What are the most recent updates from the Advisory Committee on Immunizations Practices regarding HPV vaccination?

Background

Human papillomaviruses (HPVs) represent over 100 viruses infecting human epithelial cells, and about 40 of these viruses infect the genital area.1 Genital HPVs are divided into 2 categories: low-risk and high-risk. Low-risk HPVs may cause genital warts, while high-risk HPVs may lead to cervical intraepithelial lesions and anogenital cancers. Human papillomavirus genotypes 6 and 11 cause about 90% of genital warts cases. Human papillomavirus infection, mainly from HPV genotype 16 and HPV genotype 18, is the key cause of cervical cancer.1,2 Vaginal, vulvar, penile, anal, and oropharyngeal are other cancers caused by HPV infections.2,3 Contact with mucosa or genital skin is the primary mode of HPV transmission.1 Typically, viral particles enter the basal layer of epithelium through small tears in mucosa, which leads to infection.4 Genital warts possess high viral load, and thus, are highly infectious.1 The risk factors for acquiring HPV consist of genital contact, higher number of sex partners, resistance to or inconsistent condom use, and/or a history of sexually transmitted infections.

Human papillomaviruses may cause a variety of cancers, and vaccination against HPVs is the key to the prevention of these cancers. According to data for the year 2019, new cancer cases are estimated to be 53,000 for oropharyngeal cancer, 13,170 for cervical cancer, 8,300 for anal cancer, and 6,070 for vulvar cancer.5  Human papillomaviruses are responsible for 91% of cervical cancers, 91% of anal cancers, 75% of vaginal cancers, 70% of oropharyngeal cancers, and 69% of vulvar cancers.6 The estimates predict that 80% of people will get an HPV infection.7 Vaccination against HPV may prevent up to 90% of cancers caused by HPV.3

Currently, 2 HPV vaccinations are marketed in the United States: Gardasil® and Gardasil® 9.8  Gardasil® prevents cancers, genital warts, and precancerous or dysplastic lesions caused by 4 HPV genotypes: 6, 11, 16, and 18.9 Girls, boy, women, and men who are 9 through 26 years of age are candidates for this vaccine based on the prescribing information. Gardasil® 9 prevents cancers, genital warts, and precancerous or dysplastic lesions caused by 9 HPV genotypes: 6, 11, 16, 18, 31, 33, 45, 52, and 58.10 Prescribers may administer this formulation to girls, boys, women, and men who are 9 through 45 years of age according to the prescribing information. Gardasil® and Gardasil®9 both protect against HPV 16 and 18, which cause about 66% of cervical cancers.11 Gardasil®9 protects against the additional 5 genotypes of HPV, which may lead to 15% of cervical cancers. Both vaccines protect against HPV 6 and 11, the genotypes responsible for most genital warts.9,10 Compared to Gardasil®, Gardasil®9 protects against additional cases of cervical cancer, and thus, benefits mainly women but not men. The same manufacturer produces both HPV vaccine formulations.

Recommendations

The Advisory Committee on Immunizations Practices (ACIP) releases recommendations regarding HPV vaccination, which are frequently reviewed and updated based on the available evidence (Table).7 The ACIP recommends starting HPV vaccination in adolescents aged 11 to 12 years, because the greatest benefit of the vaccine is observed in those who have not been exposed to HPV.  Providers may use any HPV vaccine formulation to complete the full series with the same recommended schedule and dosing intervals in all age groups. Vaccination should be avoided during pregnancy but may be given to women who are breastfeeding/lactating.8

Table. Recommendations from ACIP on HPV vaccination.7,8,12
Age group (years)Recommended scheduleComments
9 to 142 dose schedule: 2 doses separated by 6 to 12 monthsSame immunoprotection in this age group as with 3-dose schedule in older adolescents and young adults; may use 2-dose schedule if the first dose given before the 15th birthday
15 to 263 dose schedule: At 0, 1 to 2, and 6 monthsNo need to repeat vaccines if schedule is interrupted
27 to 45*3 dose schedule: At 0, 1 to 2, and 6 monthsRecommended only as part of the shared clinical decision making for patients most likely to benefit
*Only Gardasil® 9 is approved for patients 26 through 45 years of age, but the ACIP recommendation does not make a distinction on the formulation to use.8-10

