Human Papillomavirus (HPV) Vaccines

Human papillomaviruses (HPVs) are a group of more than 200 related viruses. More than 40 HPV types can be easily spread through direct sexual contact, from the skin and mucous membranes of infected people to the skin and mucous membranes of their partners. They can be spread by vaginal, anal, and oral sex (1). Other HPV types are responsible for non-genital warts, which are not sexually transmitted.

Sexually transmitted HPV types fall into two categories:

• Low-risk HPVs, which do not cause cancer but can cause skin warts (technically known as condylomata acuminata) on or around the genitals and anus. For example, HPV types 6 and 11 cause 90% of all genital warts. HPV types 6 and 11 also cause recurrent respiratory papillomatosis, a disease in which benign tumors grow in the air passages leading from the nose and mouth into the lungs.
• High-risk HPVs, which can cause cancer. About a dozen high-risk HPV types have been identified. Two of these, HPV types 16 and 18, are responsible for most HPV-caused cancers (2, 3).

HPV infections are the most common sexually transmitted infections in the United States. About 14 million new genital HPV infections occur each year (4). In fact, the Centers for Disease Control (CDC) estimates that more than 90% and 80%, respectively, of sexually active men and women will be infected with at least one type of HPV at some point in their lives (5). Around one-half of these infections are with a high-risk HPV type (6).

Most high-risk HPV infections occur without any symptoms, go away within 1 to 2 years, and do not cause cancer. Some HPV infections, however, can persist for many years. Persistent infections with high-risk HPV types can lead to cell changes that, if untreated, may progress to cancer.

High-risk HPVs cause several types of cancer.

• Cervical cancer: Virtually all cases of cervical cancer are caused by HPV, and just two HPV types, 16 and 18, are responsible for about 70% of all cases (7,8).
• Anal cancer: About 95% of anal cancers are caused by HPV. Most of these are caused by HPV type 16.
• Oropharyngeal cancers (cancers of the middle part of the throat, including the soft palate, the base of the tongue, and the tonsils): About 70% of oropharyngeal cancers are caused by HPV. In the United States, more than half of cancers diagnosed in the oropharynx are linked to HPV type 16 (9).
• Rarer cancers: HPV causes about 65% of vaginal cancers, 50% of vulvar cancers, and 35% of penile cancers (10). Most of these are caused by HPV type 16.

High-risk HPV types cause approximately 5% of all cancers worldwide (11). In the United States, high-risk HPV types cause approximately 3% of all cancer cases among women and 2% of all cancer cases among men (12).

Anyone who has ever been sexually active (that is, engaged in skin-to-skin sexual conduct, including vaginal, anal, or oral sex) can get HPV. HPV is easily passed between partners through sexual contact.  HPV infections are more likely in those who have many sex partners or have sex with someone who has had many partners. Because the infection is so common, most people get HPV infections shortly after becoming sexually active for the first time (13, 14). A person who has had only one partner can get HPV.

Someone can have an HPV infection even if they have no symptoms and their only sexual contact with an HPV-infected person happened many years ago.

Correct and consistent condom use is associated with reduced HPV transmission between sexual partners, but less frequent condom use is not (8). However, because areas not covered by a condom can be infected by the virus (7), condoms are unlikely to provide complete protection against the infection.

Three vaccines are approved by the FDA to prevent HPV infection: Gardasil, Gardasil 9, and Cervarix. All three vaccines prevent infections with 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-associated cancers (9, 10). Gardasil also prevents infection with HPV types 6 and 11, which cause 90% of genital warts (17). Gardasil 9 prevents infection with the same four HPV types plus five additional high-risk HPV types (31, 33, 45, 52, and 58).

In addition to providing protection against the HPV types included in these vaccines, the vaccines have been found to provide partial protection against a few additional HPV types that can cause cancer, a phenomenon called cross-protection. The vaccines do not prevent other sexually transmitted diseases, nor do they treat existing HPV infections or HPV-caused disease.

Because none of the currently available HPV vaccines protects against all HPV infections that cause cancer, it is important for vaccinated women to continue to undergo cervical cancer screening. There could be some future changes in recommendations for vaccinated women.

The FDA has approved Gardasil and Gardasil 9 for use in females ages 9 through 26 for the prevention of HPV-caused cervical, vulvar, vaginal, and anal cancers; precancerous cervical, vulvar, vaginal, and anal lesions; and genital warts. Gardasil and Gardasil 9 are also approved for use in males for the prevention of HPV-caused anal cancer, precancerous anal lesions, and genital warts. Gardasil is approved for use in males ages 9 through 26, and Gardasil 9 is approved for use in males ages 9 through 15. Cervarix is approved for use in females ages 9 through 25 for the prevention of HPV-caused cervical cancer.

