Human Papillomavirus (HPV) Vaccine

Number: 0726

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

---

Policy

Scope of Policy

This Clinical Policy Bulletin addresses human papillomavirus (HPV) vaccine.

1. Medical Necessity

   1. Aetna considers human papillomavirus (HPV) 9-valent vaccine (Gardasil 9) a medically necessary preventive service for persons age 9 to 45 years.
   2. Aetna considers Gardasil 9 vaccination not medically necessary for persons who have completed a three-dose series with Gardasil or Cervarix. If vaccination providers do not know or do not have available the HPV vaccine product previously administered, then Gardasil 9 HPV vaccine product is considered medically necessary to continue or complete the three-dose series.

   Note: Since 2017, Gardasil 9 (Merck & Co., Inc.) has been the only HPV vaccine available and distributed in the United States.

2. Experimental, Investigational, or Unproven

   Aetna considers Gardasil 9 experimental, investigational, or unproven for the following indications (not an all-inclusive list) because their effectiveness for these indications have not been established:

   • Prevention of recurrence of anogenital warts
   • Treatment of:
     
     
     • Active genital warts 
     • Anal squamous cell carcinoma
     • Benign squamous papilloma
     • Cervical cancer
     • High-grade anal dysplasia
     • Post-treatment HPV vaccination as adjunctive treatment of women undergoing excision of cervical intraepithelial neoplasia
     • Use of human papillomavirus vaccine as adjuvant therapy for juvenile-onset recurrent respiratory papillomatosis
     • Vulvar and vaginal cancer.

3. Policy Limitations and Exclusions

   1. Not all plans provide coverage of preventive services. Please check benefit plan descriptions for details.
   2. Bivalent Cervarix and quadrivalent Gardasil are no longer being distributed in the United States. 

4. Related Policies 

   • CPB 0443 - Cervical Cancer Screening and Diagnosis

---

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
CPT codes covered if selection criteria are met:
90651	Human Papillomavirus vaccine types 6, 11, 16, 18, 31, 33, 45, 52, 58, nonavalent (9vHPV), 3 dose schedule, for intramuscular use
CPT codes not covered for indications listed in the CPB:
90649	Human Papillomavirus vaccine, types 6, 11, 16, 18, quadrivalent (4vHPV), 3 dose schedule, for intramuscular use
90650	Human papillomavirus vaccine, types 16, 18, bivalent (2vHPV), 3 dose schedule, for intramuscular use
Other CPT codes related to the CPB:
90471	Immunization administration (includes percutaneous, intradermal, subcutaneous, or intramuscular injections); one vaccine (single or combination vaccine/toxoid)
90472	each additional vaccine (single or combination vaccine/toxoid) (List separately in addition to code for primary procedure)
Other HCPCS codes related to the CPB:
D1781	Vaccine administration – human papillomavirus – Dose 1
D1782	Vaccine administration – human papillomavirus – Dose 2
D1783	Vaccine administration – human papillomavirus – Dose 3
ICD-10 codes not covered for indications listed in the CPB:
A63.0	Anogenital (venereal) warts
C44.520	Squamous cell carcinoma of anal skin
C51.0 - C53.9	Malignant neoplasm of vulva, vagina and cervix uteri
D06.0 - D07.2	Carcinoma in situ of cervix uteri, vulva and vagina
D10.0 - D10.9	Benign neoplasm of mouth and pharynx [benign squamous papilloma]
D14.1	Benign neoplasm of larynx [benign squamous papilloma][Juvenile-onset recurrent respiratory papillomatosis]
K62.82	Dysplasia of anus
N87.0 - N87.9	Dysplasia of cervix uteri

---

Background

Human papillomavirus (HPV) is the most common sexually transmitted infection (STI) in the United States, which, in some individuals, can lead to certain types of cancer. According to the Centers for Disease Control and Prevention (CDC), every year about 14 million Americans become infected with HPV, which is spread through genital contact (vaginal, anal, or oral sex) with someone who has the virus and may not be aware of it. Sexually active adolescents are at particularly high risk for HPV infection. Although most HPV infections will resolve on their own, for some, the infection can last longer than two years and, over time, may develop into cancer, such as cancer of the cervix, vagina, and vulva in women; penile cancer in men; and cancer of the anus and oropharynx for both women and men. Per the CDC, HPV causes 33,700 cases of cancer each year in the United States, with cervical cancer being the most common cancer among women and oropharyngeal cancer the most common among men (CDC, 2018; CDC, 2019). Studies show that HPV vaccinations are safe and highly effective in preventing a lasting infection, reducing precancerous lesions, and leading to fewer cancers caused by the HPV infection (ASCO, 2019).

There are over 100 different types of HPV, with most men and women having no symptoms or health problems to indicate when they have HPV. Although not all HPV infections will cause cancer, some low-risk HPV types (e.g., HPV-6 or HPV-11) can cause papillomas or genital warts, a common benign condition that causes significant morbidity. The high-risk types, such as HPV 16 and 18, can develop into cancer over time. Cervical cancer, a major health problem for women, is causally associated with 14 high-risk types of HPV (Williamson et al., 2005). The American Cancer Society estimates the annual incidence of cervical cancer in the U.S. to be approximately 13,170 new cases and predicts 4,250 will die from the disease in 2019. The five-year survival rate for all women with cervical cancer is 66%; however, when detected at an early stage, the overall five-year survival rate for invasive cervical cancer is about 92% (Cancer.net, 2019). Per the CDC, HPV is thought to be responsible for more than 90% of anal and cervical cancers, about 70% of vaginal and vulvar cancers, and more than 60% of penile cancers. Oropharyngeal cancers traditionally have been caused by tobacco and alcohol; however, studies now show that about 70% of cancers of the oropharynx may be linked to HPV. Many cancers of the oropharynx may be caused by a combination of tobacco, alcohol, and HPV (CDC, 2018).

