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Gardasil Safe-FDA/CDC. Gardasil Vaccine Safety:
Information from FDA And CDC on the Safety of Gardasil Vaccine
 
 
  Gardasil Safe-FDA/CDC. Gardasil Vaccine Safety: Information from FDA And CDC on the Safety of Gardasil Vaccine

http://www.fda.gov August 20, 2009

Consumers, parents, health care professionals and others have raised questions regarding the safety of the human papillomavirus (HPV) vaccine, Gardasil. FDA and the U.S. Centers for Disease Control and Prevention (CDC) take all concerns about vaccine safety seriously, and have been closely monitoring the safety of Gardasil.

Below is a summary of Gardasil vaccine safety monitoring activities and findings. Based on ongoing assessments of vaccine safety information, FDA and CDC continue to find that Gardasil is a safe and effective vaccine. FDA and CDC continue to monitor the safety of this vaccine, with the public?s health and safety our top priority.

Gardasil Background

FDA approved Gardasil on June 8, 2006. It is approved for females 9-26 years of age to protect against cervical, vulvar and vaginal cancers caused by Human Papillomavirus (HPV) types 16 and 18 and genital warts caused by HPV types 6 and 11. CDC's Advisory Committee on Immunization Practices (ACIP) recommended a routine 3-dose vaccination series for girls 11 and 12 years of age. The vaccine is also recommended for girls and women ages 13 through 26 years who have not yet been vaccinated or who have not received all 3 doses.

Studies involving approximately 21,000 girls and women were conducted to evaluate the safety and effectiveness of Gardasil before receiving approval by FDA. Approximately half of the study participants received the vaccine, and the other half received a control. These studies showed that in women who have never been infected by HPV types 6, 11, 16 or 18, the vaccine is highly effective, both in preventing precancerous lesions that often develop into cancer of the cervix, vagina and vulva, and in preventing genital warts caused by these HPV types.

This vaccine is an important cervical cancer prevention tool that will potentially benefit the health of millions of women. Every year, about 12,000 women are diagnosed with cervical cancer and almost 4,000 die from this disease in the United States. Worldwide, cervical cancer is the second most common cancer in women, causing an estimated 470,000 new cases and 233,000 deaths per year.

Monitoring the Safety of Gardasil

Vaccine Safety Overview


FDA and CDC closely monitor the safety of all vaccines through the Vaccine Adverse Event Reporting System (VAERS). VAERS receives unconfirmed reports of possible side effects following the use of Gardasil and all vaccines licensed in the U.S. VAERS reports are regularly reviewed for safety concerns or trends of adverse events (possible side effects).

Vaccines are manufactured in batches called lots. All vaccine lots are routinely tested and must pass all tests before they can be used, and vaccine manufacturers must comply with strict manufacturing standards. FDA also analyzes adverse events (possible side effects) associated with individual lots to look for any unusual patterns. No such patterns have been observed in FDA's review of HPV vaccine lots since the vaccine was licensed.

In addition to VAERS, CDC has two other systems in place to monitor the safety of all licensed vaccines. The Vaccine Safety Datalink (VSD) Project is a collaborative effort between CDC and eight managed care organizations that monitors vaccine safety and addresses the gaps in scientific knowledge about rare and serious side effects following immunization. The Clinical Immunization Safety Assessment (CISA) Network is a collaboration with six academic centers in the United States to conduct clinical research on vaccine-associated adverse events.

Adverse Event Reports following Gardasil

Given the large number of doses distributed, it is expected that, by chance alone, serious adverse events and some deaths will be reported in this large population during the time period following vaccinations. Our monitoring and analysis of reports, including in-depth medical review, statistical data mining techniques, and analysis of reporting rates (number of adverse events/number of doses distributed) are designed to detect serious events that occur at rates greater than expected.

