HPV Vaccine Safety and Effectiveness Data
More than 12 years of monitoring and research have accumulated reassuring evidence that human papillomavirus (HPV) vaccination provides safe, effective, and long-lasting protection against cancers caused by HPV infections.
Data from Clinical Trials
Each HPV vaccine—9-valent HPV vaccine (Gardasil® 9), quadrivalent HPV vaccine (Gardasil®), and bivalent HPV vaccine (Cervarix®)—went through years of extensive safety testing before it was licensed by the U.S. Food and Drug Administration (FDA). FDA only licenses a vaccine if it is safe and effective, including that the benefits outweigh the risks. Each vaccine was found to be safe and effective in clinical trials.
Gardasil® 9 was studied in clinical trials with more than 15,000 females and males.
Gardasil® was studied in clinical trials with more than 29,000 females and males.
Cervarix® was studied in clinical trials with more than 30,000 females.
Vaccine Safety Monitoring Data
With more than 120 million doses of HPV vaccines distributed in the United States, there are robust data showing that HPV vaccines are safe.
- Like any vaccine or medicine, HPV vaccines can cause side effects. The most common side effects reported through CDC’s Vaccine Adverse Event Reporting System (VAERS) are pain, redness, or swelling in the arm where the vaccine was given, dizziness, syncope (fainting), nausea, and headache.
- With the exception of syncope, which is more common among adolescents after receiving any vaccine, there have been no confirmed adverse events occurring at higher than expected rates following HPV vaccination.
- On very rare occasions, a person may have a serious allergic reaction (anaphylaxis) to any vaccine, including HPV vaccines. In the United States, anaphylaxis following vaccination has a reported rate of 3 cases per 1 million doses administered. People with severe allergies to any component of a vaccine should not receive that vaccine.
The United States monitors safety of all vaccines through several systems:
- Vaccine Adverse Events Reporting System (VAERS) is a spontaneous reporting system that serves as an early warning system to detect possible safety problems that may be related to vaccination. Anyone can submit a report to VAERS. However, it is generally not possible to find out from VAERS data if a vaccine caused the adverse event, and the reports often lack details and sometimes contain errors.
- Vaccine Safety Datalink (VSD) is a collaborative project between CDC and eight healthcare organizations, which monitors the safety of vaccines and conducts rigorous vaccine safety assessments.
- Clinical Immunization Safety Assessment Project (CISA) addresses vaccine safety clinical research and assesses complex clinical adverse events following vaccination.
- Post-licensure Rapid Immunization Safety Monitoring System (PRISM)external icon, a part of FDA’s Sentinel Systemexternal icon, is used to evaluate the safety of vaccines from health insurance claims data.
While only Gardasil® 9 has been available for use in the United States since late 2016, safety studies of Gardasil® have provided important safety information relevant for Gardasil® 9 (Gardasil® and Gardasil® 9 are similar types of vaccines and are produced by the same manufacturer). Studies of Cervarix® have also shown a favorable safety profile. While the vaccines target some different HPV types, all three HPV vaccines are similar and made from a single protein of the human papillomavirus.
- An “adverse event” is any health problem that happens after a shot or other vaccine. An adverse event might be truly caused by a vaccine, or it might be pure coincidence.
- An adverse event is defined by law as “serious”external icon if it is life-threatening or results in death, a persistent or significant disability or incapacity, congenital anomaly or birth defect, hospitalization, or prolongation of existing hospitalization.
- VAERS data alone usually cannot be used to answer the question, “Does a certain vaccine cause a certain adverse event?” This is mainly because adverse events reported to VAERS may or may not be caused by vaccines.
- VAERS reports help provide medical professionals at CDC and FDA with a signal of a potential adverse event that needs to be studied further.
Data on Gardasil® 9 (9vHPV)
- VAERS (data from December 2014 through December 2017external icon)
- ~28 million doses of Gardasil® 9 distributed in the United States
- 7,244 reports of adverse events (AEs).
- 97% of AEs classified as non-serious and 3% classified as serious.*
- VSD (data from October 2015 and October 2017external icon)
- Weekly analyses to detect associations between Gardasil® 9 administration and pre-specified adverse events (anaphylaxis, allergic reaction, appendicitis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, injection site reaction, pancreatitis, seizure, stroke, syncope, and venous thromboembolism) among males and females 9–26 years of age from seven VSD sites.
