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What is the history of HPV vaccine use in America?
In the early 1980’s, studies confirmed the presence of HPV types 16 and 18 in cervical cancer cells, prompting research and development of a vaccine to prevent human papillomavirus (HPV). The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) first discussed HPV vaccine and issues related to assessing effectiveness at its licensure at the November 2001 meeting.
Both Merck, the manufacturer of Gardasil and Gardasil 9, and GlaxoSmithKline, the manufacturer of Cervarix utilized new Virus-Like Particle (VLP) technology patented in 1994, to develop their HPV vaccines. VLPs contain particular proteins from the outside layer of the virus but lacks the genetic material to actually cause an infection. When injected, VLPs have the ability to produce an immune response due to the presence of foreign material.
Merck’s original Gardasil vaccine was the first FDA approved HPV vaccine. It targeted HPV types 6, 11, 16, and 18. Gardasil was granted Fast Track approval by the FDA after only a six month review process. According to the FDA, Fast Track approval is a program designed to accelerate the review of medications targeting “serious conditions and fill an unmet medical need.” To meet the criteria of “unmet need”, a drug must demonstrate a greater benefit over the currently available treatment.
Prior to Gardasil vaccination, prevention of cervical cancer included regular Pap smears and additional treatment options including colposcopy and removal of any abnormal lesions by techniques such as Laser Electrosurgical Excision Procedure (LEEP). These treatment options continue to be the standard of care for screening and prevention of cervical cancer and are credited with decreasing the U.S. cervical cancer by 75 percent.
Despite the availability of effective treatment options for the detection and prevention of cervical cancer, Gardasil was granted Fast Track status and an accelerated approval by the FDA. Accelerated approval is designed to allow drugs to be approved before they show any clinical benefit to the patient. Approval is based on findings associated with use of a “surrogate endpoint”, such as a physical marker, laboratory finding such as antibody levels or “other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit.” In other words, Gardasil did not have to demonstrate true effectiveness – prevention of cervical cancer – prior to being determined to be effective and granted approval and licensed by the FDA.
Invasive cervical cancer from an unresolved HPV infection can take decades to develop, and as a result, Merck’s pre-licensing studies of Gardasil, limited to five years, could not clinically confirm that its vaccine would actually prevent cervical cancer. The FDA also permitted Merck to use Amorphous Aluminum Hydroxyphosphate Sulfate (AAHS), an aluminum adjuvant, in lieu of a saline placebo, as a control in pre-licensure clinical trials of the original Gardasil. The safety of aluminum adjuvants in vaccines had previously been called into question prior to use in HPV vaccines and continued research on aluminum hydroxide in vaccines found it to be associated with long-term cognitive dysfunction in addition to chronic pain and fatigue. Yet, even with studies that linked aluminum to inflammation and chronic health issues, Merck was granted permission to use it as a control in pre-licensure safety studies.
On May 18, 2006, Merck presented data to the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC), which showed that Gardasil prevented cervical intraepithelial neoplasia (CIN) grades 1, 2, and 3 and, as a result, the FDA approved the vaccine for use in girls and women ages 9 through 26.
No clinical data to confirm Gardasil’s ability to prevent cervical cancer was available to VRBPAC. As a result, a “surrogate endpoint” – reduction in HPV related CIN 1, 2, and 3 related HPV types 16 and 18 – was used to infer whether the vaccine was likely to be effective. Using that metric, VRBPAC concluded that the vaccine was effective even though it had not been demonstrated to prevent cervical cancer. VRBPAC also voted to approve Gardasil for use in girls as young as 9 years of age even though very few girls between the ages of 9 and 15 were enrolled in pre-licensure studies.
Concerns about the state of science at the point of licensure and prior to being reviewed by the CDC were summarized in a June 2006 NVIC press release. Issues included clinical trial methods that involved use of bioreactive active placebos and known safety problems associated with injected aluminum, safety signals reported during pre-licensure clinical trials, inappropriate small sample sizes of the target population slated for vaccination, and an absence of proof of effectiveness.