There is no treatment for the virus itself. HPV management consists of screening, monitoring, and, if medically feasible, the removal of warts, lesions, or cancerous tissue via chemical or surgical procedures. Currently, there is no cure for HPV; however, protection with vaccination is now readily available in the United States. Gardasil 9 (9vHPV, Merck) is the only HPV vaccine being distributed in the U.S. to prevent certain types of HPV infection. Bivalent Cervarix (2vHPV, GlaxoSmithKline) and quadrivalent Gardasil (4vHPV, Merck) are no longer being distributed in the United States. Gardasil 9 offers protection against seven oncogenic (cancer-causing) HPV types (16, 18, 31, 33, 45, 52, and 58) and two HPV types that cause most genital warts (6 and 11) (Immunization Action Coalition, 2019).

Most cervical cancers are squamous cell carcinomas (Castellsague et al., 2006). Although the incidence of cervical squamous cell carcinomas has decreased, that of cervical adenocarcinoma has increased in recent years. The extent to which HPV infection and co-factors may explain this differential trend is unclear. Castellsague et al. (2006) found that HPV16 and HPV18 were the two most commonly detected HPV types in patients with invasive cervical adenocarcinoma and control subjects. These two HPV types were present in 82% of the patients. Co-factors that showed clear statistically significant positive associations with cervical adenocarcinoma overall and among HPV-positive women included never schooling, poor hygiene, sexual behavior-related variables, long-term use of hormonal contraception, high parity, as well as herpes simplex virus-2 sero-positivity. Human papillomavirus appears to be the principal risk factor for cervical adenocarcinoma. Although cervical cancer screening has lowered the incidence of and mortality from invasive cervical cancer, it is not completely protective. Vaccination against main HPV types should reduce the incidence of cervical cancer.

The Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination of females aged 11 or 12 with three doses of either HPV2 or HPV4. The vaccination series can be started beginning at age nine years. Both vaccines might provide protection against some other HPV-related cancers in addition to cervical cancer, although there are currently only data sufficient to recommend HPV4 for protection against vulvar and vaginal cancers and precancers. HPV4 is recommended for the prevention of genital warts.

Mathematical modeling suggests that adding male HPV vaccination to a female-only HPV vaccination program is not the most cost-effective vaccination strategy for reducing the overall burden of HPV-associated conditions in males and females when vaccination coverage of females is high (>80%).

According to NCCN, both the bivalent and quadrivalent vaccines are recommended in women for the prevention of cervical cancer. Although HPV 16 and 18 are responsible for an estimated 70% of cervical cancer, vaccinated women are still at risk for cervical cancer related to less common types of oncogenic HPV. Both HPV vaccines offer cross-protection against non-HPV vaccine types that also cause cervical cancer. However, HPV vaccination does not alter screening recommendations. Vaccinated women should continue cervical cancer screening according to the guidelines.

In a randomized, double-blind, placebo-controlled, phase II clinical trial, Villa and associates (2005) evaluated the effectiveness of a prophylactic quadrivalent vaccine targeting the HPV types associated with 70% of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11). A total of 277 young women (mean age of 20.2 years) were randomly assigned to the quadrivalent HPV (20 µg type 6, 40 µg type 11, 40 µg type 16, and 20 µg type 18) L1 virus-like particle (VLP) vaccine, and 275 young women (mean age of 20.0 years) to one of two placebo preparations at day 1, month 2, and month 6. For 36 months, subjects underwent regular gynecological examinations, cervico-vaginal sampling for HPV DNA, testing for serum antibodies to HPV, and Pap testing. The primary endpoint was the combined incidence of infection with HPV type 6, 11, 16, or 18, or cervical or external genital disease (namely, persistent HPV infection, HPV detection at the last recorded visit, cervical intraepithelial neoplasia [CIN], cervical cancer, or external genital lesions caused by the HPV types in the vaccine). Main analyses were done per protocol. The combined incidence of persistent infection or disease with HPV type 6, 11, 16, or 18 fell by 90% (95% confidence interval [CI]: 71 to 97%, p < 0.0001) in those assigned to the vaccine compared with those assigned to placebo. These investigators concluded that a vaccine targeting HPV types 6, 11, 16, and 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types. This is in agreement with the findings of Harper and colleagues (2004), who reported that the bivalent HPV16/HPV18 L1 VLP vaccine was effective in preventing incident and persistent cervical infections with HPV16 and HPV18, as well as associated cytological abnormalities and lesions (n = 1,113), and that of Koutsky and co-workers (2002), who reported that administration of the HPV16 vaccine reduced the incidence of both HPV16 infection and HPV16-related CIN (n = 2,392).

