Human Papillomavirus (HPV) Vaccine

HPV vaccines protect against infection with human papillomaviruses (HPV). HPV is a group of more than 200 related viruses, of which more than 40 are spread through direct sexual contact. Among these, two HPV types cause genital warts, and about a dozen HPV types can cause certain types of cancer—cervical, anal, oropharyngeal, penile, vulvar, and vaginal.

Three vaccines that prevent infection with disease-causing HPV have been licensed in the United States: Gardasil, Gardasil 9, and Cervarix. Gardasil 9 has, since 2016, been the only HPV vaccine used in the United States. It prevents infection with the following nine HPV types:

• HPV types 6 and 11, which cause 90% of genital warts (1)
• HPV types 16 and 18, two high-risk HPVs that cause about 70% of cervical cancers and an even higher percentage of some of the other HPV-caused cancers (2–4)
• HPV types 31, 33, 45, 52, and 58, high-risk HPVs that account for an additional 10% to 20% of cervical cancers

Cervarix prevents infection with types 16 and 18, and Gardasil prevents infection with types 6, 11, 16, and 18. Both vaccines are still used in some other countries.

The Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP) develops recommendations regarding all vaccination in the United States, including HPV vaccination. The current ACIP recommendations for HPV vaccination are (5):

• Children and adults ages 9 through 26 years. HPV vaccination is routinely recommended at age 11 or 12 years; vaccination can be started at age 9 years. HPV vaccination is recommended for all persons through age 26 years who were not adequately vaccinated earlier.
• Adults ages 27 through 45 years. Although the HPV vaccine is Food and Drug Administration (FDA) approved to be given through age 45 years, HPV vaccination is not recommended for all adults ages 27 through 45 years. Instead, ACIP recommends that clinicians consider discussing with their patients in this age group who were not adequately vaccinated earlier whether HPV vaccination is right for them. HPV vaccination in this age range provides less benefit because more people have already been exposed to the virus.
• Persons who are pregnant. HPV vaccination should be delayed until after pregnancy, but pregnancy testing is not required before vaccination. There is no evidence that vaccination will affect a pregnancy or harm a fetus.

Clinical trials have shown that HPV vaccines are highly effective in preventing cervical infection with the types of HPV they target when given before first exposure to the virus—that is, before individuals begin to engage in sexual activity. HPV vaccines have also been found to reduce infections in other tissues that HPV infects, including the anus (7) and oral region (8, 9).

Because the cell changes and cancers caused by HPV take years to develop, it has only recently been confirmed that the vaccines reduce the risk of these outcomes as well. Trials and real-world data from population-based studies have now demonstrated that the vaccines greatly reduce the risk of precancers and cancers of the cervix, vagina, and vulva in vaccinated women (10–13). A clinical trial of Gardasil in men indicated that it can prevent anal cell changes caused by persistent infection (14). The trials that led to approval of Gardasil 9 found it to be nearly 100% effective in preventing cervical, vulvar, and vaginal infections and precancers caused by all seven cancer-causing HPV types (16, 18, 31, 33, 45, 52, and 58) that it targets (10).

Although Cervarix and Gardasil prevent infection with just two high-risk HPV types, HPV16 and HPV18, these two HPV types are responsible for most HPV-caused cancers. In a 2017 position paper, the World Health Organization stated that the HPV vaccines have comparable efficacy (15). In addition, Cervarix has been found to provide substantial protection against a few additional cancer-causing HPV types, a phenomenon called cross-protection (16). Women who received three doses of Cervarix experienced strong protection against new infections with HPV types 31, 33, and 45 (17).

To date, protection against infections with the targeted HPV types has been found to last for at least 10 years with Gardasil (18), up to 11 years with Cervarix (17), and at least 6 years with Gardasil 9 (19). Long-term studies of vaccine efficacy that are still in progress will help scientists better understand how long protection lasts (20).

Like other immunizations that guard against viral infection, HPV vaccines stimulate the body to produce antibodies that, in future encounters with HPV, bind to the virus and prevent it from infecting cells.

The current HPV vaccines are based on virus-like particles (VLPs) that are formed by HPV surface components. VLPs are not infectious because they lack the virus’s DNA. However, they closely resemble the natural virus, and antibodies against the VLPs also have activity against the natural virus. The VLPs have been found to be strongly immunogenic, which means that they induce high levels of antibody production by the body. This makes the vaccines highly effective.

The vaccines do not prevent other sexually transmitted diseases, nor do they treat existing HPV infections or HPV-caused disease.

The combination of HPV vaccination and cervical screening can provide the greatest protection against cervical cancer. Also, HPV vaccination reduces the risk of developing cancers caused by HPV at sites other than the cervix.

Not only does vaccination protect vaccinated individuals against infection by the HPV types targeted by the vaccine that is used (and possibly other types, depending on the extent of cross protection), but vaccination can also reduce the prevalence of the vaccine-targeted HPV types in the population, thereby reducing infection in individuals who are not vaccinated (a phenomenon called herd protection, or herd immunity). For example, in Australia, where a high proportion of girls are vaccinated with Gardasil, the incidence of genital warts went down during the first 4 years of the vaccination program among young males—who were not being vaccinated at the time—as well as among young females (21).

Further evidence that large-scale HPV vaccination confers protection for unvaccinated individuals comes from a 2019 meta-analysis of girls-only HPV vaccination programs in 14 high-income countries that included 60 million vaccinated people (22). That analysis showed that, up to 8 years after the start of vaccination, diagnoses of anogenital warts decreased by 31% among women aged 25–29 years, by 48% among boys aged 15–19 years, and by 32% among men aged 20–24 years, compared with the period before vaccination began.