Within weeks of Gardasil’s FDA approval, the CDC’s Advisory Committee on Immunization Practices (ACIP) voted to recommend three doses of the vaccine for all 11 and 12 year old girls with a “catch up” schedule for females between the age of 13 and 26. Though Gardasil was recommended for use prior to the onset of sexual activity, females who were currently sexually active were also encouraged to take it without prescreening for current HPV infection, even though pre-licensing data noted that the vaccine had the potential to exacerbate a current HPV infection. The CDC’s press release on Gardasil’s recommendation for routine use failed to report the vaccine’s inability to treat pre-existing HPV infections, pre-cancerous lesions or cervical cancer.
At the time of release, Gardasil was the most expensive vaccine in history, costing an average of $360 plus additional costs associated with medical office visits to complete the recommended three dose series. As a result, cost estimates to vaccinate all US females between the age of 11 and 18 years of age were pegged at $2 billion.
In 2005, one year prior to Gardasil’s FDA approval, over 1,500 Merck drug reps were redirected to focus on the Gardasil vaccine and Merck’s contributions to women’s health organizations and political campaigns increased substantially.
Following FDA licensure and ACIP recommendation, Merck launched a highly aggressive marketing campaign targeting teenage girls by encouraging them to be “one less” victim of cervical cancer. In addition to the advertising campaigns directed at young women, Merck began extensive state level lobbying campaigns to make HPV vaccination mandatory for school entry. Merck’s efforts included lobbying state legislators, drafting legislation, seeking support from female legislators and physician trade organizations, and pushing to be the primary source of information on HPV vaccination. By 2007, 41 states and the District of Columbia had introduced HPV vaccine legislation including bills in 24 states that would make HPV vaccination a requirement for entry into 6th grade.
In early 2007, HPV vaccine mandates and Merck’s legislative involvement was met with an enormous backlash from many consumer and family organizations that strongly opposed HPV vaccination mandates which were viewed as a violation of parental rights. Additionally, the Association of American Physicians and Surgeons and American Academy of Pediatrics expressed concerns related to safety, long-term effectiveness and reimbursement for such a costly vaccine.
Early February 2007, Texas Governor Rick Perry signed an executive order mandating the HPV vaccine for all 6th grade girls but this order was short-lived. Within three weeks of Perry’s decision to mandate the vaccine for school entry, the Texas House Committee on Public Health voted to rescind the executive order. The Senate followed suit and with both the Texas House and Senate’s overwhelming support of legislation to override the executive order, Perry opt to allow the override bill to become law. It was reported that Perry received $6,000 dollars in campaign contributions during his re-election campaign and one of the three Merck lobbyists in Texas previously worked as Perry’s chief of staff. Additionally, the mother-in-law of his chief of staff was also a state director for Women in Government, a national non-profit organization of female state legislators, that received substantial contributions from Merck to direct attention on cervical cancer, HPV infections, and Gardasil.
By late February 2007, Merck’s aggressive state legislative lobbying efforts had backfired and it publicly announced the end of its campaign aimed at mandating the HPV vaccine for girls entering the 6th grade. Merck cited public accusations that profits, not public health, were motivating its campaigns as its reason for ceasing efforts to make Gardasil a mandatory vaccine. Only the District of Columbia and the Commonwealth of Virginia enacted legislation requiring HPV vaccination for all 6th grade girls. These laws, however, provided parents with the option of declining the vaccine for their daughters. In 2015, Rhode Island became the third jurisdiction to enact HPV vaccination legislation by requiring vaccination for both girls and boys entering the 7th grade. Hawaii, in July 2020, became the fourth jurisdiction to require HPV vaccination for students entering 7th grade and higher. In July 2021, Virginia implemented an updated HPV vaccine policy to mandate that all boys and girls receive the vaccine as a condition of entry into 7th grade.
Reports of serious adverse events and deaths to the Vaccine Adverse Events Reporting System (VAERS) following vaccination with Gardasil began within weeks of FDA licensure and ACIP recommendation. In February 2007, NVIC released a press release and the first of three analyses of adverse reactions reported to VAERS. By May 2007, after being on the market for less than one year, VAERS had received 2,227 reports of serious adverse events following the administration of Gardasil. The early adverse reaction reports included seven deaths following receipt of Gardasil.
