to the increase in the proportion of oropharyngeal cancer cases attributed to HPV.1,4

Prevention

The best way to prevent acquisition of genital HPV infection in adolescents is to abstain from genital-to-genital contact. Primary prevention of HPV infection can be achieved through prophylactic vaccination, which provides protection from vaccine-related HPV types prior to exposure (see section below on HPV vaccine).2 The chance of infection can be decreased by consistent and correct condom use; having fewer sexual partners; having a sexual partner who has not had a previous partner or has fewer partners; and monogamy. Male circumcision has been shown to reduce the risk of HPV infection in both the male and their female partners.2

Screening

Cervical cancer screening programs have been very effective in identifying precancerous lesions that can be treated to reduce cervical cancers and deaths.1 These programs remain important because a significant decline in cases is not anticipated for several decades after widespread uptake of the vaccine.7 However, in consideration of costs and possible negative reproductive health outcomes associated with diagnostic tests and treatment for lesions commonly regressing on their own, cervical cancer screening is now recommended starting at age 21 years in the US. Younger women are only screened if they are HIV-positive or immunocompromised.7

With respect to oropharyngeal cancers, no reliable screening techniques have been developed that would obtain an adequate sampling of the correct epithelium or have a positive predictive value that would accurately identify at-risk people at a general population level.8 Although some centers perform anal cytology and anoscopy, particularly for high-risk populations (eg, HIV infection, males who have sex with males), there is poor correlation between cytology and histology and insufficient evidence to recommend routine screening with anal cytology.2,9,10 Even surveillance with rectal examination and anoscopy is suboptimal.10

HPV Vaccine

Types

When given prior to exposure, HPV vaccination has the potential to prevent many of these HPV-related cancers as well as the benign, but difficult to treat, HPV 6-related and HPV 11-related lesions. Because the vaccines are prophylactic vaccines, there is only protection from the HPV types in the vaccine to which the patient has not been previously exposed. Vaccination is still recommended even in people with abnormal Pap tests, HPV-associated precancer lesions, or genital warts.2 There are currently three licensed vaccines, all of which use recombinant DNA technology to create noninfectious virus-like particle (VLP) shells that contain the L1 structural protein without viral DNA.1

Bivalent vaccine. The bivalent vaccine (Cervarix; GlaxoSmithKline, Middlesex, UK) contains the VLPs HPV 16 and 18, which cause approximately 66% of cervical cancers in the US and also are associated with other anogenital or oropharyngeal cancers.1,11 Although not licensed for use in males in the US, the WHO recommends use in both males and females to prevent anogenital cancers related to these viral types.1,11

Quadrivalent vaccine. In addition to VLPs HPV 16 and 18, the quadrivalent vaccine (Gardasil; Merck & Co., Kenilworth, NJ) contains VLPs 6 and 11, which address the cause of more than 90% of genital warts. This vaccine also has US Food and Drug Administration indications for the prevention of cervical, vulvar, vaginal, and anal cancers and their precursors, and it is approved for both males and females.1,11

9-Valent vaccine. In addition to the VLPs HPV 6, 11, 16, and 18, the 9-valent vaccine (Gardasil9; Merck & Co., Kenilworth, NJ) contains five additional HPV VLPs (31, 33, 45, 52, 58) that increase coverage for cervical cancer by 15%, thereby covering more than 80% of HPV-related cervical cancer in the US and 90% on a global level.1,2,11 Females derive the most additional benefit from this vaccine, although 4% of HPV-attributable cancers in males are caused by theses five additional types.11 It is estimated that the 9-valent vaccine could prevent approximately 90% of the cancers attributed to HPV annually in the US based on data from 2011 to 2015.5

All three vaccines are endorsed by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention,11 American Academy of Pediatrics,12 and American College of Obstetricians and Gynecologists.13 ACIP recommends routine vaccination for 11- or 12-year-old girls with catch-up vaccination for women up to age 26 years who have not been previously vaccinated or completed the series. The series can start at age 9 years, and this age is recommended for youth with a history of sexual abuse or assault. Either the quadrivalent or 9-valent vaccine can be used for routine vaccination of 11- or 12-year-old boys and girls with catch up for women through age 26 years and men through age 21 years. ACIP recommends vaccination for men and women who are immunocompromised or men who have sex with men through age 26 years.11 Although all three vaccines are available worldwide, only the 9-valent vaccine is currently available in the US.11

