by C.H. Weaver M.D. updated 7/2019
Human papillomaviruses (HPV) have a wide range of health effects, but vaccines continue to offer hope for prevention and perhaps may even lead to the eradication of HPV related diseases.
In 2008 Harald zur Hausen, DSc, MD, of Germany was awarded half the Nobel Prize in Physiology or Medicine for his pioneering work in the discovery of human papillomaviruses as the primary cause of cervical cancer. Although a link with HPV seemed far-fetched when he began his research in the 1970s, work conducted by Dr. zur Hausen and others firmly established the relationship between HPV and cervical cancer and ultimately led to the development of HPV vaccines. Currently available vaccines have the potential to prevent an estimated 70 percent of all cervical cancers.
The story of HPV does not end there, however. Work continues to understand the full range of HPV’s effects; in addition to contributing to cervical cancer, high-risk types of HPV have been linked with cancers of the vulva, vagina, penis, anus, and some cancers of the head and neck. Researchers also continue to monitor HPV vaccine safety and have extended vaccine recommendations to additional segments of the population, such as boys. The ultimate goal is the eradication of cancers that claim more than 300,000 lives worldwide each year and to reduce the occurrence of other HPV related diseases.
An Overview of HPV
Human papillomaviruses consist of more than 100 different types. Some types of HPV cause warts on the hands or feet; others cause genital warts; and some have been linked with cancer, most notably cervical cancer.
The types of HPV that are linked with cervical cancer and genital warts are transmitted sexually. Genital HPV infection is extremely common and generally occurs soon after an individual becomes sexually active. The likelihood that an HPV infection will develop into cancer depends in part on the HPV type and the persistence of the infection. Certain types of HPV have been more strongly linked with cancer than others and are referred to as “high-risk.” HPV types 16 and 18, for example, are high-risk types that are thought to account for roughly 70 percent of all cases of cervical cancer. Among women infected with a high-risk type of HPV, persistent infection is the major risk factor for cervical cancer.
Infection with a high-risk type of HPV does not necessarily lead to cancer. Many infections disappear on their own, and others may persist without causing cancer. Infection with a high-risk type of HPV does, however, increase the risk of cancer, and virtually all cases of cervical cancer can be linked to infection with a high-risk type of HPV. Among women infected with HPV, smoking appears to significantly increase the risk of cervical abnormalities, providing yet another reason for women to avoid tobacco.
Gardasil® and Cervarix,® are commercially available HPV vaccines intended to prevent infection with certain types of HPV; these vaccines do not treat existing HPV infections or cervical abnormalities. It’s also important to keep in mind that these vaccines do not protect against all types of HPV; women who are vaccinated should continue to be screened for cervical cancer.
Gardasil protects against HPV types 6 and 11 (which are linked to genital warts) as well as the cancer-associated types 16 and 18. The vaccine was approved in 2006 for use in girls and women between the ages of 9 and 26 years. Because the vaccine is not effective against existing infections, it is likely to have the greatest effect when given before a girl becomes sexually active. The Advisory Committee on Immunization Practices at the U.S. Centers for Disease Control and Prevention (CDC) recommends routine vaccination of girls 11 to 12 years of age.(3)
Since its licensure Gardasil has been featured prominently in the media, as scientists, healthcare providers, policy makers, and parents have discussed issues of the effectiveness, safety, and scope of vaccine recommendations. According to John Iskander, MD, MPH, associate director for science in the Immunization Safety Office of the CDC, such attention was not unexpected: “This vaccine was not only new but novel. It was targeting a sexually transmitted disease; it was targeting adolescents, who are not traditionally a major target for vaccines; and it was targeting cancer prevention. When you look at all of those factors together, it’s not surprising that it’s drawn this degree of interest.”