- > 838,991 doses of Gardasil® 9
- No statistically significant risk for any of the pre-specified AEs following Gardasil® 9 vaccination was detected.
Data on Gardasil® (4vHPV)
- VAERS (data from June 2006 through December 2017)
- > 80 million doses distributed in the United States
- 36,142 reports of adverse events (AEs)
- 93% of AEs classified as non-serious reports and 7% classified as serious.*
- VSD (data from August 2006 through October 2009external icon)(3)
- Weekly analyses to detect associations between Gardasil® administration and pre-specified AEs (Guillain–Barré syndrome, stroke, venous thromboembolism, appendicitis, seizures, syncope, allergic reactions, and anaphylaxis) among 9- to 26-year-old females from seven VSD sites.
- > 600,000 doses of Gardasil®
- No statistically significant risk for any of the pre-specified AEs following Gardasil® was detected
Gardasil® is no longer available in the United States.
Data on Cervarix®(2vHPV)
- VAERS (data from October 2009 through December 2017external icon)(4)
- ~720,000 doses of Cervarix® distributed in the United States
- 245 reports of adverse events (AEs).
- 96% of AEs classified as non-serious and 4% classified as serious.*
Cervarix® is no longer available in the United States and was not administered at any of the VSD sites; therefore, no safety monitoring was conducted through the VSD network.
Vaccine Safety Studies of Specific Conditions
- More than 160 studies have been conducted in multiple countries to look at whether specific adverse events can be linked to HPV vaccine.(5) These studies have shown HPV vaccines have a reassuring safety profile with no confirmed serious adverse events following vaccination.
- Some studies have focused on specific outcomes such as venous thromboembolism, Guillain–Barré syndrome, and diabetes, while other studies have investigated multiple different health problems.(3, 6-23)
Complex Regional Pain Syndrome (CRPS)
- VAERS (data from June 2006 through July 2015)
- >67 million doses of Cervarix® and Gardasil® distributed in the United States.
- 21 reports of CRPS following Gardasil® and one report following Cervarix®external icon out of the total 31,935 reports of adverse events following HPV vaccination in VAERS.(21) These 22 reports were not confirmed as CRPS cases.
- VAERS (data from December 2014 through December 2017)
- ~29 million doses of Gardasil® 9 distributed in the United States
- One report of CRPSexternal icon following Gardasil® 9 identified out of the total 7,244 reports.(1)
- As the information provided in VAERS was insufficient to confirm the diagnosis, the case was classified as possible CRPS.
Postural Orthostatic Tachycardia Syndrome (POTS)
- VAERS (data from June 2006 through July 2015)
- >84 million Gardasil® doses distributed in the United States
- 13 confirmed cases of POTSexternal icon identified following Gardasil® identified out of the total 40,735 reports.(24)
- VAERS (data from December 2014 through December 2017) (1)
- ~29 million doses of Gardasil® 9 distributed in the United States
- 17 possible cases of POTSexternal icon following Gardasil® 9 identified out of the total 7,224 reports.
- Six reports met clinical diagnostic criteria.
- Remaining reports did not contain enough information to confirm a diagnosis of POTS.
Primary Ovarian Insufficiency (POI)
- VAERS (data from January 2009 through December 2015)
- >60 million doses of Gardasil® distributed in the United States
- 17 reports of POIexternal icon following Gardasil® identified out of the total 19,760 reports.(25)
- Two reports had a physician diagnosis of POI.
- The remaining 15 reports were considered hearsay reports, meaning there was not enough information to confirm diagnosis.
- FDA and CDC reviewed the confirmed POI reports, investigating whether there was a pattern that might indicate the vaccine was causing the problem. No unusual or unexpected patterns were detected, making it unlikely the vaccine was the cause.
- VSD conducted a study of POI following adolescent vaccinationsexternal icon, including HPV vaccination.
- Study included 199,078 females 9–26 years of age.(18)
- Only one confirmed case of POI was identified where the patient received HPV vaccine.
