Human Papillomavirus Vaccination

The American College of Obstetricians and Gynecologists (the College) makes the following recommendations and conclusions:

Human papillomavirus (HPV) is associated with anogenital cancer (including cervical, vaginal, vulvar, penile, and anal), oropharyngeal cancer, and genital wats. Of the more than 150 HPV genotypes, 13 genotypes have been shown to cause cervical cancer. Most cases of HPV-associated cancer are caused by HPV genotypes 16 and 18. In the United States, HPV genotypes 16 and 18 account for 66% of cases of cervical cancer, and HPV genotypes 31, 33, 45, 52 and 58 account for an additional 15% of cases of cervical cancer. For cervical intraepithelial neoplasia 2+, 50-60% of cases are caused by HPV genotypes 16 and 18, and 25% of cases are caused by HPV genotypes 31, 33, 45, 52 and 58. Approximately 90% of cases of genital warts are caused by HPV genotypes 6 and 11.

Despite cervical cytology screening in the United States, each year cervical cancer is diagnosed in more than 13,000 women and nearly 4,000 die from the disease. Most of these cases of cancer occur because of a lack of adequate screening. Human papillomavirus-associated cancer also occurs in males. The average number of anogenital or oropharyngeal cancer in makes per year is 15,793 and 10,200 (65%) of these are associated with HPV 16 or HPV 18.

The HPV vaccine significantly reduces the incidence of anogenital cancer and genital warts. Additionally, HPV vaccination may decrease the incidence of oropharyngeal cancer as well as the maternal transmittal of HPV to infants. Human papillomavirus in infants may result in recurrent laryngeal papillomatosis, although definitive prevention trials have not been completed for these two disease endpoints. In the United States, the prevalence of vaccine-type HPV decreased 56% among females aged 14-19 years between 2006 (when the quadrivalent HPV vaccine was introduced) and 2010. Despite the benefits of HPV vaccines, only 41.9% of females in the recommended age group, and only 28.1% of males in the recommended age group have received all recommended doses. Compared with many other countries HPV vaccination rates in the United States are unacceptably low.

The Advisory Committee on Immunization Practices and the College recommend routine HPV vaccination for girls and boys at the target age of 11-12 years (but it may be given from the age of 9 years) as part of the adolescent immunization platform in order to help reduce the incidence of anogenital cancer and genital warts associated with HPV infection. Bivalent, quadrivalent, and 9-valent vaccines are approved for females aged 9-26 years and quadrivalent and 9-valent vaccines are approved for males aged 9-26 years. Recently, the bivalent vaccine has been withdrawn from the U.S. market. The 9-valent vaccine, which covers five additional cancer-related HPV serotypes will soon replace the quadrivalent vaccine. Studies show that two doses of HPV vaccine given 6 months apart in individuals aged 9-14 years resulted in antibody titers equal to those in individuals aged 15-26 years who were given three doses. Hence, only two doses, 6-12 months apart, are needed if HPV vaccination is initiated before 15 years of age in boys and girls. The 6-month interval between these two doses is critical for ensuring adequate immune titers and durability of protection. If the interval between the two doses is less than 5 months, a third dose is recommended. In addition to the ability to use two doses instead of three doses, earlier vaccination also is preferred because HPV vaccines are most effective when given before prior exposure and infection with HPV, which coincide with the onset of sexual activity. Statistics show that one in three ninth graders and two in three 12th graders have engaged in sexual intercourse. In Sweden, vaccine effectiveness in preventing genital warts was 93% among girls vaccinated between 10 years and 13 years of age compared with 48% and 21% if vaccinated at ages 20-22 years and 23-26 years, respectively. All of these findings underscore the importance of vaccination at the target age (11-12 years), which is before the onset of potential exposure in the vast majority.

Vaccination is recommended regardless of sexual activity or prior exposure to HPV. Although the vaccine may be less effective in previously infected individuals, it is expected that some benefit will be experienced because prior exposure to all nine vaccine types is highly unlikely. Vaccination is recommended even if the patient is tested for HPV DNA and the results are positive. Testing for HPV DNA is not recommended before vaccination.

The 9-valent HPV vaccine was licensed by the U.S. Food and Drug Administration in December 2014. The Advisory Committee on Immunization Practices has recommended similar schedules as those for quadrivalent vaccine. In a phase III efficacy trial that made a comparison of the 9-valent HPV vaccine with the quadrivalent HPV vaccine among approximately 14,000 females aged 16-26 years, the 9-valent HPV vaccine had high efficacy for prevention of cervical intraepithelial neoplasia 2+, vulvar intraepithelial neoplasia 2 or 3, and vaginal intraepithelial neoplasia 2 or 3 due to HPV genotypes 31, 33, 45, 52, and 58 (see Table below). The antibody titer against HPV genotypes 6, 11, 16, and 18 was not reduced with the addition of the other five HPV genotypes. Revaccination with the 9-valent HPV vaccine in individuals who previously completed the three-dose series with the quadrivalent HPV vaccine or the bivalent HPV vaccine currently is not a routine recommendation. If obstetrician—gynecologists or other health care providers do not know or do not have the same HPV vaccine product previously administered, or are in settings that are transitioning to the 9-valent HPV vaccine, any available HPV vaccine product may be used to continue or complete the series for females for protection against HPV genotypes 16 and 18; the 9-valent HPV vaccine or the quadrivalent HPV vaccine may be used to continue or complete the series for males.

