Clinical Context

The human papillomavirus (HPV) infection has been linked with cervical, vaginal, vulvar, penile, oropharyngeal, and anal cancers, as well as genital warts. To prevent HPV infections, cancers, and other HPV-associated diseases, current recommendations call for vaccination against HPV. Since 2006, the Advisory Committee on Immunization Practices (ACIP) has recommended that girls undergo routine vaccination at age 11 or 12 years; the committee issued similar recommendations for boys in 2011.

According to new clinical trial data, ACIP has now issued new recommendations and guidance for use of HPV vaccines, updating its 2014 and 2015 ACIP HPV vaccination recommendations.

Synopsis and Perspective

Children 9 to 14 years old can now receive the HPV vaccine on a 2-dose schedule, rather than a 3-dose one, according to updated recommendations issued by the Centers for Disease Control and Prevention (CDC).

The recommendations are based on the findings of a year-long review of new clinical trial data conducted by the ACIP. The data show that among girls and boys in this age range, immunogenicity associated with the 2-dose regimen was not inferior to, and in some cases was superior to, that seen with the 3-dose regimen.

HPV infection causes cancer of the cervix, vulva, and vagina in women; in men, it causes cancer of the penis. In both sexes, it can cause anal and oropharyngeal cancer, as well as genital warts.

"HPV vaccines are highly effective and safe, and a powerful prevention tool for reducing HPV infections and HPV-associated cancers," lead author Elissa Meites, MD, and colleagues write in an article published in the December 16 issue of the Morbidity and Mortality Weekly Report.^[1]

Routine vaccination is recommended at ages 11 to 12 years for both sexes. However, vaccination as young as age 9 years is recommended if a child has been sexually abused or assaulted.

In addition, catch-up vaccinations are recommended through age 26 years for those not already vaccinated.

The agency continues to recommend 3 doses for people who are immunocompromised or who do not begin the vaccine series before their 15th birthday.

Prelicensure vaccine efficacy trials were conducted with use of the 3-dose series. However, follow-up analyses and a large study comparing the 2-dose vs the 3-dose regimens suggested that, for some people, 2 doses might be as effective as 3 doses, prompting a reexamination of the original recommendations.

In October 2016, after considering the new evidence, both the ACIP and the US Food and Drug Administration (FDA) approved the 2-dose series for individuals who receive the first vaccination dose on or after their ninth birthday and before their 15th birthday,^[2] with the second dose administered 6 to 12 months after the first.

"Assuming both efficacy and duration of protection are similar with either schedule, a 2-dose series would be cost-saving and have similar population impact to a 3-dose series," the authors point out. "Even if duration of protection is 20 years for a 2-dose series and lifelong for a 3-dose series, additional benefits of a 3-dose series would be relatively small, and a 2-dose series would be more cost-effective."

ACIP evaluated the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, supplemented with information from other studies, Dr Meites, from the Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, CDC, and colleagues write. CDC recommendations are also developed with use of the GRADE framework.

Two-Dose Regimen Noninferior

The committee revised its recommendations based on evidence from a clinical trial comparing the effects of the 2-dose regimen in girls and boys 9 through 14 years old vs those of a 3-dose regimen in young women 16 through 26 years old. Of the 1377 participants, at least 97.9% seroconverted to all of the vaccine-preventable HPV types within 4 weeks after receiving the last vaccine dose.

Individuals receiving the 2-dose regimen met noninferiority criteria for seroconversion and geometric mean titers (GMTs) compared with participants receiving the 3-dose regimen. This was seen whether the second dose was administered 6 or 12 months after the first.

In fact, GMTs were significantly higher "among persons aged 9 through 14 years who received 2 doses compared with females aged 16-26 years who received 3 doses [on a 0-, 2-month, and 6-month schedule]," the authors write.

The investigators saw no waning of protection in people who were observed for up to 10 years after receiving the 3-dose series. "Because antibody kinetics are similar with 2-dose and 3-dose series, duration of protection is also expected to be long-lasting after a 2-dose series."