- This patient received HPV vaccine 23 months before her first clinical evaluation of having a delayed first period.
- Overall, the study found no increased risk of POI following HPV vaccination or any adolescent vaccination.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
- VAERS (data from June 2006 through September 2015)
- >80 million doses of HPV vaccine distributed in United States
- 20 reports of ME/CFS following Gardasil® identified out of the total 40,735 reports.
- No unusual or unexpected patterns of reporting ME/CFS following HPV vaccine were detected.
- A study from Norwayexternal icon found no increased risk of ME/CFS among girls aged 10–17 years who received Gardasil®.(10)
- A study from Netherlandsexternal icon found no increased incidence of long-term fatigue among adolescent girls following introduction of Cervarix®.(19)
Several large studies have looked at whether HPV vaccines cause autoimmune disease. Many different autoimmune diseases have been studied, including Guillain–Barré syndrome, multiple sclerosis, and diabetes. To date, these studies have not found any association between HPV vaccination and autoimmune conditions.(6-9, 12-18, 20, 26)
- VAERS received seven reports of death following Gardasil® 9 from December 1, 2014, through December 31, 2017, when about 29 million doses had been distributed in the United States.
- VAERS also received 183 reports of death following Gardasil® from June 2006 through September 2015, when about 80 million doses had been distributed.
- With about 720,000 doses of Cervarix® distributed in the United States, VAERS received no reports of death following this vaccine.
- Five of the reported deaths for Gardasil® 9 and 116 for Gardasil® could not be further studied because there was not enough information included in the report to verify that a person had died.
- Among the remaining reports, CDC reviewed medical records, autopsy reports, or death certificates and verified the person had died.
- The review of available information did not suggest a causal link between HPV vaccines and the reported deaths.
Vaccine Effectiveness Studies
Studies in the United States and other countries have shown that HPV vaccination is preventing cancer-causing infections, genital warts, and cervical precancers. This suggests that there will be decreases in cancers caused by HPV in the future.
- Monitoring HPV vaccine prevalence is ongoing in the United States. As early as 4 years after Gardasil® licensure, vaccine-type HPV infections decreasedexternal icon 56% among 14- to 19-year-old females.(27)
- Within 10 years of vaccine introduction, infections with the four HPV types targeted by Gardasil® decreasedexternal icon 86% among 14- to 19-year-old females and 71% among 20- to 24-year-old females in the United States.(28)
- An analysisexternal icon of healthcare claims data examined trends in anogenital warts among a large group of private health insurance enrollees in the United States. The study found that between 2006 (the year HPV vaccine was recommended for routine vaccination of females) and 2014, prevalence of anogenital warts among females decreased 61% among 15–19-year-olds and 44% among 20–24-year-olds.(29)
- Small declines in males in these age groups were observed starting after 2009. The initial decline in males was likely due to herd effects, as routine vaccination of boys was recommended in 2011.
- Compared to 2008-2009, cervical precancer ratesexternal icon among screened females in 2014-2015 were 50% lower in 18- to 20-year-olds and 36% lower in 21- to 24-year-olds.(30)
- The percentage of cervical lesions due to types that are prevented by the HPV vaccineexternal icon has dropped by 40% in vaccinated women since the vaccine was introduced.(31)
- Decreases in prevalence of vaccine-type HPV infections, anogenital warts, and cervical precancersexternal icon also have been observed in more than 14 countries with HPV vaccination programs, including Australia, Scotland, and others.(32)
Duration of Protection Studies
Data from clinical trials and ongoing research show that HPV vaccination provides long-lasting protection.
- Protection by HPV vaccination lasts at least 10 years without becoming less effective.(33, 34)
- Studies are ongoing to further evaluate the duration of protection.
- No data indicate that the protection from HPV vaccination lessens over time.
- Shimabukuro TT, Su JR, Marquez PL. Safety of the 9-valent human papillomavirus vaccine. Pediatrics. 2019. Published ahead of print. e20191791; DOI: https://doi.org/10.1542/peds.2019-1791external icon.
- Donahue JG, Kieke BA, Lewis EM. Near real-time surveillance to assess the safety of the 9-valent human papillomavirus vaccine. Pediatrics. 2019. Published ahead of print. e20191808; DOI: https://doi.org/10.1542/peds.2019-1808external icon.