Mao and colleagues (2006) noted that HPV VLP vaccines have demonstrated effectiveness in preventing persistent HPV infections. Whether protection lasts longer than 18 months and, thus, impacts rates of CIN 2-3, has not yet been established. In a randomized, double-blind, placebo-controlled study, these investigators presented results from an HPV16 L1 VLP vaccine trial through 48 months. A total of 2,391 women, aged 16 to 23 years, participated in this trial. Either 40 µg HPV16 L1 VLP vaccine or placebo was administered intramuscularly at day 1, month 2, and month 6. Genital samples for HPV16 DNA and Pap tests were obtained at day 1, month 7, and then every six months through month 48. Colposcopy and cervical biopsies were performed if clinically indicated and at study exit. Serum HPV16 antibody titer was measured by radioimmunoassay. Among 750 placebo recipients in the per-protocol population, 12 women developed HPV16-related CIN 2-3 (6 CIN2 and 6 CIN3). Among 755 vaccinated subjects, there were no cases (vaccine efficacy 100%, 95% CI: 65 to 100%). There were 111 cases of persistent HPV16 infection in placebo recipients and 7 cases in vaccinated subjects (vaccine efficacy 94%, 95% CI: 88 to 98%). After immunization, HPV16 serum antibody geometric mean titers peaked at month 7 (1,519 milli-Merck units [mMU]/ml), declined through month 18 (202 mMU/ml), and remained relatively stable between month 30 and month 48 (128 to 150 mMU/ml). These researchers concluded that the HPV16 L1 VLP vaccine provides high-level protection against persistent HPV16 infection and HPV16-related CIN 2-3 for at least 3.5 years after immunization. Administration of L1 VLP vaccines targeting HPV16 is likely to reduce the risk for cervical cancer.

Saslow and colleagues (2020) noted that the American Cancer Society (ACS) presents an adaptation of the current ACIP recommendations for HPV vaccination. The ACS recommends routine HPV vaccination between ages 9 and 12 years to achieve higher on-time vaccination rates, which will lead to increased numbers of cancers prevented. Health care providers are encouraged to start offering the HPV vaccine series at age 9 or 10 years. Catch-up HPV vaccination is recommended for all persons through age 26 years who are not adequately vaccinated. Providers should inform individuals aged 22 to 26 years who have not been previously vaccinated or who have not completed the series that vaccination at older ages is less effective in lowering cancer risk. Catch-up HPV vaccination is not recommended for adults older than 26 years. The ACS does not endorse the 2019 ACIP recommendation for shared clinical decision-making for some adults aged 27 through 45 years who are not adequately vaccinated because of the low effectiveness and low cancer prevention potential of vaccination in this age group, the burden of decision-making on patients and clinicians, and the lack of sufficient guidance on the selection of individuals who might benefit.

The ACOG Committee Opinion on “Human Papillomavirus Vaccination” (2020) stated that HPV causes significant morbidity and mortality in women and men. The HPV vaccine significantly reduces the incidence of anogenital cancer and genital warts in both women and men. Human papillomavirus vaccines are among the most effective vaccines available worldwide, with unequivocal data demonstrating greater than 99% efficacy when administered to women who have not been exposed to that particular type of HPV. Obstetrician-gynecologists and other health care professionals should strongly recommend HPV vaccination to eligible patients and stress the benefits and safety of the HPV vaccine. Furthermore, obstetrician-gynecologists are encouraged to stock and administer HPV vaccines in their offices when feasible. Ideally, the HPV vaccine should be given in early adolescence because vaccination is most effective before exposure to HPV through sexual activity. Unvaccinated women aged 26 years and younger should receive the HPV vaccine series regardless of sexual activity, prior exposure to HPV, or sexual orientation. The HPV vaccine is now licensed in the U.S. for women and men through the age of 45 years. For some women aged 27 to 45 years who are previously unvaccinated, obstetrician-gynecologists and other health care professionals may use shared clinical decision-making regarding HPV vaccination, considering the patient's risk for acquisition of a new HPV infection and whether the HPV vaccine may provide benefit.

Cervarix

Cervarix (human papillomavirus bivalent [types 16 and 18] vaccine, recombinant) was a noninfectious, AS04-adjuvanted vaccine developed to prevent infection with oncogenic HPV types 16 and 18, which account for approximately 70% to 75% of cervical cancers. The vaccine contained recombinant L1 virus-like particles and induced neutralizing antibodies directed against HPV capsid proteins. On October 16, 2009, the U.S. Food and Drug Administration (FDA) approved Cervarix for use in females aged 9 through 25 years for the prevention of cervical cancer, cervical intraepithelial neoplasia (CIN), and adenocarcinoma in situ associated with HPV types 16 and 18.

FDA approval was based on clinical trials involving nearly 30,000 girls and young women. In these studies, Cervarix demonstrated 93% efficacy in preventing cervical precancerous lesions associated with HPV types 16 and 18 among women without prior exposure to those HPV types. Cervarix was intended as a prophylactic vaccine and was not indicated for treatment of existing HPV infection or HPV-related disease. Cervarix has since been withdrawn from the U.S. market, all available doses have expired, and the vaccine is no longer included in the Advisory Committee on Immunization Practices (ACIP) immunization schedule.