All three vaccines were studied as three-dose vaccine regimens and more than 99% of participants seroconverted in the vaccine trials, with the younger age group (age 9–15 years) having higher titers than the older participants.2,11 However, in 2016, based on studies with all three HPV vaccines, the recommendations were changed to give two doses 6 to 12 months apart if the first dose was given prior to age 15 years.14 This recommendation was based on data showing that 9- to 14-year-old youth who received two doses had noninferior immunogenicity and higher titers than the 16- to 26-year-old participants who received three doses. In the clinical vaccine trials, only immunogenicity studies (without genital examinations) were conducted in participants age 9 to 15 years for the quadrivalent/9-valent vaccines, and age 9 to 14 years for the bivalent vaccine.2,11 However, because clinical efficacy for preventing vaccine-related HPV disease was demonstrated for the 16- to 26-year-old age group and the antibody kinetics is similar for both dosing regimens, waning protection is not anticipated. The only exception would be that anyone who is immunocompromised should continue with three doses regardless of age because of concern that immune response may be attenuated1,14 (Table 2).

Human Papillomavirus Vaccines

Table 2.

Human Papillomavirus Vaccines

Although none of the vaccine trials were specifically designed to evaluate vaccine efficacy in preventing oropharyngeal cancers, studies have indicated the potential for HPV vaccine to be effective for these cancers. After vaccination with the quadrivalent vaccine, there is evidence of HPV 16 and 18 antibodies in the oral cavity that correlate with serum antibody levels15 and these oral antibodies can neutralize HPV pseudovirions in vitro.16 Another study tested for the presence of HPV 16 and 18 DNA in oral fluids 4 years after immunization with the bivalent vaccine and demonstrated lower prevalence in the immunized group compared to the control group.17 An analysis of National Health and Nutrition Examination Survey (NHANES) data from 2011 to 2014 found a statistically significant reduction in oral HPV 6, 11, 16, and 18 infections in 18- to 33-year-olds who had received at least one dose of HPV vaccine by age 26 years compared to those who were unvaccinated.18

Vaccine Immunogenicity and Efficacy

High vaccine efficacy was demonstrated during clinical trials for all three vaccines among participants negative for the vaccine HPV type during the 6-month vaccination period. All three vaccines prevented cervical intraepithelial neoplasia 2 or 3, adenocarcinoma in situ, vulvar and vaginal intraepithelial neoplasia 2 or 3, and in the case of the quadrivalent vaccine, anal intraepithelial neoplasia 1, 2, 3 and genital warts related to the HPV types present in each vaccine.2,10,19

Long-term follow-up studies from the vaccine trials have shown sustained elevation of antibody titers after vaccination for up to 9.4 years for the bivalent vaccine,20 9 years for the quadrivalent vaccine,21 and 5 years for the 9-valent vaccine.19 To date, there is no evidence that efficacy against infection or vaccine-related cervical lesions wanes over time.1 Studies have also demonstrated lack of HPV vaccine type infection or cyto-histopathological abnormalities for up to 9.4 years with the bivalent vaccine;20 lack of cervical intraepithelial neoplasia 2 or worse for at least 10 years with the quadrivalent vaccine;22 and 97.4% efficacy up to 6 years after vaccination for high-grade cervical, vulvar, and vaginal disease related to HPV 31, 33, 45, 52, and 58.19 Long-term follow-up over 8 years of initially sexually naïve girls and boys age 9 to 15 years who received the quadrivalent vaccine demonstrated sustained antibody titers and no cases of HPV vaccine-type anogenital disease despite evidence of initiation of sexual activity by a history of new sexual partners and positive testing for STIs.23

Population surveillance and review of medical claims after introduction of the vaccine has shown declines in HPV prevalence and disease endpoints.2,24 Systematic review and meta-analysis of population level real-world experiences after vaccine implementation in nine high-income countries found a 68% decrease in HPV 16 and 18 infections and a 61% decrease in anogenital warts among females age 13 to 19 years. In countries with vaccination rates for females of more than 50%, there was evidence of herd effects, with reductions in anogenital warts in males younger than age 20 years and in women age 20 to 39 years.25 Other studies have demonstrated reduction in abnormal cervical cytological26 and high-grade cervical lesions24,27 in adolescent girls. Analysis of data from US Cancer Statistics found a 29% decrease in the average annual incidence rates for cervical cancer in 15- to 24-year-olds comparing the postvaccine introduction years of 2011 to 2014 to the prevaccine years of 2003 to 2006.28 Data from the 2003 to 2014 NHANES showed a decrease in quadrivalent HPV type prevalence from cervicovaginal specimens of 71% in 14- to 19-year-olds and 61% in 20- to 24-year-olds within 8 years of vaccine availability. The decrease in prevalence was 89% among vaccinated 14- to 24-year-olds and 34% in those who were unvaccinated, demonstrating herd protection for unvaccinated females.29