- Gee J, Naleway A, Shui I, Baggs J, Yin R, Li R, et al. Monitoring the safety of quadrivalent human papillomavirus vaccine: findings from the Vaccine Safety Datalink. Vaccine. 2011;29(46):8279-84.
- Suragh TA, Lewis P, Arana J, Mba-Jonas A, Li R, Stewart B, et al. Safety of bivalent human papillomavirus vaccine in the US vaccine adverse event reporting system (VAERS), 2009-2017. Br J Clin Pharmacol. 2018;84(12):2928-32.
- Phillips A, Patel C, Pillsbury A, Brotherton J, Macartney K. Safety of Human Papillomavirus Vaccines: An Updated Review. Drug Saf. 2018;41(4):329-46.
- Andrews N, Stowe J, Miller E. No increased risk of Guillain-Barre syndrome after human papilloma virus vaccine: A self-controlled case-series study in England. Vaccine. 2017;35(13):1729-32.
- Arnheim-Dahlstrom L, Pasternak B, Svanstrom H, Sparen P, Hviid A. Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study. BMJ. 2013;347:f5906.
- Chao C, Klein NP, Velicer CM, Sy LS, Slezak JM, Takhar H, et al. Surveillance of autoimmune conditions following routine use of quadrivalent human papillomavirus vaccine. J Intern Med. 2012;271(2):193-203.
- Deceuninck G, Sauvageau C, Gilca V, Boulianne N, De Serres G. Absence of association between Guillain-Barre syndrome hospitalizations and HPV-vaccine. Expert Rev Vaccines. 2018;17(1):99-102.
- Feiring B, Laake I, Bakken IJ, Greve-Isdahl M, Wyller VB, Haberg SE, et al. HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: A nationwide register-based study from Norway. Vaccine. 2017;35(33):4203-12.
- Frisch M, Besson A, Clemmensen KKB, Valentiner-Branth P, Molbak K, Hviid A. Quadrivalent human papillomavirus vaccination in boys and risk of autoimmune diseases, neurological diseases and venous thromboembolism. Int J Epidemiol. 2018;47(2):634-41.
- Gee J, Sukumaran L, Weintraub E. Risk of Guillain-Barre Syndrome following quadrivalent human papillomavirus vaccine in the Vaccine Safety Datalink. Vaccine. 2017;35(43):5756-8.
- Grimaldi-Bensouda L, Guillemot D, Godeau B, Benichou J, Lebrun-Frenay C, Papeix C, et al. Autoimmune disorders and quadrivalent human papillomavirus vaccination of young female subjects. J Intern Med. 2014;275(4):398-408.
- Grimaldi-Bensouda L, Rossignol M, Kone-Paut I, Krivitzky A, Lebrun-Frenay C, Clet J, et al. Risk of autoimmune diseases and human papilloma virus (HPV) vaccines: Six years of case-referent surveillance. J Autoimmun. 2017;79:84-90.
- Hviid A, Svanstrom H, Scheller NM, Gronlund O, Pasternak B, Arnheim-Dahlstrom L. Human papillomavirus vaccination of adult women and risk of autoimmune and neurological diseases. J Intern Med. 2018;283(2):154-65.
- Klein NP, Goddard K, Lewis E, Ross P, Gee J, DeStefano F, et al. Long term risk of developing type 1 diabetes after HPV vaccination in males and females. Vaccine. 2019;37(14):1938-44.
- Liu EY, Smith LM, Ellis AK, Whitaker H, Law B, Kwong JC, et al. Quadrivalent human papillomavirus vaccination in girls and the risk of autoimmune disorders: the Ontario Grade 8 HPV Vaccine Cohort Study. CMAJ. 2018;190(21):E648-e55.
- Naleway AL, Mittendorf KF, Irving SA, Henninger ML, Crane B, Smith N, et al. Primary Ovarian Insufficiency and Adolescent Vaccination. Pediatrics. 2018;142(3).
- Schurink-Van’t Klooster TM, Kemmeren JM, van der Maas NAT, van de Putte EM, Ter Wolbeek M, Nijhof SL, et al. No evidence found for an increased risk of long-term fatigue following human papillomavirus vaccination of adolescent girls. Vaccine. 2018;36(45):6796-802.