Additionally, an early NVIC analysis of VAERS data found a significantly greater risk of severe adverse events including Guillain-Barre Syndrome, respiratory and cardiac problems, central nervous system problems, convulsions, coordination and neuromuscular problems when Gardasil was administered along with another vaccine, Menectra, a meningococcal vaccine routinely administered to adolescents. No pre-licensure clinical trials evaluated safety when Gardasil was administered along with other vaccines targeted for use in teenagers.
In June 2008, Judicial Watch, a conservative, non-partisan foundation, promoting transparency, accountability and integrity in government, published a 25-page special report detailing Gardasil’s approval process, marketing practices, side-effects, and safety concerns. At the time their report was published, 8,864 adverse reactions following Gardasil vaccination had been reported to VAERS, including 18 deaths. Reported side effects included blood clots, Guillain-Barre Syndrome (GBS), growth of warts, dizziness, nausea, convulsions, and headaches. The report also highlighted reports of miscarriages noting that Gardasil was not studied in pregnant women and evaluated as to whether it could cause fetal harm.
Reports of serious reactions and deaths following HPV vaccination were also appearing in the media. These reports included seizures, paralysis, collapse, Guillain-Barre Syndrome as well as unexplained deaths. Yet, despite these concerns, the CDC continued to recommend the vaccine for all girls and young women, publicly denying any serious adverse events to be related to vaccination.
In July 2008, the CDC updated its Technical Instructions for the Medical Examination of Aliens in the United States and added the HPV vaccine as a requirement for all immigrant females between the age of 11 and 26, beginning August 1, 2008. While the update was intended to follow current guidelines requiring all immigrants to receive all appropriate CDC recommended vaccines, the update was criticized by many and on December 14, 2009, HPV vaccination was removed from the list of vaccines required for immigrants to the US.
To address the growing concerns raised by the public and medical professionals about Gardasil’s safety, in August 2009, the FDA and CDC posted a document on the FDA’s website that summarized the approval process and an overview of the safety monitoring process and findings to date.
Additionally, federal agency staff published the same information in a 2009 Journal of the American Medical Association (JAMA) article summarizing the Gardasil’s safety. After reviewing 12,424 VAERS reports the authors noted that 772 (6 percent of reports) were for serious events including 32 deaths. The article provided the reporting rates for syncope, local site reactions, dizziness, nausea, headache, hypersensitivity reactions, urticarial, venous thromboembolic events, autoimmune disorders and Guillain-Barre Syndrome, anaphylaxis, pancreatitis, transverse myelitis, motor neuron disease and death. The authors concluded that the rates of these events, except for syncope and venous thromboembolic events, were no different than background rates. The methods used and conclusions drawn for the analysis were criticized in a published letter to JAMA’s editor, which concluded that the reassurances of Gardasil’s safety were unsupported.
Merck continued to push for expanded use of its Gardasil vaccine and on October 16, 2009, the FDA approved Gardasil for use in boys and young men ages nine to twenty-six for the prevention of genital warts associated with HPV types 6 and 11, even though the vaccine had been studied in only about 3,000 males. Again, nearly all pre-licensing clinical trials failed to use an inert true placebo as a control and instead, used the novel bioactive aluminum adjuvant (Amorphous Aluminum Hydoxyphosphate Sulfate). While ACIP declined to recommend Gardasil for routine use in males, it did state that Gardasil could be administered to boys and men, ages 9 to 26 for the purpose of reducing the risk of developing genital warts associated with HPV types 6 and 11. Two years later, in October 2011, the ACIP voted to recommend routine vaccination with 3 doses of Gardasil for all boys ages 11-12 years with a catch up schedule for males ages 13 through 21 years.
Merck also submitted a request to the FDA for Gardasil to be approved in women between the ages of 27 and 45, but the FDA declined this request August 2010 due to a lack of data supporting substantial benefit for this population.