Gardasil

Gardasil (quadrivalent human papillomavirus [HPV] recombinant vaccine) was developed to prevent infection with HPV types 6, 11, 16, and 18. HPV types 16 and 18 are responsible for approximately 70% of cervical cancers, whereas HPV types 6 and 11 cause approximately 90% of genital warts. The vaccine was initially approved by the U.S. Food and Drug Administration (FDA) for females aged 9 to 26 years for the prevention of cervical, vulvar, vaginal, and anal cancers and associated precancerous lesions caused by vaccine HPV types, as well as genital warts. Subsequent FDA approvals expanded indications to include males aged 9 to 26 years for the prevention of genital warts, anal cancer, and associated anal intraepithelial neoplasia related to HPV types included in the vaccine. Gardasil was administered as a three-dose intramuscular series over six months and was intended as a prophylactic vaccine, providing the greatest benefit when given before exposure to HPV. Vaccination does not eliminate the need for routine cervical cancer screening and does not protect against HPV types not contained in the vaccine (CDC/ACIP, 2007; CDC/ACIP, 2011).

FDA approval was supported by phase II and phase III randomized controlled trials involving more than 20,000 women aged 16 to 26 years, which demonstrated high efficacy in preventing HPV type-specific cervical, vulvar, vaginal, and anal precancerous lesions and genital warts among individuals not previously exposed to the relevant HPV types. In pivotal studies, Gardasil was highly effective in preventing cervical intraepithelial neoplasia, adenocarcinoma in situ, vulvar intraepithelial neoplasia, vaginal intraepithelial neoplasia, and genital warts associated with HPV types 6, 11, 16, and 18 (Garland et al., 2007; Joura et al., 2007). Studies in males demonstrated efficacy in preventing genital warts and HPV-associated anal intraepithelial neoplasia, supporting later indication expansions (FDA, 2009; FDA, 2010). Importantly, evidence indicates that HPV vaccination does not accelerate clearance of existing HPV infections or treat established HPV-related disease, reinforcing its role as a preventive rather than therapeutic intervention (Hildesheim et al., 2007). The quadrivalent vaccine was subsequently replaced in the United States by the 9-valent HPV vaccine (Gardasil 9), and Gardasil-4 is no longer available for use in the U.S. (Markowitz et al., 2018).

Gardasil 9

Gardasil 9 (human papillomavirus 9-valent vaccine, recombinant) is a prophylactic vaccine, by Merck Sharp & Dohme, designed to prevent infection and disease caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. On December 10, 2014, the U.S. Food and Drug Administration (FDA) approved Gardasil 9 for use in females aged 9 through 26 years and males aged 9 through 15 years. Compared with the previously licensed quadrivalent HPV vaccine, Gardasil 9 provides protection against five additional oncogenic HPV types (31, 33, 45, 52, and 58), extending coverage to HPV types associated with approximately 90% of cervical, vulvar, vaginal, and anal cancers. At the time of approval, indications included prevention of cervical, vulvar, vaginal, and anal cancers caused by HPV types 16, 18, 31, 33, 45, 52, and 58, as well as genital warts caused by HPV types 6 and 11 (FDA, 2014).

FDA approval was supported by a randomized controlled clinical trial involving approximately 14,000 females aged 16 through 26 years who were HPV DNA-negative for vaccine types at enrollment. Gardasil 9 demonstrated 97% efficacy in preventing high-grade cervical, vulvar, and vaginal disease associated with the five additional HPV types not included in the quadrivalent vaccine. Immunogenicity studies also demonstrated antibody responses comparable to those observed with quadrivalent Gardasil for HPV types 6, 11, 16, and 18, supporting similar effectiveness against diseases caused by those HPV types. Additional immunogenicity studies in approximately 4,000 males and females aged 9 through 15 years demonstrated immune responses comparable to those observed in females aged 16 through 26 years, supporting use in younger adolescents (FDA, 2014).

Gardasil 9 is administered intramuscularly and was initially approved as a three-dose series administered at 0, 2, and 6 months. Consistent with other HPV vaccines, the greatest benefit is achieved when vaccination occurs before exposure to vaccine HPV types. In 2015, the Advisory Committee on Immunization Practices (ACIP) recommended Gardasil 9 as an option for routine HPV vaccination of adolescents aged 11 to 12 years and for catch-up vaccination of eligible individuals who had not completed the vaccination series. ACIP further stated that Gardasil 9 may be used to continue or complete a vaccination series initiated with another HPV vaccine product (Petrosky et al., 2015). In 2016, ACIP updated its recommendations to include a 2-dose schedule for immunocompetent adolescents who initiate vaccination between ages 9 and 14 years, administered 6 to 12 months apart, while individuals initiating vaccination at age 15 years or older continue to require a 3-dose series (Meites et al., 2016).

In October 2018, the FDA approved an age expansion for the Gardasil 9 vaccine to include women and men aged 27 through 45 years. FDA approval for the expanded age range was based on data from a clinical trial evaluating Gardasil (quadrivalent) in 3,253 women ages 27 through 45 years who were randomized 1:1 to receive either Gardasil or placebo, with a median follow-up of 3.5 years post-dose 3. Gardasil was found to be 87.7% (95% CI: 75.4%, 94.6%) effective in the prevention of a combined endpoint of persistent infection, genital warts, vulvar and vaginal precancerous lesions, cervical precancerous lesions, and cervical cancer related to HPV types covered by the vaccine. In the long-term extension of that study, subjects from Colombia (n=600) randomized to the Gardasil group were monitored for HPV 6-, 11-, 16-, and 18-related genital warts or cervical dysplasia. The median follow-up post-dose 3 was 8.9 years. During the long-term extension phase, no cases of HPV 6-, 11-, 16-, or 18-related CIN (any grade) or genital warts were observed in the per-protocol efficacy (PPE) population (FDA, 2018; Luna, 2013; Merck, 2018).