All three vaccines are given through a series of three injections into muscle tissue over a 6-month period. In October 2016, the FDA approved a 2-dose schedule for boys and girls initiating vaccination with Gardasil 9 at ages 9 to 14 years (the second dose is to be administered 6–12 months after the first). Those initiating the HPV vaccination series at older ages (including teens who begin getting vaccinated after they turn 15 years old) or who are immunocompromised should still be vaccinated according to the 3-dose schedule.

Individuals who have previously received Gardasil may be able to also receive Gardasil 9. FDA has information for patients about Gardasil 9 available at http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM426460.pdf.

After a vaccine is licensed by the FDA, the Advisory Committee on Immunization Practices (ACIP), a group of 15 medical and public health experts that develops recommendations on how to use vaccines to control diseases in the United States, makes additional recommendations to the Secretary of the U.S. Department of Health and Human Services and the Director of the CDC on who should receive the vaccine, at what age, how often, the appropriate dose, and situations in which it should not be administered. 

ACIP has developed the following recommendations regarding HPV vaccination (18):

• initiation of routine HPV vaccination at age 11 or 12 years (the vaccination series can be started beginning at age 9 years)
• vaccination of females aged 13 through 26 years and of males aged 13 through 21 years who have not been vaccinated previously or who have not completed the 3-dose vaccination series. Males aged 22 through 26 years may be vaccinated.
• vaccination through age 26 years of men who have sex with men and for immunocompromised persons if not vaccinated previously
• when the HPV vaccine product previously administered is not known or unavailable or the provider is switching to use of Gardasil 9, any available HPV vaccine product can be used to continue or complete the series for females; Gardasil 9 or Gardasil may be used to continue or complete the series for males

As of October 2016, CDC and ACIP also now recommend that 11- and 12-year-olds receive two doses of HPV vaccine at least 6 months apart rather than the previously recommended three doses.

Like other immunizations that guard against viral infections, 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 VLP technology that is used in the HPV vaccines was developed by NCI and other scientists. NCI licensed the technology to Merck and GSK to develop HPV vaccines for widespread distribution.

HPV vaccines are highly effective in preventing infection with the types of HPV they target when given before initial exposure to the virus—which means before individuals begin to engage in sexual activity. In the trials that led to approval of Gardasil and Cervarix, these vaccines were found to provide nearly 100% protection against persistent cervical infections with HPV types 16 and 18 and the cervical cell changes that these persistent infections can cause. Gardasil 9 is as effective as Gardasil for the prevention of diseases caused by the four shared HPV types (6, 11, 16, and 18), based on similar antibody responses in participants in clinical studies. The trials that led to approval of Gardasil 9 found it to be 97% effective in preventing cervical, vulvar, and vaginal disease caused by the five additional HPV types (31, 33, 45, 52, and 58) that it targets (19).

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To date, protection against the targeted HPV types has been found to last for at least 8 years with Gardasil (20) and at least 9 years with Cervarix (21). The duration of protection with Gardasil 9 is not yet known. Long-term studies of vaccine efficacy that are still in progress will help scientists better understand the total duration of protection.

A clinical trial of Gardasil in men indicated that it can prevent anal cell changes caused by persistent infection and genital warts (22). Analyses of data from women participating in a clinical trial of Cervarix found that this vaccine can protect women against persistent HPV 16 and 18 infections in the anus (23) and the oral cavity (24).

The HPV vaccines were originally approved to be given to people in three doses over a 6-month period. However, one study conducted by the NCI showed that women who received only two doses of Cervarix had as much protection from persistent HPV 16/18 infections as women who received three doses, and the protection was observed through 4 years of follow up (25). Even one dose provided protection. In other studies, young adolescents given two doses of Cervarix or Gardasil were found to have as strong an immune response as 15-to-25-year-olds who received three doses (26, 27). Based on the evidence to date, the World Health Organization has recommended two doses as the standard delivery for these vaccines, and in the United States two doses are recommended for those who begin vaccination at ages 9 through 14.

Widespread vaccination with Cervarix or Gardasil has the potential to reduce cervical cancer incidence around the world by as much as two-thirds, while Gardasil 9 could prevent an even higher proportion. In addition, the vaccines can reduce the need for 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 (28).