The durability of the immune response (ie, how long protection lasts) of the HPV vaccine is being monitored in long-term studies, and currently there is no indication for a booster vaccine. The vaccine series does not need to be restarted in the case of a delay in administration of the second or third dose, regardless of the amount of time of the delay. Further, revaccination with the 9-valent HPV vaccine in individuals who previously completed the three-dose series with the quadrivalent HPV vaccine or the bivalent HPV vaccine is not a routine recommendation. The bivalent and quadrivalent vaccines have been shown to be extremely effective at pre- venting HPV-related disease.If obstetrician–gynecologists or other health care professionals do not know or do not have the same HPV vaccine product previously administered, or are in settings that are transitioning to the 9-valent HPV vaccine, any available HPV vaccine product may be used to continue or complete the series for women for protection against HPV genotypes 16 and 18; the 9-valent HPV vaccine or the quadrivalent HPV vaccine may be used to continue or complete the series for men.

The HPV vaccine is now licensed in the United States for women and men through age 45 years. Although administration of the HPV vaccine is safe in patients aged 27–45, and can prevent new infections in women not previously exposed to the HPV-type protection generated by the vaccine, most women in this age range will have been exposed to HPV already. The overall public health benefit of HPV vaccination in women aged 27–45 years is markedly diminished compared with use in the target age range.Ideally, the HPV vaccine should be given in early adolescence because vaccination is most effective before exposure to HPV through sexual activity. For some women aged 27–45 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. Those women aged 27–45 years who are most likely to benefit from vaccination are those at greater risk for HPV exposure or acquisition: younger women, women who are not in committed monogamous relationships, and women with recently diagnosed sexually transmitted infections. When counseling patients, clinicians should explain that women aged 27–45 years in long-term monogamous relationships are not likely at risk of acquiring a new HPV infection. It is not routinely recommended that these women receive the vaccine.Clinicians should keep in mind that catch-up HPV vaccination is not recommended for all adults older than 26 years and that HPV vaccination does not need to be discussed with most adults older than 26 years. The American College of Obstetricians and Gynecologists does not recommend that an individual who received the quadrivalent HPV vaccine be revaccinated with 9-valent HPV vaccine, including those aged 27–45 years who previously completed some, but not all, of the vaccine series when they were younger. Further, having a new partner increases the risk of a new HPV infection at any age; however, with increasing age and more past exposure to HPV, it is less likely that vaccination provides benefit.Typically, routine vaccine recommendations are made for specific at-risk populations (identified either by age group or underlying health-related conditions) after considering vaccination cost, availability, and public health impact. The 9-valent HPV vaccine is costly and in short supply globally. In addition, routine HPV vaccination of all women age 27–45 would be expected to have a very limited effect on the global fight to prevent cervical cancer. Thus, in this case, the shared clinical decision making approach is recommended by the Centers for Disease Control and Prevention and ACOG.

Although HPV vaccination in pregnancy is not recommended, neither is routine pregnancy testing before vaccination. Available safety data regarding the inadvertent administration of the vaccine during pregnancy are reassuring. Patients and obstetrician-gynecologists or other health care providers are encouraged to register women exposed to the 9-valent HPV vaccine around the time the pregnancy began or during pregnancy by contacting the manufacturer (www.merckpregnancyregistries.com). Pregnancy registries for the quadrivalent HPV vaccine and bivalent HPV vaccine have been closed. If a vaccine series is started and a patient then becomes pregnant, completion of the vaccine series should be delayed until that pregnancy is completed. Lactating women can receive any HPV vaccine because inactivated vaccines like HPV do not affect the safety of breastfeeding for these women or their infants. The presence of immunosuppression, like that experienced in patients with human immunodeficiency virus (HIV) infection or organ transplantation, is not a contraindication to HPV vaccination. However, the immune response may be less robust in the immunocompromised patient. The three-dose regimen is recommended for immunosuppressed men and women. Human papillomavirus vaccines are not currently licensed in the United States for women older than 26 years. Off-label use may be indicated on a case-by-case basis.

High rates of HPV vaccination will reduce the burden of HPV-related disease in the United States. Current vaccination rates are unacceptably low. Studies have shown that physicians' recommendations play a crucial role in the acceptance of HPV vaccination by patients and parents of patients.

Obstetrician-gynecologists and other health care providers should stress to parents and patients the benefits and safety of HPV vaccination and offer HPV vaccines in their offices. Obstetrician-gynecologists play a critical role and should assess and vaccinate adolescent girls and young women during the catch-up period (ages 13-26 years). According to the Centers for Disease Control and Prevention, if health care providers increase HPV vaccination rates in eligible recipients to 80%, it is estimated that an additional 53,000 cases of cervical cancer could be prevented during the lifetime of those younger than 12 years.

Furthermore, for every year that the vaccination rate does not increase, an additional 4,400 women will develop cervical cancer.