Age expansion

In June 2019, the ACIP stated that some adults 27 through 45 years of age may benefit from HPV vaccination.8 Prior to this recommendation, in October 2018, the FDA approved expanding the indication for use of Gardasil®9 to men and women through age 45 years. The current ACIP recommendation advises clinicians to participate in shared clinical decision-making regarding HPV vaccination with patients between the ages of 27 through 45 years to identify those who may benefit the most from the vaccination. The discussion is not necessary with most adults over 26 years old. The following are general considerations from ACIP for this age group of patients (specific recommendations about which patients to vaccinate in this age group are lacking):

  • Having a new sex partner increases the risk of acquiring HPV infection.
  • The risk for a new HPV infection is lower in patients in long-term, monogamous sexual partnerships.
  • Vaccination may be less effective in patients with several risk factors for HPV infection (eg, presence of multiple lifetime sexual partners) or with immunocompromising conditions.

Both clinical data and economic models informed these recommendations.8 Economic models reported the increase in incremental cost per quality-adjusted life year (QALY) gained to exceed $300,000 by vaccinating patients through age 45 years. Also, numbers needed to vaccinate (NNV) to prevent 1 case of anogenital warts, high-grade cervical intraepithelial neoplasia, and cancer are 120, 800, and 6,500, respectively, when expanding vaccination to adults through 45 years of age.

Long-term efficacy of HPV vaccine

The ACIP recommendation to expand HPV vaccination to those through the age of 45 years is based on data from 11 clinical trials for Gardasil®, Gardasil®9, and Cervarix (a bivalent vaccine no longer available in the United States market).8,13-29  Some of the trials were performed outside the United States in countries such as China, Canada, Brazil, Germany, and Poland. Two trials explored the use of HPV vaccination in people with human immunodeficiency virus (HIV).19,20 Overall, seroconversion ranged between 93.6% and 100% after 3 doses of HPV vaccination in patients older than 26 years.8,13-29 The trial by Castellsague et al of 3,819 women aged 24 to 45 years showed that the efficacy of Gardasil® to prevent persistent HPV infection, cervical intraepithelial neoplasia, and external genital lesions was 88.7% (95% CI, 78.1 to 94.8) in women who completed the HPV vaccination series and had no prior history of HPV and 47.5% (95% CI, 16.9 to 67.4) in women who have received at least 1 dose of HPV vaccination (these patients could be HPV positive at vaccination initiation).14 This trial served as the evidence for the expanded age of use for Gardasil®9.10 Another trial revealed a similar immune response to Gardasil® between men aged 27 to 45 years and younger men and these results provided the evidence for the age expansion of Gardasil®9 in males.10,18  Interestingly, the manufacturer used the data from trials with Gardasil® to expand the approved age for Gardasil®9 but not Gardasil®.9,10

Conclusion

About 80% of people will acquire an HPV infection, and HPV vaccination may prevent up to 90% of cancers caused by HPV infection.3,7 In June 2019, the ACIP expanded the recommended age for HPV vaccination to adult patients through the age of 45 years. Both clinical data and economic models informed the recommendations. Clinical data showed high seroconversion rates and effectiveness to prevent HPV infection, cervical intraepithelial neoplasia, and external genital lesions in patients without HPV history and in patients aged 24 through 45 years who receive the full series of HPV vaccination. But economic models revealed high incremental cost per QALY gained and relatively high numbers of patients need to be vaccinated in order to prevent 1 case of anogenital warts, high-grade cervical intraepithelial neoplasia, and cancer with the expanded age indication. Therefore, clinicians must participate in the shared clinical decision-making regarding HPV vaccination with patients aged 27 through 45 years to identify those who may benefit the most from the vaccination.