In October 2009 Cervarix, a bivalent recombinant vaccine manufactured by GlaxoSmithKline targeting HPV types 16 and 18, received FDA approval for use in girls ages 10 through 25 years of age for the prevention of CIN grades 1, 2 and higher, adenocarcinoma in situ, and cervical cancer. Cervarix contained a novel adjuvant named AS04 which is made of a lipid (MPL) and aluminum and had not previously been used in vaccines licensed in the U.S. In pre-clinical trials, the safety of Cervarix was assessed by comparing it to a licensed vaccine that is assumed to be safe - Hepatitis A which contained up to 500 mcg of Aluminum Hydroxide (AL(0H)3). Within days of FDA approval, the CDC’s Advisory Committee on Immunization Practices (ACIP) voted to recommend 3 doses of Cervarix for routine administration to girls ages 11 or 12, with a catch up schedule for females ages 13 through 26. However, by October of 2016, citing low demand for its product, GlaxoSmithKline announced that Cervarix would no longer be marketed in the United States.
In 2011, at the request of SaneVax, a non-profit organization promoting “only Safe, Affordable, Necessary & Effective vaccines and vaccination practices through education and information,” Sin Hang Lee, a Board Certified Pathologist, tested 13 different vials of Gardasil vaccine and discovered that each one contained Human Papillomavirus (HPV) DNA. In August 2011, SaneVax notified the FDA of these findings and requested an investigation and information about the effect of HPV DNA presence on vaccine safety. In response, on October 21, 2011, the FDA released a statement acknowledging the presence of HPV DNA fragments in the vaccine and stating that they regarded this as normal due to the vaccine’s manufacturing process rather than a vaccine contamination problem. No additional studies were recommended to determine whether the presence of HPV DNA in the vaccine posed any risks to vaccine recipients.
Severe adverse reactions following HPV vaccination continued to be reported in the United States and abroad. In June of 2013, the Japanese government withdrew their support of HPV vaccination, citing safety concerns related to the high number of serious adverse reactions reported following vaccination. Three years later, in July of 2016, Japanese victims of HPV vaccination launched a class action lawsuit against the Japanese government, Merck, the maker of Gardasil, and GlaxoSmithKline, the maker of Cervarix, for damages related to the numerous health problems suffered post-vaccination. Japan relaunched its HPV vaccine campaign in spring of 2022, after a national survey reportedly concluded that unvaccinated girls suffered symptoms that were attributed to HPV vaccine at a similar rate as those who received the vaccine.
American journalist Katie Couric, profiled HPV vaccination during a December 2013 segment of her TV talk show, Katie. The program discussed the benefits and risks of vaccination and interviewed two mothers who reported sudden serious health issues that followed their daughters HPV vaccinations. Couric’s program resulted in an onslaught of attacks from numerous media sources accusing her of promoting junk science and fear mongering. After enduring several days of negative media stories, Couric published a blog commentary in the Huffington Post stating that the show should have focused more on the vaccine’s safety and efficacy, and less on the “serious adverse events that have been reported in very rare cases following the vaccine.”
While mainstream media in the US has effectively silenced nearly all discussion questioning the safety of HPV vaccination, reports in other countries have continued to surface.
In March 2015, one of Denmark’s national television stations aired a documentary focusing on the serious side effects reported following HPV vaccination and profiling the stories of three young women who developed chronic health problems following HPV vaccination. At the request of Danish scientists and clinicians, the European Medicines Agency (EMA), the agency responsible for safety monitoring and scientific evaluation of drugs and vaccines in Europe, reviewed two commonly reported side effects of HPV vaccination, postural orthostatic tachycardia syndrome (POTS) and complex regional pain syndrome (CRPS), and determined that no link existed between these symptoms and HPV vaccination. However, several scientists and doctors objected to the report, expressing concerns over conflicts of interest and use of inappropriate methods that relied on previously published data.
Ireland’s TV3 television station aired a similar documentary December 2015 profiling several girls who developed debilitating health problems following HPV vaccination. In 2017, Sacrificial Virgins, a United Kingdom documentary which discussed the lack of evidence proving that HPV vaccination prevented cervical cancer, the reports of debilitating side effects and death, and the HPV vaccine litigation in Japan, Spain, and Columbia was shown at several independent film festivals. Despite numerous reports of serious side effects and death following HPV vaccination globally, in most cases, government health agencies have continued to actively promote HPV vaccine use and contend that the vaccine is effective and is not linked to any serious side effects or death.
