Summary of Key Facts
- This multiple-part series offers a thorough analysis of concerns raised about HPV vaccination following the global HPV campaign, which commenced in 2006.
- In the United States, the HPV vaccine was reported to have a disproportionately higher percentage of adverse events of fainting and blood clots in the veins. The U.S. Food and Drug Administration (FDA) acknowledges that fainting can happen following the HPV vaccine, and recommends sitting or lying down to get the shot, then waiting for 15 minutes afterward.
- International scientists found that the U.S. Centers for Disease Control and Prevention's (CDC) Vaccine Adverse Events Reporting System (VAERS) logged a substantial increase in reports of premature ovarian failure (POF) from 1.4 per year before 2006 to 22.2 per year after the HPV vaccine approval, yielding a Proportional Reporting Ratio of 46.1.
In this HPV vaccine series, Parts I and II explain how the vaccine works and the evidence suggesting there may be legitimate safety concerns. The remaining parts present questions about real-world vaccine effectiveness and identify specific ingredients which may pose harm.
The information presented here is drawn from peer-reviewed scientific literature from the United States, Australia, Denmark, Sweden, France, and Japan, as well as statistics published by public health agencies in each of these countries. More than 100 hours of research and internal peer review among scientists with experience in infectious diseases, virology, clinical trials, and vaccine epidemiology have been invested in presenting this summary of the evidence.
Large registry-based studies have identified plausible associations between HPV vaccination and autoimmune conditions, including premature ovarian insufficiency or failure (POI/POF), Guillain-Barré syndrome (GBS), postural orthostatic tachycardia syndrome (POTS), and chronic regional pain syndrome (CRPS).
What Is Human Papillomavirus (HPV)?According to the CDC, HPV is the most common sexually transmitted infection (STI) in the United States.
HPV is a small DNA virus infecting human cutaneous epithelial cells in the mucosa and skin. More than 150 strains of the HPV virus have been identified.
HPV infection is so common that the majority of sexually active people will get it at some point in their lives, even if they have only one or very few sexual partners. It can spread through sexual intercourse and oral sex. It can also pass between people through skin-to-skin contact, even by people who have no symptoms.
HPV-Associated CancersHigh-risk HPV types (types 16, 18, and others) can cause cervical cell abnormalities that are precursors to cancers.
An additional five high-risk types, 31, 33, 45, 52, and 58, are linked with another 15 percent of cervical cancers and 11 percent of all HPV-associated cancers.
Infection with a high-risk HPV type is associated with a higher chance of the development of cervical cancer but, by itself, HPV infection is not the sole risk factor to cause cancer. There are many other reasons, as discussed in this paper.
HPV VaccinesThree HPV vaccines—bivalent HPV vaccine (Cervarix, 2vHPV), quadrivalent HPV vaccine (Gardasil, 4vHPV), and 9-valent HPV vaccine (Gardasil 9, 9vHPV)—have been licensed by the FDA.
Cervarix, developed by GlaxoSmithKline, is a bivalent vaccine against HPV types 16 and 18, that was pulled from the U.S. market in 2016 due to "very low market demand."Merck’s original Gardasil vaccine was designed to prevent infections from four strains (types 6, 11, 16, and 18).
On Oct. 16, 2009, the FDA approved Gardasil (qHPV) for use in boys ages 9 through 26 for the prevention of genital warts caused by HPV types 6 and 11, but not for cancer.
In 2010, it approved Gardasil for the prevention of anal cancer in males and females ages 9 to 26.
Four years later, the FDA approved an updated vaccine, Merck’s Gardasil 9, for use in girls ages 9 to 26 and boys ages 9 to 15 for the prevention of cervical, vaginal, and anal cancers.
HPV VAERS Reports From 2 Large Countries
US HPV Vaccine Adverse EventsOn Aug. 19, 2009, the Journal of the American Medical Association (JAMA) published an article authored by scientists from the FDA and CDC that reviewed the safety data for Gardasil for adverse events reported to the VAERS between June 2006 through December 2008.
During that time, there were 12,424 reports of adverse events. Of these, 772 (6.2 percent) were serious.
Nevertheless, it is a useful and important tool for detecting postmarket safety issues with vaccines.
A disproportionately high percentage of Gardasil VAERS reports were of syncope (fainting) and venous thromboembolic events (blood clots in the veins) compared with other vaccines. There were 8.2 syncope events per 100,000 HPV doses and 0.2 venous thromboembolic events (VTE) per 100,000 HPV doses reported, respectively.