References

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  2. Committee opinion no. 704: human papillomavirus vaccination. Obstet Gynecol. 2017;129(6):e173-e178.
  3. HPV cancers are preventable. Centers for Disease Control and Prevention website. https://www.cdc.gov/hpv/hcp/protecting-patients.html. Updated November 13, 2019. Accessed November 25, 2019.
  4. Human papillomavirus (HPV) vaccine. In: DynaMed. Ipswich, MA: EBSCO Information Services; 2019. https://www.dynamed.com/drug-review/human-papillomavirus-hpv-vaccine#GUID-18720948-AF29-48BF-A290-689F9C1F113F. Accessed November 25, 2019.
  5. Cancer stat facts. National Cancer Institute website. https://seer.cancer.gov/statfacts/. Accessed November 25, 2019.
  6. How many cancers are linked with HPV each year? Centers for Disease Control and Prevention website. https://www.cdc.gov/cancer/hpv/statistics/cases.htm. Updated August 2, 2019. Accessed November 25, 2019.
  7. HPV vaccine schedule and dosing. Centers for Disease Control and Prevention website. https://www.cdc.gov/hpv/hcp/schedules-recommendations.html. Updated August 15, 2019. Accessed November 25, 2019.
  8. 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.
  9. Gardasil [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; April 2015.
  10. Gardasil 9 [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; November 2019.
  11. Administering HPV vaccine. Centers for Disease Control and Prevention website. https://www.cdc.gov/vaccines/vpd/hpv/hcp/administration.html. Updated December 15, 2016. Accessed November 25, 2019.
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  13. Munoz N, Manalastas R, Jr., Pitisuttithum P, et al. Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24-45 years: a randomised, double-blind trial. Lancet. 2009;373(9679):1949-1957.
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  16. Einstein MH, Baron M, Levin MJ, et al. Comparison of the immunogenicity and safety of Cervarix and Gardasil human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18-45 years. Hum Vaccin. 2009;5(10):705-719.
  17. Einstein MH, Levin MJ, Chatterjee A, et al. Comparative humoral and cellular immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and HPV-6/11/16/18 vaccine in healthy women aged 18-45 years: follow-up through Month 48 in a Phase III randomized study. Hum Vaccin Immunother. 2014;10(12):3455-3465.
  18. Giuliano AR, Isaacs-Soriano K, Torres BN, et al. Immunogenicity and safety of Gardasil among mid-adult aged men (27-45 years)–The MAM Study. Vaccine. 2015;33(42):5640-5646.
  19. Money DM, Moses E, Blitz S, et al. HIV viral suppression results in higher antibody responses in HIV-positive women vaccinated with the quadrivalent human papillomavirus vaccine. Vaccine. 2016;34(40):4799-4806.
  20. Wilkin TJ, Chen H, Cespedes MS, et al. A randomized, placebo-controlled trial of the quadrivalent human papillomavirus vaccine in human immunodeficiency virus-infected adults aged 27 years or older: AIDS Clinical Trials Group protocol A5298. Clin Infect Dis. 2018;67(9):1339-1346.
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  22. Wheeler CM, Skinner SR, Del Rosario-Raymundo MR, et al. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 7-year follow-up of the phase 3, double-blind, randomised controlled VIVIANE study. Lancet Infect Dis. 2016;16(10):1154-1168.
  23. Schwarz TF, Spaczynski M, Schneider A, et al. Persistence of immune response to HPV-16/18 AS04-adjuvanted cervical cancer vaccine in women aged 15-55 years. Hum Vaccin. 2011;7(9):958-965.
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  25. Schwarz T, Spaczynski M, Kaufmann A, et al. Persistence of immune responses to the HPV-16/18 AS04-adjuvanted vaccine in women aged 15-55 years and first-time modelling of antibody responses in mature women: results from an open-label 6-year follow-up study. BJOG. 2015;122(1):107-118.
  26. Schwarz TF, Spaczynski M, Schneider A, et al. Immunogenicity and tolerability of an HPV-16/18 AS04-adjuvanted prophylactic cervical cancer vaccine in women aged 15-55 years. Vaccine. 2009;27(4):581-587.
  27. Zhu F, Li J, Hu Y, et al. Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in healthy Chinese girls and women aged 9 to 45 years. Hum Vaccin Immunother. 2014;10(7):1795-1806.
  28. Huang T, Liu Y, Li Y, et al. Evaluation on the persistence of anti-HPV immune responses to the quadrivalent HPV vaccine in Chinese females and males: up to 3.5years of follow-up. Vaccine. 2018;36(11):1368-1374.
  29. Grading of recommendations assessment, development and evaluation (GRADE) for use of HPV vaccine in adults ages 27 through 45 years. Centers for Disease Control and Prevention website. https://www.cdc.gov/vaccines/acip/recs/grade/HPV-adults.html. Updated August 15, 2019. Accessed November 25, 2019.

Prepared by:
Janna Afanasjeva, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois At Chicago College of Pharmacy

December 2019

The information presented is current as November 25, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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