The authors note that as of late 2016, the only type of HPV vaccine distributed in the United States is the 9-valent form (9vHPV). This vaccine targets HPV 16 and 18, which cause most HPV-associated cancers, as well as HPV 6, 11, 31, 33, 45, 52, and 58. It is licensed for use in both sexes from ages 9 through 26 years.

Until recently, bivalent (2vHPV) and quadrivalent (4vHPV) forms of the vaccine also were available in the United States and are still used in some countries, Dr Meites and colleagues point out. People who have started a vaccine series with either of these products can complete the series with 9vHPV, and if they have already received the full series of 2vHPV or 4vHPV, "there is no ACIP recommendation regarding additional vaccination with 9vHPV."

The authors have disclosed no relevant financial relationships.

Morb Mortal Wkly Rep. 2016;65:1405-1408.

Recommendation Highlights

• A year-long ACIP review of new clinical trial data showed that among girls and boys starting HPV vaccination at ages 9 to 14 years, immunogenicity resulting from the 2-dose regimen was not inferior to, and was sometimes superior to, that seen with the 3-dose regimen.
• According to this review, ACIP and the FDA approved the 2-dose series in October 2016 for persons beginning vaccination between their ninth and 15th birthday; the second dose is to be given 6 to 12 months after the first.
• Rationale favoring the 2-dose schedule also includes cost saving and cost effectiveness.
• ACIP recommends that routine HPV vaccination begin at age 11 or 12 years in both sexes and may begin at age 9 years.
• Young women through age 26 years and young men through age 21 years (in some cases, through age 26 years) should receive catch-up vaccinations if they were not adequately vaccinated previously.
• ACIP now recommends a 2-dose immunization schedule for persons beginning vaccination before their 15th birthday, with the second dose given 6 to 12 months after the first dose.
• Persons who began vaccination with 9vHPV, 4vHPV, or 2vHPV before their 15th birthday and received 2 or 3 doses of any HPV vaccine at the recommended dosing schedule are considered adequately vaccinated.
• Persons beginning vaccination on or after their 15th birthday should receive a 3-dose schedule, with the second dose given 1 to 2 months after the first dose, and the third dose given 6 months after the first dose.
• Persons who began vaccination with 9vHPV, 4vHPV, or 2vHPV on or after their 15th birthday and received 3 doses of any HPV vaccine at the recommended dosing schedule are considered adequately vaccinated.
• Persons who began a vaccination series with 4vHPV or 2vHPV may receive 9vHPV to continue or complete the series.
• The series does not need to be restarted if the vaccination schedule is interrupted; age at receipt of the first dose determines the number of recommended doses.
• Children with a history of sexual abuse or assault should undergo routine HPV vaccination beginning at age 9 years.
• As for all men, men who have sex with men should undergo routine HPV vaccination and should be vaccinated through age 26 years if not adequately vaccinated previously.
• Transgender persons should be routinely vaccinated against HPV as for all adolescents, and they should receive vaccination through age 26 years if they were not adequately vaccinated previously.
• Girls and women and boys and men 9 through 26 years old with primary or secondary immunocompromising conditions that might lower cell-mediated or humoral immunity (B-lymphocyte antibody deficiencies, T-lymphocyte complete or partial defects, HIV infection, malignant neoplasm, transplantation, autoimmune disease, or immunosuppressive therapy) should be vaccinated with the 3-dose schedule.
• Contraindications and precautions, including those associated with pregnancy, are unchanged from previous recommendations.
• Clinicians should report adverse events occurring after administration of any vaccine to the Vaccine Adverse Event Reporting System.

Clinical Implications

• Updated ACIP recommendations now include a 2-dose schedule for girls and boys who begin the HPV vaccination series at ages 9 through 14 years.
• For persons beginning the vaccination series at ages 15 through 26 years, and for immunocompromised persons, ACIP still recommends 3 doses.
• Implications for the Healthcare Team: Healthcare providers should keep in mind that children with a history of sexual abuse or assault should undergo routine HPV vaccination beginning at age 9 years.

CME Test