Safety

HPV vaccines have been proven to be safe based on the prelicensure clinical trials and postlicensure monitoring. In January 2016, the WHO Global Advisory Committee for Vaccine Safety concluded that there were no safety concerns related to the HPV vaccines.1 Similarly, no significant safety concerns have been raised in the US through the vaccine safety monitoring systems.24 The most common side effects are syncope, dizziness, nausea, headache, and fever. Syncope is a known adverse event after any injection, hence the recommendation for observing patients for 15 minutes after vaccination. In addition, injection site reactions with pain, swelling, and erythema that are usually mild or moderate can occur. The 9-valent vaccine does have more injection site adverse events than the quadrivalent vaccine.1,2,11,24 There is no evidence that HPV vaccines cause immune-mediated diseases, venous thromboembolic events, neurologic disorders, complex regional pain syndromes, postural orthostatic tachycardia syndrome, or primary ovarian insufficiency.1,2 The vaccines can be given during minor acute illnesses and coadministered with other age-appropriate vaccines including tetanus-diptheria-acellular pertussis (Tdap) and meningococcal conjugate vaccines.1,2

HPV vaccination is not recommended in pregnancy because well-controlled studies have not been conducted. However, there have been no vaccine-related adverse pregnancy outcomes identified among women who were inadvertently vaccinated while pregnant.1,11 Pregnancy testing prior to vaccination is not needed and no interventions are indicated if given during pregnancy. Completion of the HPV series should be held until the end of the pregnancy.1,11

Vaccine Uptake

Despite the data showing excellent efficacy and safety for the HPV vaccines, uptake remains below the Healthy People 2020 target of having 80% of 13- to 15-year old girls complete the series by receiving two or three doses of HPV vaccine depending on their age at vaccine initiation.6 Vaccine uptake has been improving with an annual increase of 5% in series initiation among adolescents since 2013 and an increase of 4% for series completion by age 13 years for each successive birth cohort. However, the latest data from the 2017 National Immunization Survey-Teen shows that only 65.5% of 13- to 17-year-olds had received at least one dose of HPV vaccine and only 53.1% of girls and 44.3% of boys had completed the series.30 Among 13-year-old youth who should have completed the HPV series, 64.5% of girls and 57.1% of boys had received one HPV dose but only 43.7% of girls and 34.4% of boys had received both doses.30 Initiation of HPV vaccine is lower than the other vaccines on the adolescent platform, as 85.1% had received at least one dose of quadrivalent meningococcal conjugate vaccine (MenACWY) and 88.7% had received Tdap.30

Many studies have been conducted to better understand HPV vaccination rates. One recent qualitative systematic review of the literature looked at clinicians' knowledge, attitudes, and practices in the US.31 Factors that were related to vaccination rates being lower than expected, based on clinician recommendation, included absence of strong and consistent recommendations; inadequate time to address the vaccine or concerns raised by the parent; and acceding to vaccine refusal by a patient or parent or a parent's request for deferral. Factors that predicted the three outcomes of intention to recommend the HPV vaccine, vaccine recommendations, and vaccination rates included (1) clinicians being pediatricians, more knowledgeable about HPV, and believing in the safety and efficacy of the vaccine; (2) patients being older or female and parents believing in the risk that HPV posed for their child; and (3) having systems that facilitated vaccine delivery including recall/reminder systems, vaccine registries, and insurance coverage and reimbursement. A number of studies in this review found that clinicians recommended other vaccines more strongly than HPV vaccine, including presenting the vaccine as optional.31 Although parents raise concern that HPV vaccine will promote sexual activity or riskier sexual behavior, multiple studies comparing vaccinated to unvaccinated adolescent girls have failed to find riskier sexual behaviors when assessing for pregnancy,32,33 STIs,32,33 condom use,34 or increase in total number of sexual partners.34