The effectiveness of Gardasil 9 in men aged 27 through 45 years is inferred from the data described in the Gardasil trial with women aged 27 through 45 years, as well as efficacy data from Gardasil in younger men (16 through 26 years of age) and immunogenicity data from a clinical trial in which 150 men aged 27 through 45 years received a 3-dose regimen of Gardasil over 6 months (FDA, 2018). Per the FDA, since Gardasil-4 and Gardasil-9 are manufactured similarly, the effectiveness of Gardasil in these patient populations is relevant to Gardasil-9, which covers the same four HPV types (6, 11, 16, 18) plus an additional five HPV types (31, 33, 45, 52, and 58).

At a June 2019 CDC Advisory Committee for Immunization Practices (ACIP) meeting, ACIP members reviewed the available data and voted to recommend that persons aged 27 through 45 years engage in shared decision-making when considering the 9-valent HPV vaccine. Although the public health benefit of HPV vaccination in this age range is minimal, shared clinical decision-making is recommended because some persons who are not adequately vaccinated might benefit. In addition, the committee voted to recommend "catch-up" vaccination for males through age 26 years who are not adequately vaccinated. The previous recommendation was through age 21 years (Meites et al., 2019).

Vaccination in Individuals Over 26 Years of Age

The Centers for Disease Control and Prevention (CDC) website (2024) states, "Vaccination is not recommended for everyone older than age 26 years. Some adults ages 27 through 45 years might decide to get the HPV vaccine based on discussion with their clinician, if they did not get adequately vaccinated when they were younger. HPV vaccination of people in this age range provides less benefit, for several reasons, including that more people in this age range have already been exposed to HPV. For adults ages 27 through 45 years, clinicians can consider discussing HPV vaccination with people who are most likely to benefit."

Efficacy and Immunogenicity of a Single-Dose of HPV Vaccine Compared to Multi-Dose Vaccination Regimens or No Vaccination

Markowitz and colleagues (2018) conducted a systematic literature review of HPV vaccine effectiveness by number of doses, including assessment of biases and impact of varying buffer periods (time between vaccination and outcome counting). Of 3,787 articles identified, 26 full articles were assessed and 14 included in this review. All studies were conducted within the context of recommended 3-dose schedules of bivalent (3 studies) or quadrivalent HPV vaccine (11 studies); 2 studies evaluated effectiveness for prevention of HPV prevalence, 6 anogenital warts, and 6 abnormal cervical cytology or histology. Many studies found differences between 3-, 2- and 1-dose vaccine recipients, indicating possible differences in HPV exposure prior to vaccination or in risk behavior. Adjusted or stratified analyses were conducted to control for potential confounding. All studies found significant vaccine effectiveness with 3 doses, 11 studies with 2 doses at various intervals, and 6 studies with 1 dose. Most studies showed a relationship (not always statistically significant) between effectiveness and number of doses, with greater decreases in HPV-related outcomes with t3, followed by 2 and 1 dose(s). Few studies conducted formal comparisons of 3 versus fewer doses; 3 of 4 studies that examined buffer periods found higher effectiveness and a smaller difference by number of doses with longer periods. The authors concluded that most post-licensure studies reported highest effectiveness with 3 doses; some found no statistically significant difference between 2 and 3 doses. Additionally, almost 50% found some effectiveness with 1 dose. These researchers noted that several biases impacted estimates, with most biasing 2- and 1-dose results away from showing effectiveness. They stated that future effectiveness studies, examining persons vaccinated prior to sexual activity and using methods to reduce potential sources of bias, can help inform vaccination policy.

In a systematic review, Whitworth et al. (2024) examined the available evidence on the effectiveness and immunogenicity of single-dose HPV vaccination compared to multi-dose schedules or no HPV vaccination. These investigators searched 4 databases for relevant studies published from January 1999 to February 2023. Articles were examined for eligibility for inclusion using pre-defined criteria. Relevant data were extracted from eligible studies and a descriptive quality assessment was carried out for each study. A narrative data synthesis was performed, examining HPV infection, other clinical outcomes and immunogenicity responses by dose schedule. A total of 15 articles reporting data from 6 studies (all in healthy young females) were included. One article was included from each of 3 studies that prospectively randomized subjects to receive a single HPV vaccine dose versus 1 or more comparator schedule(s). The other 12 articles reported data from 3 studies that randomized subjects to receive multi-dose HPV vaccine (or control vaccine) schedules; in those studies, some subjects failed to complete their allocated schedule, and evaluations were carried out to compare subjects who actually received 1, 2, or 3 doses. Across all effectiveness studies, the incidence or prevalence of HPV16/18 infection was very low among HPV-vaccinated subjects, regardless of the number of doses received; with no evidence for a difference between dose groups. In immunogenicity studies, HPV16/18 antibody sero-positivity rates were high among all HPV-vaccinated subjects. Antibody levels were significantly lower with 1 dose compared to 2 or 3 doses; however, levels with 1 dose were stable and sustained to 11 years post-vaccination. The authors concluded that findings from this review supported recent World Health Organization (WHO) recommendations allowing either 1- or 2-dose HPV vaccination in healthy young females. Moreover, these investigators stated that longer-term effectiveness and immunogenicity data from ongoing studies are awaited. Randomized trials of single-dose HPV-vaccination are needed in other populations, e.g., boys, older, as well as individuals with HIV.