An issue of great importance to parents and girls is vaccine safety. The most common adverse events identified in pre-licensure studies of Gardasil were pain at the injection site, swelling, redness, and fever.(4) The safety of Gardasil has also been closely monitored post-licensure using two primary sources: the Vaccine Adverse Event Reporting System (VAERS) and the Vaccine Safety Datalink (VSD). VAERS is managed jointly by the CDC and the FDA and collects reports about adverse events following vaccination. These reports come from many sources, including healthcare providers, patients, and parents. VAERS reports can neither prove nor disprove that vaccination caused a particular adverse event (some events follow vaccination but are not caused by vaccination), but the information reported to VAERS allows researchers to identify potential areas of concern that warrant additional investigation. The VSD links medical record information from several large managed-care organizations and allows researchers to conduct more in-depth analyses of potential safety concerns. “The overall findings so far from both systems, which we summarized for a major CDC advisory committee about four months ago, is that there have been no new serious, unexpected adverse events or safety concerns detected,” says Dr. Iskander.
In spite of these reassuring findings, a survey of healthcare providers found that some parents are still concerned that Gardasil is “too new.”(5) Asked to respond to this concern, Dr. Iskander explains, “Historically, most major safety concerns after vaccines are licensed show up within about the first 3 million doses or so. For example, with the first rotavirus vaccine and bowel obstruction, that showed up after about a million doses had been distributed. With Gardasil, I don’t have the exact numbers, but we’re past the 23-million-doses-distributed mark. At some point the argument of ‘it’s too new’ needs to be looked at a little more critically. In my almost 10 years working in vaccine safety, this is a very heavily studied vaccine.”
Something that parents may want to be aware of is the risk of fainting post-vaccination. Information from both VAERS and VSD suggests that fainting after vaccination is on the rise, particularly among adolescents. The main concern about fainting is that it could lead to injury as a result of falling. To address this concern, it is recommended that people of all ages be observed for 15 minutes after vaccination.
The Burden of HPV-related Cancers
As HPV research has progressed, it’s become apparent that cervical cancer is just one piece of the puzzle. HPV has also been linked to other anogenital cancers (cancers of the vulva, vagina, penis, and anus) and with certain types of head and neck cancer. This suggests that the benefits of HPV vaccination could extend well beyond cervical cancer.
Cervical cancer is the most common HPV-related cancer. Worldwide there are an estimated 555,000 new diagnoses of cervical cancer each year and more than 300,000 deaths. More than 80 percent of these deaths occur in developing countries.(7) Cervical cancer is less common in the United States, where effective screening programs have led to the detection and the treatment of precancerous changes to the cervix, but there are still roughly 11,000 new diagnoses of cervical cancer in the United States each year.(8)
Non-cervical cancers that have been linked with HPV include other anogenital cancers as well as oropharyngeal cancers. The oropharynx is the part of the throat that includes the soft palate, the base of the tongue, and the tonsils. Although many cases of oropharyngeal cancer can be attributed to smoking and alcohol use, it’s now apparent that some cases are caused by infection with high-risk types of HPV, particularly HPV 16.(9) The potential importance of HPV as a cause of oropharyngeal cancer is reflected in patterns of this cancer over time: although overall rates of head and neck cancer have declined as smoking rates have declined, rates of oropharyngeal cancer have not declined and appear to be increasing in young adults.(10) The way in which the oropharynx becomes infected with HPV remains uncertain, but sexual transmission appears likely.
In the United States, the total number of noncervical cancers caused by HPV is approximately the same as the total number of cervical cancers.(11) Furthermore, these non-cervical HPV-related cancers are evenly divided between men and women, suggesting that approximately 25 percent of all HPV-related cancers in the United States occur in men. Because many of these cancers are thought to be caused by HPV types 16 and 18 (the HPV types included in current vaccines), vaccination may provide important benefits to both men and women. It must be remembered, however, that HPV vaccines have not yet been shown to be effective against oropharyngeal cancer, anal cancer, and penile cancer; a benefit of vaccination against these cancers is plausible but unconfirmed.