Australia HPV Vaccines Adverse EventsIn 2007, Australia reported an annual adverse drug reaction rate of 7.3/100,000, the highest since 2003, representing an 85 percent increase from 2006.
Per the analysis of the Adverse Drug Reactions System (ADRS) database by the Australian Department of Health and Aging, this increase was "almost entirely due to" reports following the national rollout of the three-dose HPV vaccination program for young females in April 2007; 705 of the 1,538 adverse drug reactions reported that year were from the Gardasil vaccine.
Moreover, though people may take different vaccines other than HPV, the HPV vaccine was the only suspected vaccine to cause adverse reactions in 96 percent of records. Twenty-nine percent had causality ratings of “certain” or “probable” and 6 percent were defined as “serious.”
Japan Withdraws Recommendation, Vaccine Acceptance PlungedIn 2013, the Japanese raised concerns about a variety of widely reported post-vaccination serious adverse events. This led the government to suspend recommending the HPV vaccine for six years. Vaccine acceptance of HPV in Japan plunged significantly after 2013, from 42.9 percent to 14.3 percent., or from 65.4 percent to 3.9 percent.
Ovarian InsufficiencyConcerns that the vaccine may be negatively affecting fertility have been detailed in the scientific literature.
VAERS Analysis on Ovarian FailureTwo recent publications based on VAERS reports (first study, second study) found that events with a probable autoimmune background were significantly more frequent after HPV vaccination compared to other vaccinations.
The team of international scientists that did the second study evaluated reports between 1990 and 2018. They found that among the 228,341 POF reports, 0.1 percent was considered to be associated with HPV vaccination with a median age of 15 years and the time to onset was 20.5 days following vaccination. The primary symptoms were amenorrhea (80.4 percent) and premature menopause (15.3 percent).
Most strikingly, the mean number of POF cases increased significantly from 1.4 per year prior to 2006 to 22.2 per year after the HPV vaccine was approved, with a proportional reporting ratio of 46.
The investigators noted that the WHO and CDC declared the HPV vaccine safe regardless of lacking adequate research into safety concerns.
In summary, the researchers detected a strong safety signal even after accounting for a potential upswing in reports due to media coverage after the product launch (they refer to this as “notoriety bias”). Because VAERS is a passive reporting system, the data may be incomplete and are often unconfirmed by physicians. Therefore, this study cannot provide a definitive link between HPV vaccination and POI or POF but does generate a hypothetical link.
The authors of the second study conclude by insisting that “...this signal warrants well-designed and appropriate epidemiological research.” They note that “if the signal is confirmed, the risk is small compared to the lifetime risk of cervical cancer.”
However, the benefit-risk profile on an individual level is not uniform.
3 Case Reports on Ovarian InsufficiencyIn the 2014 investigation mentioned above, a general practitioner in Australia noticed that three girls developed premature ovarian insufficiency (POI) following HPV4 vaccination. As a result of vaccination, each of the girls (ages 16, 16, and 18) had been prescribed oral contraception to treat menstrual cycle irregularities. Typically, women present with amenorrhea (no periods) or oligomenorrhea (infrequent periods) as the initial symptom of POI.
One girl had irregular periods following three doses of HPV vaccination. She then became amenorrheic and was diagnosed with POI.
Another girl's periods were “like clockwork” until after the third HPV dose, which she received at age 15. Her first cycle after being vaccinated for the third time started two weeks late, and her next cycle was two months late. The final cycle began nine months later. The patient had no family history of early menopause. She was diagnosed with premature ovarian failure at 16. Lab work found hormone levels consistent with those of postmenopausal women, but her bone mineral density was normal.
Danish Retrospective Cohort Study Finds No LinkA 2021 study also evaluated POI in a nationwide cohort of nearly 1 million Danish females ages 11 to 34 years. The researchers used Cox proportional hazard regression to detect an increased risk of POI diagnosis by HPV4 vaccination status during the years 2007–2016. The hazard ratio for POI (vaccinated versus unvaccinated) was 0.96.
One limitation was that data on age at menarche (first menstruation) and oral contraceptive use were not available. Girls who had not yet reached menarche would not be at risk for POI, of course.
The authors excluded girls under age 15 in a sensitivity analysis and still found no signal, concluding that no association was found between HPV4 vaccination and POI.