Prevention of Recurrence / Treatment of Anogenital Warts

Husein-ElAhmed (2020) noted that HPV is the most prevalent sexually transmitted infection worldwide, and anogenital warts (AGWs) are highly infectious. This virus is transmitted through sexual, anal, or oral contact, as well as skin-to-skin contact. Treatment for this condition has significant morbidity, and it can be frustrating in certain cases. The HPV vaccination has been demonstrated as a promising strategy for secondary prevention in HPV-related diseases such as head and neck cancers, cervical diseases, and recurrent respiratory papillomatosis. Regarding AGWs, it is unclear whether vaccination can provide analogous clinical benefit. These investigators reviewed the literature regarding HPV vaccination for secondary disease prevention after treatment of AGWs. From October to December 2018, a systematic search for clinical trials was carried out in five databases: PubMed, Medline, Embase, Cochrane, and clinicaltrials.gov, using a combination of the following descriptors: “gardasil” OR “cervarix” OR “nine-valent” OR “9-valent” OR “vaccine” AND “recurrence” OR “relapse” AND “hpv” OR “papillomavirus” AND “warts” OR “condyloma.” Data were synthesized and entered into the Review Manager software (RevMan 5.3.5) to perform the meta-analysis. The search yielded 824 potentially relevant studies; two studies fulfilled the eligibility criteria involving 656 subjects. The meta-analysis estimated that the rate of recurrence of AGWs was similar between the vaccine group and the control group. The overall effect estimate was 1.02 (0.75 to 1.38). This was the first meta-analysis examining the effect of the HPV vaccine in preventing the relapse of AGWs. The authors concluded that these findings suggested that HPV vaccination did not provide secondary benefit in patients with previous AGWs. However, these results cannot be generalized due to the scarce number of RCTs currently available in the literature. Outcomes from future RCTs are needed to further clarify the precise effect of the vaccine.

Villemure and Wilby (2024) noted that AGWs caused by HPV are a common manifestation of HPV infection. Treatment strategies usually entail topical therapies to promote wart regression or removal through surgical or other means. These strategies are effective but are associated with high rates of recurrence. HPV vaccines are known to be effective for the prevention of AGWs; however, preliminary data suggested they may offer therapeutic benefit for regression of active AGWs. In a systematic review, these researchers examined the effectiveness of HPV vaccines for the treatment of active AGWs. They carried out a systematic search of PubMed, Embase, and the Cochrane Database of Systematic Reviews in July 2023, with no limits on the date of publication. The search was supplemented with a manual review of references from identified articles and pertinent review articles. Articles were included if they reported at least one patient with active AGWs who received at least one dose of any HPV vaccine. The primary outcome of interest was complete or partial regression of AGWs over any time period. The risk of bias was assessed for each study meeting inclusion criteria. A total of seven articles—one RCT, one non-RCT, three case series, and two case reports—were included. All seven studies were deemed to have a high risk of bias. Study results showed evidence that HPV vaccines may offer therapeutic benefits to those with active AGWs. Studies reported outcomes for both intralesional and systemically administered vaccines. Outcomes reported improvement according to both partial and complete regression of AGWs. The authors concluded that this systematic review found evidence that HPV vaccines may have a role in the treatment of active AGWs. Findings supported the notion that the vaccine should be offered to previously unvaccinated patients, but the role of intralesional administration of the vaccine to vaccinated patients is still unclear.

Treatment of Anal Squamous Cell Carcinoma and High-Grade Anal Dysplasia

Nichols et al. (2018) noted that squamous cell carcinoma (SCC) is the second most common form of skin cancer, and its incidence is rising. When surgery is not an option, finding a safe and effective treatment is a challenge. Mounting evidence suggests that HPV is involved in the pathogenesis of some SCCs. These researchers examined whether the 9-valent HPV vaccine could be an effective treatment strategy for cutaneous SCC. A woman in her 90s with multiple, inoperable cutaneous basaloid SCCs was successfully treated at a university-based outpatient dermatology clinic with a combination of systemic and intra-tumoral delivery of the 9-valent HPV vaccine from March 17, 2016, through February 27, 2017, and then followed up through May 21, 2018. Main outcomes and measures included reduction in tumor size and number after a combination of systemic and intra-tumoral administration of the HPV vaccine. All tumors resolved 11 months after the first intra-tumoral injection of the vaccine, and the subject remained tumor-free at the end of follow-up. The authors concluded that, to their knowledge, this was the first report of complete regression of a cutaneous malignant tumor following combined systemic and direct intra-tumoral injection of the 9-valent HPV vaccine. They stated that the findings of this study suggested that the HPV vaccine may have therapeutic utility for SCCs in patients who are poor surgical candidates, have multiple lesions, or defer surgery.