Other Conditions Caused by HPV
In addition to targeting HPV types 16 and 18, Gardasil prevents infection with HPV types 6 and 11, which account for most cases of genital warts. Although not life-threatening, genital warts can have profound psychological consequences and can be difficult and expensive to treat.(12)
HPV types 6 and 11 are also responsible for a less common but potentially serious condition known as recurrent respiratory papillomatosis (RRP).(13) RRP refers to benign (non-cancerous) growths in the upper airway that can interfere with breathing and speech. These growths can be surgically removed but often recur following treatment; as a result, patients with RRP often require multiple surgeries over the course of a lifetime to control the condition. RRP may develop in childhood (juvenile-onset RRP) or adulthood (adult-onset RRP). Children with RRP were most likely exposed to HPV types 6 or 11 in their mother’s genital tract during childbirth.
The Next Chapter
The work begun by Dr. zur Hausen in the 1970s continues today, as researchers expand our understanding of human papillomaviruses and their role in cancer and other diseases. This work may eventually broaden the use of currently available vaccines and could also lead to newer types of vaccines that protect against a wider range of HPV types. The result? Fewer cases of cervical cancer, certainly; but the impact of this research may extend well beyond that, ultimately improving the health of both women and men.
Answers to Frequently Asked Questions About HPV and Vaccination
If I’m vaccinated, will I still need to be screened for cervical cancer?
Yes. The vaccine does not protect against all high-risk types of HPV. Average-risk women are advised to begin cervical cancer screening within three years of becoming sexually active and no later than the age of 21.Screening generally includes a Pap test and may also include an HPV test.(14)
What vaccines are available?
There are currently two FDA-approved vaccines that protect against the types of HPV associated with cervical cancer.
- Gardasil® (quadrivalent human papillomavirus [types 6, 11, 16, 18] recombinant vaccine), which prevents infection with four types of HPV—types 6, 11, 16, and 18.
- Cervarix® (human papillomavirus bivalent [types 16 and 18] recombinant vaccine) , which targets HPV types 16 and 18. HPV types 16 and 18 cause roughly 70% of all cases of cervical cancer, and HPV types 6 and 11 account for roughly 90% of genital warts.
Does vaccination treat existing HPV infections?
No. The vaccine is intended to prevent infection with specific types of HPV. It will not treat existing infections or cervical abnormalities.(15)
Does vaccination protect against vaginal warts and other HPV related diseases?
Yes, for example one clinical trial demonstrated that Gardasil was 96-100% effective in preventing low-grade lesions or genital warts related to the HPV types the vaccine is targeted against (types 6, 11, 16, and 18).(20)
- When looking at all lesions regardless of HPV type, the efficacy of Gardasil was 30% for low-grade cervical changes; 75% for low-grade vulvar changes, 48% for low-grade vaginal changes, and 83% for genital warts.
- Protection was sustained through the four years of follow-up.
Can I become infected with HPV by being vaccinated?
No. The vaccine does not contain live virus and cannot cause infection.
What are the target age groups for vaccination?
The Advisory Committee on Immunization Practices recommends routine vaccination of girls ages 11 to 12 years. The vaccine can also be offered to girls as young as nine as well as girls and women between the ages of 13 and 26.
Is there any reason to vaccinate boys?
Vaccinating boys may provide important benefits. Vaccinating boys would reduce transmission of the virus in the population and may also protect boys against HPV-related conditions such as genital warts and cancers of the penis, anus, and oropharynx. In 2011 the CDC recommended routine vaccination of boys at ages 11-12, but the vaccine can also be given to boys as young as nine and to men up to the age of 26.(16)
How many doses of the vaccine are required?
The vaccine is given in three doses over a six-month period.
Is vaccination effective in older individuals?
Vaccination Provides Poor Protection in Women Over 18. A significant percentage of women vaccinated with Gardasil® may not be protected against high-grade squamous intraepithelial lesions (HSIL) and lesser dysplasia—especially if they were vaccinated after age 18 or had abnormal cytology before vaccination, according to the results of a study published in the Journal of Clinical Oncology.