Over time, evidence that Merck’s original Gardasil vaccine formulation was inadequate in addressing all the concerning HPV types became apparent. In response, Merck increased the number of types of HPV in its vaccine from four to nine, and on December 10, 2014, its 9-valent recombinant vaccine (Gardasil 9) received FDA approval for use in females ages 9 through 26 years of age, for the prevention of genital warts associated with HPV Types 6 and 11 and for the prevention of anal, cervical, vaginal, and vulvar cancers associated with HPV Types 16, 18, 31, 33, 45, 52, and 58. The FDA also approved Gardasil 9 for use in males ages 9 through 15 for the prevention of genital warts associated with HPV Types 6 and 11 and for the prevention of anal cancer associated with HPV Types 16, 18, 31, 33, 45, 52, and 58. In addition to doubling the amount of HPV protein antigen contained in the original Gardasil, Merck’s Gardasil 9 increased the amount of bioactive aluminum adjuvant to from 225 mcg to 500mcg.
As previously noted for Gardasil, pre-licensure studies of Gardasil 9 did not use true placebos as controls and instead, tended to compare Gardasil 9 to Gardasil. In February 2015, the CDC’s ACIP voted to recommend three doses of Gardasil 9 to be administered to all males and females ages 11-12, with a catch up dosing for females between the age of 13 and 26, males between the age of 13 and 21, and select high-risk males up to the age of 26 years of age. Gardasil 9 was recommended by the ACIP in males between the age of 13 and 21 even though the FDA had yet to approval its use in males over 15 years of age. One year later, the FDA approved Gardasil 9 for use in males ages 16 to 26 in December 2015.
In December 2016, two years after Gardasil 9 was licensed by the FDA, ACIP voted to decrease the recommended 3-dose schedule to a 2-dose schedule for HPV vaccination in females and males between the ages of 9 and 14 where the second dose was to be administered six to twelve months following the initial dose. The 3-dose vaccine schedule continued to be recommended for individuals receiving the first HPV dose after the age 15. The ACIP stated that the dosing changes were based on evidence that the immune response in persons between the age of 9 and 14 after two doses of HPV vaccine was significant enough to produce adequate long-lasting antibodies against HPV types present within the vaccine. At the same time, Gardasil 9 became the only available HPV vaccine on the market in the US. The CDC recommended using “any HPV vaccine at the recommended dosing schedule” to complete the vaccination schedule for vaccines that were no longer available even though no studies existed to support the use of “a mixed regimen of HPV vaccines”.
Despite Merck’s 2016 marketing campaign, which appeared to shame parents for declining Gardasil for their children, HPV vaccination uptake rates remained low. A 2018 published report on HPV vaccination rates in adolescents completed by the insurance company Blue Cross Blue Shield found that in 2016, only 34 percent of teenagers had received their first dose of HPV vaccine by the age of 13. This study also found that only 9 percent of adolescents had completed the series prior to the age of 13. An additional survey of over 700 parents whose children had not received the HPV vaccine reported that over half of the parents were not planning to have their child receive HPV vaccination and 60 percent of these parents cited vaccine safety concerns as the reason they decided to decline HPV vaccination for their child.
In June 2018, the FDA granted Merck a priority review of its application to expand Gardasil 9 use in both males and females 27 to 45 years of age. Previously, the FDA reviewed data for women ages 27 to 45, in August 2010 and concluded that the vaccine showed no significant benefit to this population.
In October 2018, the FDA approved Gardasil 9 for use in both males and females up to age 45, and in June 2019, ACIP voted to recommend use of the vaccine in males and females 27 through 45 through ‘shared clinical decision-making’ – a process that physicians can use to determine who might benefit from vaccination within this population.
For females over 21 years of age, HPV vaccination does not replace the need for routine Pap smear testing to detect abnormal cells that can cause cervical cancer especially considering that cervical cancer can be caused by HPV types not included in the vaccine. The effectiveness of HPV vaccination is still unknown and according to the CDC, “it may take decades to see population-level impact” from this vaccine.
IMPORTANT NOTE: NVIC encourages you to become fully informed about HPV and the HPV vaccine by reading all sections in the Table of Contents , which contain many links and resources such as the manufacturer product information inserts, and to speak with one or more trusted health care professionals before making a vaccination decision for yourself or your child. This information is for educational purposes only and is not intended as medical advice.