Pham et al. (2020) stated that HPV infections are associated with common dermatologic and non-dermatologic diseases. Although HPV vaccines are well established as preventive measures for genital warts and cervical neoplasia, their use as therapeutic agents deserves greater attention. These researchers examined the use of HPV vaccine(s) as a treatment modality for cutaneous and/or mucosal disease. They carried out a primary literature search using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in January 2019 by using the PubMed and Cochrane databases. A total of 63 articles with 4,439 patients were included. The majority of patients with cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas were successfully treated with HPV vaccination. Preliminary data on patients with pre-existing anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia are promising. The authors concluded that the commercially available 3-dose quadrivalent HPV vaccine is a potential therapeutic option for the treatment of cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas. Non-commercially available HPV vaccines demonstrate therapeutic response for treating anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia. Moreover, these investigators stated that the vaccine's effectiveness as an adjunct therapy for HPV-associated cutaneous and/or mucosal disease warrants further investigation. The authors noted that this review was limited by the lack of controls, patients' previous HPV vaccination status, as well as publication bias.

Treatment of Head and Neck Cancer

In a systematic review, Schneider and colleagues (2018) provided an overview of the current clinical trials examining therapeutic vaccines for HPV-positive head and neck cancer (HNC) and discussed the future directions of therapeutic vaccine therapy. A systematic search was conducted in PubMed, Embase, Cochrane, and clinicaltrials.gov for clinical trials involving therapeutic vaccines. These investigators included studies initiated between 2000 and 2018 with patients diagnosed with HPV-positive HNC and extracted data concerning the type of vaccine therapy, adverse events (AEs), immunogenicity, and clinical outcome measures (e.g., tumor response, progression-free survival [PFS], and overall survival [OS]). They identified 11 studies (n = 376 patients) initiated between the years 2005 and 2017; four studies (n = 34) presented preliminary results in patients with incurable, recurrent loco-regional, or distant metastatic disease, indicating a positive immune response with 74% (n = 25/34 patients) having elevated antibody levels, IFN-γ, and/or T-cell response. Five studies presented data on the vaccines' safety profile, demonstrating predominantly grade 1 and 2 toxicity. Three studies evaluated the clinical outcome: one study showed no complete response (CR) or partial response (PR), one study demonstrated stable disease (SD) as the best tumor response in 64% (n = 9/14 patients), and one study showed a 33% overall response rate (ORR), with one patient achieving a CR and seven patients achieving a PR. The authors concluded that treatment with therapeutic vaccines is a promising and seemingly safe strategy for patients with HPV-positive HNC. However, there are inadequate data to draw any further conclusions, and clinical outcome measures and tumor responses to the vaccines are still missing.

On June 12, 2020, the FDA approved an expanded indication for Gardasil 9 for the prevention of oropharyngeal and other head and neck cancers caused by HPV types 16, 18, 31, 33, 45, 52, and 58. The oropharyngeal and head and neck cancer indication is approved under accelerated approval based on effectiveness in preventing HPV-related anogenital disease. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial, which is currently underway.

Treatment of Vulval and Vaginal Intraepithelial Neoplasia

Bryan and colleagues (2019) stated that HPV DNA is found in almost 80% of vulval and vaginal intraepithelial neoplasia (VIN/VaIN). Current management is inadequate, with high recurrence rates. In a systematic review, these researchers evaluated the literature regarding the role of HPV vaccine in secondary prevention and treatment of VIN/VaIN. Database searches included Ovid Medline, Embase, Web of Science, the Cochrane Library and Clinicaltrials.gov. Search terms included HPV vaccine AND therapeutic vaccine and VIN or VAIN, published in English with no defined date limit. Searches were performed with a UCL librarian in March 2018. These investigators included any type of study design using any form of HPV vaccine in the treatment of women with a histologically confirmed diagnosis of VIN/VaIN. They excluded studies of other lower genital tract disease, vulval/vaginal carcinoma and prophylactic use of vaccines. The outcome measures were lesion response to vaccination, symptom improvement, immune response and HPV clearance. These researchers identified 93 articles, 7 studies met the inclusion criteria; these were uncontrolled case series. There were no randomized controlled trials (RCTs) or systematic reviews identified. Reduction in lesion size was reported by all 7 studies, symptom relief by 5, HPV clearance by 6, histological regression by 5, and immune response by 6. The authors concluded that this review found the evidence relating to the use of HPV vaccine in the treatment of women with VIN/VaIN was of very low quality and insufficient to guide practice. These researchers stated that more studies are needed to examine clinically important patient outcomes (symptoms, non-progression and recurrence rates) with the use of HPV vaccine in a therapeutic setting. Furthermore, it would be prudent to examine its use in secondary prevention of cancer, which would need to be assessed through further longitudinal studies. These investigators stated that the limitations of this study included the following: none of the studies directly compared a control group with HPV vaccination, all studies found were uncontrolled case series, with short-term follow-up for what is a chronic, long-term disease.

Post-Treatment HPV Vaccination for Women Undergoing Excisional Treatment for Cervical Intraepithelial Neoplasia (CIN)