Researchers from the University of Manitoba evaluated the effectiveness of Gardasil in a study that included over 13,000 women over the age of 15. The study included 3,541 females who were vaccinated with Gardasil and 9,594 age-matched, non-vaccinated females. The researchers estimated the hazard ratios for three outcomes: atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesions (LSILs), and high-grade SILs (HSILs).
They estimated that among the 15 to 17-year-olds in the study, the vaccine reduced the risk of HSIL by 35 percent, LSIL by 21 percent, and ASCUS by -1 percent. The corresponding estimates were higher among those who had at least one Pap smear after enrollment: 46 percent for HSIL, 35 percent for LSIL, and 23 percent for ASCUS.
In contrast, the vaccines effectiveness was lower among subjects 18 and older. In these women, the vaccine was associated with a 23 percent reduction in HSIL if they had no history of abnormal cytology; however, the vaccine appeared to offer no protection in those with a history of abnormal cytology.
The researchers concluded that “a significant percentage of vaccinated women may not be protected against HSIL and lesser dysplasia, especially if they were vaccinated at older age or had abnormal cytology before vaccination.” They suggest that their findings indicate the importance of early vaccination—before exposure to HPV.(17)
Are allergic reactions common with vaccination?
No, Allergic reactions to Gardasil® are uncommon and most young women who have a suspected allergic reaction can tolerate subsequent doses, according to the results of a study published in an early online issue of the British Medical Journal.
The Australian national immunization program administered more than 380,000 doses of Gardasil to girls ages 12-26 in secondary schools. In compliance with Australian protocols of reporting vaccine-related adverse events, 35 schoolgirls with suspected hypersensitivity to the drug were reported to the specialized immunization services. Of those 35 girls, 25 agreed to further evaluation.
Upon further evaluation the researchers found that most cases (23) of the suspected hypersensitivity occurred after the first dose of the vaccine. These events included rash, hives, swelling and in two cases, anaphylaxis. However, after undergoing skin prick and injection testing, only three of the 25 girls were found to have probable hypersensitivity to the vaccine. The hypersensitivity in these three girls was defined as anaphylaxis, positive skin test, or a reproducible reaction to “challenge” doses with the vaccine.
Because only three girls out of more than 300,000 who received Gardasil experienced true hypersensitivity to the vaccine, the researchers concluded that true hypersensitivity to Gardasil is uncommon and most girls tolerate subsequent doses. Although allergic reactions appear to be rare following vaccination with Gardasil, suspected allergic reactions should be evaluated before additional doses are given.(18)
Is HPV vaccination safe?
researchers evaluated the medical records of 189,629 girls and women ages 9 to 26 within the Northern and Southern California Kaiser Permanente health care systems. All participants received at least one dose of Gardasil between 2006 and 2008 and by the end of the study period, 44,000 participants had received three doses of the vaccine.
The researchers examined the rate of emergency visits and hospitalizations in the two weeks following vaccination and again a couple months later. They found that the vaccine caused fainting on the day of the injection and skin infections two weeks later in some subjects, both of which are known short-term side effects of the vaccine. However, they concluded that the vaccine was not associated with serious health effects.
Although there were reports of seizures and allergic reactions, a five-member safety committee of medical experts concluded that these reactions were not related to the vaccine.
Overall, the safety experts determined that there were no safety concerns with the vaccine. They note that fainting is a common reaction to all vaccines.(19)
Finding Reliable Information About Vaccine Safety
http://immunizationinfo.orgThe Web site of the National Network for Immunization Information (NNii) provides information about a range of immunization topics, including how to find accurate vaccine information on the Internet. Parents may also be interested in the NNii booklet titled Do Vaccines Cause That?! A Guide for Evaluating Vaccine Safety Concerns.
- Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. New England Journal of Medicine. 1998;338(7):423-28.