Until recently, the other cancers caused by HPV were less common than cervical cancer. However, the incidence of HPV-positive oropharyngeal cancer and anal cancer has been increasing (12), while the incidence of cervical cancer has declined, due mainly to highly effective cervical cancer screening programs.  Therefore, the number of HPV-positive cancers located outside the cervix (non-cervical cancers) in the United States is now similar to that of cervical cancer.  In addition, most of the HPV-positive non-cervical cancers arise in men.  There are no formal screening programs for the non-cervical cancers, so universal vaccination could have an important public health benefit.

Vaccination is the approved public health intervention for reducing the risk of developing HPV-associated cancers at sites other than the cervix. The combination of HPV vaccination and cervical screening can provide the greatest protection against cervical cancer. It is important that as many people as possible get vaccinated. Not only does vaccination protect vaccinated individuals against infection by the HPV types targeted by the respective vaccine, but also vaccination of a significant proportion of the population can reduce the prevalence of the vaccine-targeted HPV types in the population, thereby providing some protection for individuals who are not vaccinated (a phenomenon called 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 (29).

Before any vaccine is licensed, the FDA must determine that it is both safe and effective. All three HPV vaccines have been tested in tens of thousands of people in the United States and many other countries. Thus far, no serious side effects have been shown to be caused by the vaccines. 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 vaccines have not been sufficiently tested during pregnancy and, therefore, should not be used by pregnant women.

A recent safety review by the FDA and the Centers for Disease Control and Prevention (CDC) considered adverse side effects related to Gardasil immunization that have been reported to the Vaccine Adverse Events Reporting System since the vaccine was licensed (30, 31). The rates of adverse side effects in the safety review 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. However, a higher proportion of syncope (fainting) and venous thrombolic events (blood clots) were seen with Gardasil than are usually seen with other vaccines.  The patients who developed blood clots had known risk factors for developing them, such as taking oral contraceptives. A safety review of Gardasil in Denmark and Sweden did not identify an increased risk of blood clots (31).

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 at http://www.cdc.gov/vaccinesafety/Vaccines/HPV/Index.html.

Although HPV vaccines have been found to be safe when given to people who are already infected with HPV, the vaccines do not treat infection. They provide maximum benefit if a person receives them before he or she is sexually active (15).

It is likely that someone exposed to 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.

At present, there is no generally available test to show whether an individual has been exposed to HPV. The currently approved HPV tests show only whether a person has a current infection with a high-risk HPV type at the cervix and do not provide information on past infections.

ACIP recommends that women who have abnormal Pap test results that may indicate an HPV infection should still receive HPV vaccination if they are in the appropriate age group because the vaccine may protect them against high-risk HPV types that they have not yet acquired. However, these women should be told that the vaccination will not cure them of current HPV infections or treat the abnormal results of their Pap test (32).

Yes. Because HPV vaccines do not protect against all HPV types that can cause cancer, screening continues to be essential to detect precancerous changes in cervical cells before they develop into cancer. In addition, cervical screening tests—HPV DNA test alone, or HPV and Pap test together, also known as co-testing—are critically important for women who have not been vaccinated or who are already infected with HPV. There could be future changes in screening recommendations for vaccinated women.

The best way to know how much vaccination will cost is to contact the insurance plan or the clinic.

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

Medicaid covers HPV vaccination in accordance with the 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 18 and under who are Medicaid eligible, uninsured, underinsured, receiving immunizations through a Federally Qualified Health Center or Rural Health Clinic, or are Native American or Alaska Native. More information about this program is available at http://www.cdc.gov/vaccines/programs/vfc/index.html.  

Merck, the manufacturer of Gardasil and Gardasil 9, offers the Merck Vaccine Patient Assistance Program, which provides Gardasil 9 for free to people aged 19 to 26 who live in the United States, do not have health insurance, and have an annual household income less than a certain amount. More information is available at http://www.merckhelps.com/GARDASIL%209 or by telephone at 1–800–293–3881.

NCI is conducting a long-term follow-up study of women who participated in a community-based clinical trial of Cervarix in Costa Rica, where cervical cancer rates are high. This study is designed to obtain information about the vaccine’s longer-term safety, the extent and duration of protection, the extent to which fewer than three doses can provide protection, the performance of different screening tests among vaccinated women, the immune mechanisms of protection, and the natural history of infection with HPV types other than the types included in the vaccine. The manufacturers of Cervarix and Gardasil are following patients in Scandinavia for at least 15 years to verify that protection from both vaccines lasts at least that long.

Researchers at NCI and elsewhere are working to develop therapeutic HPV vaccines, which would prevent the development of cancer among women previously infected with HPV. An ideal strategy would combine a preventive and therapeutic vaccine.

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. Clinical trials are under way to test whether a topical microbicide that contains carrageenan can prevent genital HPV infection.