- Skufca J, Ollgren J, Artama M, Ruokokoski E, Nohynek H, Palmu AA. The association of adverse events with bivalent human papilloma virus vaccination: A nationwide register-based cohort study in Finland. Vaccine. 2018;36(39):5926-33.
- Weinbaum CM, Cano M. HPV Vaccination and Complex Regional Pain Syndrome: Lack of Evidence. EBioMedicine. 2015;2(9):1014-5.
- Yih WK, Greene SK, Zichittella L, Kulldorff M, Baker MA, de Jong JL, et al. Evaluation of the risk of venous thromboembolism after quadrivalent human papillomavirus vaccination among US females. Vaccine. 2016;34(1):172-8.
- Yih WK, Maro JC, Nguyen M, Baker MA, Balsbaugh C, Cole DV, et al. Assessment of Quadrivalent Human Papillomavirus Vaccine Safety Using the Self-Controlled Tree-Temporal Scan Statistic Signal-Detection Method in the Sentinel System. Am J Epidemiol. 2018;187(6):1269-76.
- Arana J, Mba-Jonas A, Jankosky C, Lewis P, Moro PL, Shimabukuro TT, et al. Reports of Postural Orthostatic Tachycardia Syndrome After Human Papillomavirus Vaccination in the Vaccine Adverse Event Reporting System. J Adolesc Health. 2017;61(5):577-82.
- Arana JE, Harrington T, Cano M, Lewis P, Mba-Jonas A, Rongxia L, et al. Post-licensure safety monitoring of quadrivalent human papillomavirus vaccine in the Vaccine Adverse Event Reporting System (VAERS), 2009-2015. Vaccine. 2018;36(13):1781-8.
- Scheller NM, Svanstrom H, Pasternak B, Arnheim-Dahlstrom L, Sundstrom K, Fink K, et al. Quadrivalent HPV vaccination and risk of multiple sclerosis and other demyelinating diseases of the central nervous system. JAMA. 2015;313(1):54-61.
- Markowitz LE, Hariri S, Lin C, Dunne EF, Steinau M, McQuillan G, et al. Reduction in human papillomavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, National Health and Nutrition Examination Surveys, 2003-2010. J Infect Dis. 2013;208(3):385-93.
- McClung NM, Gargano JW, Park IU, Whitney E, Abdullah N, Ehlers S, et al. Estimated Number of Cases of High-Grade Cervical Lesions Diagnosed Among Women – United States, 2008 and 2016. MMWR. 2019;68(15):337-43.
- Flagg EW, Torrone EA. Declines in Anogenital Warts Among Age Groups Most Likely to Be Impacted by Human Papillomavirus Vaccination, United States, 2006-2014. Am J Public Health. 2018;108(1):112-9.
- Gargano JW, Park IU, Griffin MR, Niccolai LM, Powell M, Bennett NM, et al. Trends in High-grade Cervical Lesions and Cervical Cancer Screening in 5 States, 2008-2015. Clin Infect Dis. 2019;68(8):1282-91.
- McClung NM, Gargano JW, Bennett NM, Niccolai LM, Abdullah N, Griffin MR, et al. Trends in Human Papillomavirus Vaccine Types 16 and 18 in Cervical Precancers, 2008-2014. Cancer Epidemiol Biomarkers Prev. 2019;28(3):602-9.
- Drolet M, Benard E, Perez N, Brisson M. Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis. Lancet. 2019;394(10197):497-509.
- Naud PS, Roteli-Martins CM, De Carvalho NS, Teixeira JC, de Borba PC, Sanchez N, et al. Sustained efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine: final analysis of a long-term follow-up study up to 9.4 years post-vaccination. Hum Vaccin Immunother. 2014;10(8):2147-62.
- Ferris DG, Samakoses R, Block SL, Lazcano-Ponce E, Restrepo JA, Mehlsen J, et al. 4-Valent Human Papillomavirus (4vHPV) Vaccine in Preadolescents and Adolescents After 10 Years. Pediatrics. 2017;140(6). pii: e20163947. doi: 10.1542/peds.2016-3947