In a systematic review and meta-analysis, Eriksen et al. (2022) examined whether HPV vaccination administered after excisional treatment of cervical intraepithelial neoplasia (CIN) is associated with a reduced risk of recurrence of CIN grade 2 or worse (CIN2+). These investigators carried out a systematic literature search in three online databases through June 2021. Observational studies and randomized controlled trials (RCTs) were eligible for inclusion if the prophylactic HPV vaccine was administered after excisional treatment for histologically verified CIN. Only English language literature was included. The primary outcome measure was the recurrence of CIN2+ after treatment. A meta-analysis was carried out using fixed and random-effects models, and results were reported as pooled odds ratios (OR) with 95% confidence intervals (CI). Quality assessment was performed using the ROB2 tool for RCTs and ROBINS-I for observational studies. A total of 1,561 studies were identified, of which nine, including 19,971 women, were included; two studies were RCTs and seven were observational studies. Using the fixed-effect model on the two RCTs, the OR for recurrence of CIN2+ was 0.29 (95% CI: 0.16 to 0.53). Due to considerable heterogeneity in observational studies, the random-effects model was used to estimate the pooled OR for CIN2+ recurrence in these studies. Therefore, using unadjusted data from observational studies, the OR for CIN2+ recurrence was 0.35 (95% CI: 0.18 to 0.67), whereas when using adjusted data, the OR for CIN2+ recurrence was 0.54 (95% CI: 0.21 to 1.35). However, quality assessment revealed a serious risk of bias for the majority of the studies included. The authors concluded that HPV vaccination post-treatment was associated with a significantly reduced risk of CIN2+ recurrence when using unadjusted estimates from observational studies and RCTs. These researchers found no significant effect of HPV vaccination on the risk of CIN2+ recurrence when using the outcome measure from observational studies with the least risk of bias. They stated that large, well-designed randomized, placebo-controlled trials with sufficient power and follow-up time are needed to examine whether post-treatment HPV vaccination should be recommended to all women undergoing excisional treatment for CIN.

The authors stated that the review had several drawbacks. First, these researchers observed substantial heterogeneity between studies with regard to outcome, inclusion and exclusion criteria, as well as confounders. They were unable to perform a meta-analysis by margin status, vaccine type, number of vaccine doses administered, or HPV genotype due to limited or missing information on these variables. Second, considerable indirectness of evidence must be emphasized due to the lack of adjustment for confounders in the studies included. Third, a small number of studies were included, and only two were RCTs; these two trials had different inclusion criteria, thus questioning the pooling of the ORs. Therefore, these findings may be subject to an overestimation of the effect of HPV vaccination post-treatment.

The American Society for Colposcopy and Cervical Pathology (ASCCP) recommends adherence to current CDC recommendations for vaccination of individuals aged 9 to 26 years and consideration of the possible benefit of adjuvant HPV vaccination during shared decision making for previously unvaccinated individuals aged 27 to 45 years who are undergoing treatment for CIN2+ (Sharpless et al., 2023).

The American College of Obstetricians and Gynecologists (ACOG, 2023) recommends adherence to the current Centers for Disease Control and Prevention (CDC) recommendations for vaccinations of individuals aged 9-26 years, and to consider adjuvant HPV vaccination for immunocompetent previously unvaccinated people aged 27 through 45 years who are undergoing treatment for CIN 2+. This recommendation is in alignment with guidance developed by the ASCCP.

Caia et al. (2025) conducted a prospective study evaluating the effect of adjuvant HPV vaccination following conization for high-grade cervical dysplasia in 281 women, including 168 who underwent conization alone and 113 who received conization plus HPV vaccination. During a median follow-up of approximately 25 to 28 months, the incidence of subsequent HPV-related lesions and the need for repeat conization did not differ significantly between vaccinated and unvaccinated patients. On multivariate analysis, adjuvant HPV vaccination was not associated with a statistically significant reduction in the risk of recurrent HPV-related lesions (HR 0.50; 95% CI: 0.15–1.68) or repeat conization (HR 0.90; 95% CI: 0.47-1.73). The authors concluded that adjuvant HPV vaccination did not significantly improve short-term postoperative outcomes in women undergoing conization for cervical dysplasia, highlighting the need for ongoing randomized controlled trials to better define the role of vaccination as an adjunctive intervention in this setting.

Use as Adjuvant Therapy for Juvenile-Onset Recurrent Respiratory Papillomatosis

Park et al. (20220 stated that juvenile-onset recurrent respiratory papillomatosis (JoRRP) is considered a rare disease with high morbidity and healthcare costs. The management of RRP has received much scientific attention in recent years and several treatment methodologies have been investigated, including therapeutic use of HPV vaccine. There has been increasing interest in the off-label use of the vaccine in virus-induced disease processes such as RRP, due to its immunomodulatory effect and activating role on the innate and adaptive immune system. In a systematic review, these investigators examined the effectiveness of the HPV vaccination as a therapeutic tool in the pediatric population. The review of the English literature included 3 electronic databases, PubMed, SCOPUS, and Cochrane, without publication date restrictions. Studies and reports identified by the database search were reviewed and assessed by 2 independent reviewers. The literature searches identified 768 unique citations, from which 204 duplicates were removed (n = 564). A total of 547 studies were excluded as they did not meet our inclusion criteria. A total of 12 studies (3 experimental studies, 3 case series, 6 case reports) that met the inclusion criteria and reported 1 or more of the outcomes of interest were included for this review. The assessment of the outcome measures evaluated (number of surgeries during the follow-up period, inter-surgical interval (ISI), surgeries per month (SPM), Derkay or severity scores, and remission status) revealed that 8 out of 12 studies included in the review showed varying degrees of potential benefits from the administration of the vaccine as a treatment modality compared to surgical interventions and/or concurrent adjuvant therapies alone. The authors concluded that while the therapeutic use of HPV vaccination has shown promise for some JoRRP patients; however, it overall remains uncertain with the currently available data. These researchers stated that there is a need for a prospective, multi-center study with a larger sample size to fully characterize the potential use of the vaccine in the management of JoRRP.

---

References