The quality of the clinician's communication about HPV vaccination is crucial. One study of a nationally representative group of US parents of 11- to 17-year-old youth found that having a recommendation for vaccination versus no recommendation increased the odds of initiating the HPV vaccine 4-fold.35 The odds increased 9-fold when giving a high-quality recommendation, which included saying the vaccine was very/extremely important, stating a cancer prevention message, and recommending same-day vaccination instead of allowing for delay or giving the parent a choice.35 A study of a nationally representative group of parents of 11- to 17-year-old youth found that it is worth revisiting the HPV vaccine discussion because there was secondary acceptance of vaccination (45%) or intention to accept in the next year (24%) among parents who had initially declined the vaccine. Acceptance was correlated with receiving a high-quality initial recommendation to vaccinate as well as being more satisfied with that initial communication and having higher confidence in the efficacy and safety of the vaccine.36 A recent exploratory qualitative study analyzing audio-recorded visits with unvaccinated adolescents found that when faced with hesitant parents, provider persistence, as compared to acquiescence or a mix of acquiescence and persistence, resulted in the majority of adolescents being vaccinated at the visit.37 The authors suggest that parental hesitancy be viewed as an opening for discussion to address concerns/questions and recommend the vaccine.37

In a US report from the President's Cancer Panel entitled “Accelerating HPV Vaccine Uptake: Urgency for Action to Prevent Cancer”6 recommendations are made to develop, test, and disseminate communication strategies directed at clinicians, parents/caregivers, and adolescents; encourage vaccination whenever other vaccines are administered; use electronic health records and immunization registries to avoid missed opportunities for vaccination; ensure adequate reimbursement for health care providers; promote and facilitate HPV vaccination outside of the medical home including in pharmacies; and support of global efforts for HPV vaccination. The Centers for Disease Control and Prevention recommends that the HPV vaccine be recommended and given to all 11- and 12-year-old girls and boys simultaneously with Tdap and MenACWY.30 Resources for clinicians, including fact sheets and guidance with resources, for facilitating discussions with parents and youth about HPV vaccination are available at the following websites:

Summary

HPV vaccine has been proven to be an effective and safe vaccine that has the potential to prevent the majority of HPV-related cancers in the US and worldwide. Because the vaccine is a prophylactic vaccine, intended to be given prior to exposure to the virus, and antibody titers are highest in the 9- to 15-year-old age group, facilitation of routine vaccination of 11- to 12-year-old girls and boys is key. Studies have shown that strong clinician recommendation made at the same time as the other adolescent vaccines and utilization of office-based systems and vaccine registries to prevent missed opportunities for vaccination can be implemented to improve vaccination rates.

References

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Estimated Number of Cancer Cases Associated with and Attributable to HPV Annually in the United States: 2011–2015

Site of Cancer Number of HPV Associated Cases Number of HPV Attributable Cases HPV Types 16 and 18 HPV Types 31, 33, 45, 52, 58 Other HPV Type
Cervix 11,866 10,800 7,900 1,700 1,200
Vagina 846 600 500 100 -
Vulva 3,934 2,700 1,900 600 200
Penis 1,269 800 600 100 100
Anus: female 4,333 4,000 3,400 500 100
Anus: male 2,197 1,900 1,700 100 100
Oropharynx: female 3,412 2,200 1,700 300 200
Oropharynx: male 14,814 10,700 9,400 700 600

Human Papillomavirus Vaccines

Vaccine Type Name (Manufacturer) HPV Types FDA Indications Dosing
Bivalent Cervarix (GlaxoSmithKline Biologicals, Middlesex UK) 16, 18 Females Prevention of cervical cancer and cancer precursors Age 9–14 years at first dose: 2 doses 6–12 months aparta Age 15 years at first dose: 3 doses; second dose 1–2 months after first; third dose 6 months after firstb
Quadrivalent Gardasil (Merck & Co., Kenilworth, NJ) 6, 11, 16, 18 Females and males Prevention of cervical, vaginal, vulvar, anal cancer and cancer precursors and genital warts
9-Valent Gardasil 9 (Merck & Co., Kenilworth, NJ) 6, 11, 16, 18, 31, 33, 45, 52, 58 Females and males Prevention of cervical, vaginal, vulvar, anal cancer and cancer precursors and genital warts
Authors

Paula K. Braverman, MD, is the Chief, Adolescent Medicine, Department of Pediatrics, Baystate Children's Hospital, and a Professor of Pediatrics, University of Massachusetts Medical School-Baystate.

Address correspondence to Paula K. Braverman, MD, Baystate Children's Hospital, 50 Wason Avenue, Springfield, MA 01199; email: Paula.BravermanMD@baystatehealth.org.

Disclosure: Paula K. Braverman was part of an advisory group for Merck and Co. (Kenilworth, NJ) on Gardasil from 2004 to 2007, and gave presentations until 2011.

10.3928/19382359-20190118-02

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