Similarly, a study of women aged 20–29 years in one US region found that within about 10 years of vaccine introduction, the prevalence of HPV types targeted by the vaccine decreased in both vaccinated and unvaccinated women, providing evidence of both direct and herd protection (23).

Widespread HPV vaccination has the potential to reduce cervical cancer incidence around the world by as much as 90% (16, 19). In addition, the vaccines may reduce the need for screening and subsequent medical care, biopsies, and invasive procedures associated with follow-up from abnormal cervical screening, thus helping to reduce health care costs and anxieties related to follow-up procedures (24).

As the incidence of cervical cancer has declined in the United States, due mainly to cervical cancer screening, the incidence of HPV-associated oropharyngeal, vulvar, and anal cancers has been increasing (25). Indeed, analyses of data for 2012–2016 found that HPV caused more oropharyngeal cancers than cervical cancers in the United States (2). There are no formal screening programs for the non-cervical cancers, so universal HPV vaccination could have a large public health impact.

Yes. More than 12 years of safety monitoring show that the vaccines have caused no serious side effects. The most common problems have been brief soreness and other local symptoms at the injection site. These problems are similar to those commonly experienced with other vaccines.

The FDA and the CDC conducted a safety review of adverse side effect s related to Gardasil immunization that have been reported to the Vaccine Adverse Events Reporting System since the vaccine was licensed (26–28). The rates of adverse side effects were consistent with what was seen in safety studies carried out before the vaccine was approved and were similar to those seen with other vaccines. The most recent safety data review for HPV vaccines continues to indicate that these vaccines are safe (29, 30).

Syncope (fainting) is sometimes observed with Gardasil, as with other vaccines. Falls after fainting may sometimes cause serious injuries, such as head injuries. These can largely be prevented by keeping the person seated for up to 15 minutes after vaccination. The FDA and CDC have reminded health care providers that, to prevent falls and injuries, all vaccine recipients should remain seated or lying down and be closely observed for 15 minutes after vaccination. More information is available from the CDC on its Human Papillomavirus (HPV) Vaccine page.

ACIP recommends that people who have an HPV infection and/or an abnormal Pap test result that may indicate an HPV infection should still receive the HPV vaccine if they are in the appropriate age group (9 through 26 years) because the vaccine may protect them against high-risk HPV types that they have not yet acquired. However, these people should be told that the vaccination will not cure them of current HPV infections or treat the abnormal results of their Pap test (31).

Although HPV vaccines have been found to be safe when given to people who are already infected with HPV, the vaccines provide maximum benefit if a person receives them before he or she is sexually active (32, 33).

It is likely that someone previously infected with HPV will still get some residual benefit from vaccination, even if he or she has already been infected with one or more of the HPV types included in the vaccines.

Yes. Because HPV vaccines do not protect against all HPV types that can cause cancer, women who have been vaccinated are advised to follow the same screening recommendations as unvaccinated women. There could be future changes in screening recommendations for vaccinated women.

Most private insurance plans cover HPV vaccination. The federal Affordable Care Act requires most private insurance plans to cover recommended preventive services (including HPV vaccination) with no copay or deductible.

Medicaid covers HPV vaccination in accordance with ACIP recommendations, and immunizations are a mandatory service under Medicaid for eligible individuals under age 21. In addition, the federal Vaccines for Children Program provides immunization services for children younger than 19 years who are Medicaid eligible, uninsured, underinsured, or Native American or Alaska Native.

Merck, the manufacturer of Gardasil 9, offers the Merck Vaccine Patient Assistance ProgramExit Disclaimer, which provides Gardasil 9 for free to people aged 19 to 45 years who live in the United States, do not have health insurance, and have an annual household income less than a certain amount.

If a single dose of HPV vaccine were effective, that would be an important advance. A large observational study using national data from women across Australia found that one dose of HPV vaccine was as effective as two or three doses in preventing high-grade cervical lesions (34). An analysis of data from a community-based clinical trial of Cervarix in Costa Rica, found that even one dose of the vaccine caused the body to produce approximately nine times more antibodies against HPV than the body produces in response to a natural HPV infection, and those antibody levels persisted for 11 years (35). In addition, the rates of HPV infection remained low for at least 10 years (35).

Two NCI-led clinical trials have been launched in Costa Rica to confirm and extend these findings. The ESCUDDO study, a randomized double-blind controlled trial involving 20,000 girls ages 12–16 years, is testing whether one dose of either Cervarix or Gardasil 9 is as effective as two doses at preventing persistent cervical infection with HPV. PRIMAVERA-ESCUDDO, a non-randomized open-label trial, will provide earlier and complementary results to ESCUDDO about the immunogenicity of one dose of Cervarix in girls ages 9–14 years compared with three doses of Gardasil in women ages 18–25 years.

Another prevention strategy that is being explored is topical microbicides. Carrageenan, a compound that is extracted from a type of seaweed and used widely in foods and other products, has been found to inhibit HPV infection in laboratory studies. An interim analysis of data from a randomized clinical trial showed that consistent use of a lubricant gel that contains carrageenan reduced the risk of genital HPV infection in healthy women (36).

Researchers are working to develop therapeutic HPV vaccines, which instead of preventing HPV infection would prevent cancer from developing among women previously infected with HPV (37–40). These vaccines work by stimulating the immune system to specifically target and kill infected cells. Ongoing clinical trials are testing the safety and efficacy of a therapeutic DNA vaccine to treat HPV-related cervical and vulvar lesions.