- Wang SS, Zuna RE, Wentzensen N, et al. Human papillomavirus cofactors by disease progression and human papillomavirus types in the Study to Understand Cervical Cancer Early Endpoints and Determinants. Cancer Epidemiology, Biomarkers, and Prevention. 2009;18(1):113-20.
- Markowitz LE, Dunne EF, Saraiya M, et al. Quadrivalent human papillomavirus vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2007;56(RR-2):1-24.
- Gardasil® Prescribing Information. Merck Web site. Available at: http://www.gardasil.com/prescribing-information-about-gardasil.html. Accessed April 8, 2009.
- Advisory Committee on Immunization Practices. Minutes of the October 2008 meeting. Centers for Disease Control and Prevention Web site. Available at: http://www.cdc.gov/vaccines/recs/acip/meetings.htm. Accessed April 8, 2009.
- Kroger AT, Atkinson WL, Marcuse EK, et al. General recommendations on immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2006;55(RR-15):1-48.
- Global Cancer Facts & Figures 2007. American Cancer Society Web site. Available at: http://www.cancer.org/docroot/STT/content/STT_1x_Global_Cancer_Facts_and_Figures_2007.asp. Accessed April 8, 2009.
- Cancer Facts & Figures 2018. American Cancer Society Web site. Available at: http://www.cancer.org/docroot/stt/stt_0.asp.
- Ryerson AB, Peters ES, Coughlin SS, et al. Burden of potentially human papillomavirus-associated cancers of the oropharynx and oral cavity in the US, 1998-2003. Cancer. 113(10 Suppl):2901-9.
- Sturgis EM, Cinciripini PM. Trends in head and neck cancer incidence in relation to smoking prevalence: An emerging epidemic of human papillomavirus-associated cancers? Cancer. 2007;110(7):1429-35.
- Gillison ML, Chaturvedi AK, Lowy DR. HPV prophylactic vaccines and the potential prevention of noncervical cancers in both men and women. Cancer. 2008;113(10 Suppl):3036-46.
- Lacey CJ, Lowndes CM, Shah KV. Chapter 4: Burden and management of non-cancerous HPV-related conditions: HPV-6/11 disease. Vaccine. 2006;24(3 Suppl:S3/35-S3/41.
- Lacey CJN, Lowndes CM, Shah KV. Chapter 4: Burden and management of non-cancerous HPV-related conditions: HPV-6/11 disease. Vaccine. 2006;24(3 Suppl):S35-S41.
- Smith RA, Cokkinides V, Brawley OW. Cancer screening in the United States, 2008: A review of current American Cancer Society guidelines and cancer screening issues. CA: A Cancer Journal for Clinicians. 2008;58(3);161-79.
- Hildesheim A, Herrero R, Wacholder S et al. Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection. JAMA. 2007;298:743-753.
- CDC Media Advisory. ACIP recommends all 11-12 year-old males get vaccinated against HPV. Recommendations subject to approval by CDC. October 25, 2011.
- Mahmud SM, Kliewer EV, Lambert P, et al: Effectiveness of the Quadrivalent Human Papillomavirus Vaccine Against Cervical Dysplasia in Manitoba, Canada. Journal of Clinical Oncology. Published early online January 6, 2014. doi: 10.1200/JCO.2013.52.4645
- Kang LW, Crawford N, Tang MLK, et al. Hypersensitivity reactions to human papillomavirus vaccine in Australian schoolgirls: Retrospective cohort study. British Medical Journal. 2008;337:a2642, doi: 10.1136/bmj.a2642 (Published 2 December 2008)
- Klein NP, Hansen J, Chao C, et al. Safety of quadrivalent human papillomavirus vaccine administered routinely to females. Archives of Pediatrics & Adolescent Medicine. Published early online October 2012. doi:10.1001/archpediatrics.2012.1451.
- The FUTURE I/II Study Group. Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial. BMJ. 2010;341:c3493.