VAERS receives reports of many events that occur following immunization. Some of these events may occur coincidentally during the time period following vaccination, while others may actually be caused by vaccination. In our analysis of VAERS data, we look for patterns of adverse events that may be plausibly linked to a vaccine. Such patterns of adverse events may require further study.

On August 19, 2009, the Journal of the American Medical Association (JAMA) published an article coauthored by FDA and CDC that reviews the safety data for Gardasil for select adverse events that have been reported to VAERS, from the time period starting from product licensure in June 2006 through December 31, 2008 (JAMA. 2009;302(7):750-757). The article describes 12,424 reports of adverse events following Gardasil vaccination. Of these, 772 were reports of serious events (6.2% of the reports) and the remaining 11,652 (93.8%) were classified as non-serious. During this time period, the manufacturer, Merck and Co., has distributed over 23 million doses of Gardasil in the United States. The information contained in this update is based on the same information contained in the article published in JAMA. FDA will provide a future update to information on the number of reports of adverse events and doses distributed.

The Gardasil safety review assessed the following adverse events: local injection site reactions, syncope, dizziness, and nausea, headaches, hypersensitivity reactions, such as rashes, hives, itching, anaphylaxis, Guillain-Barre syndrome (GBS), transverse myelitis, motor neuron disease, venous thromboembolic events (VTEs), pancreatitis, autoimmune disorders, pregnancy, and deaths. All of these events are included in Gardasil?s labeling. In VAERS, a higher proportion of Gardasil reports were of syncope and VTEs compared with other vaccines. However, none of the adverse events in the safety review, including syncope and VTEs, were reported at rates (number of adverse events/number of doses distributed) greater than expected in a population of this age and gender and with other known contributing factors to these adverse events.

VAERS reports include syncope (fainting), pain at the injection site, headache, nausea and fever. Fainting is common after injections and vaccinations, especially in adolescents. Falls after syncope may sometimes cause serious injuries, such as head injuries, which can be prevented with simple steps, such as keeping the vaccinated person seated for up to 15 minutes after vaccination. FDA and CDC have taken steps to remind immunization providers about the recommendation that individuals be watched carefully for 15 minutes after vaccination to avoid potential injury from a fall. FDA approved revised labeling on June 9, 2009, to highlight this information in the Warnings and Precautions section, and new information was added noting that individuals who faint sometimes have tonic-clonic (jerking) movements and seizure-like activity. As a part of a Back to School immunization campaign, FDA and CDC are also continuing to remind health care providers to take measures to prevent fainting and the possible traumatic injury resulting from fainting.

Thromboembolic disorders (blood clots) have been reported to VAERS in people who have received Gardasil. Most of these individuals had risk factors for blood clots such as use of oral contraceptives which are known to increase the risk of clotting. The JAMA article describes 56 cases, 31 of which were confirmed blood clot reports. Twenty eight reports (90%) had underlying known risk factors such as hormonal birth control, genetic clotting abnormalities, obesity, smoking, and immobility. In the CDC?s VSD, blood clots have not been found to occur more often than expected after over 450,000 doses of Gardasil.

Concerns have been raised about reports of deaths occurring in individuals after receiving Gardasil. As of December 31, 2008, 32 deaths had been reported to VAERS. There was not a common pattern to the deaths that would suggest they were caused by the vaccine. In the majority of cases with available autopsy, death certificate and medical records, the cause of death was explained by factors other than the vaccine.

Guillain-Barre Syndrome (GBS) has also been reported in individuals following vaccination with Gardasil. GBS is a rare neurological disorder that causes muscle weakness. It occurs spontaneously in unvaccinated individuals after a variety of specific infections. FDA and CDC have reviewed the reports of GBS that have been submitted to VAERS. To date, there is no evidence that Gardasil has increased the rate of GBS above that expected in the population. While we continue to carefully analyze all reports of GBS submitted to VAERS, the data do not currently suggest an association between Gardasil and GBS.

Because VAERS data are subject to many limitations of passive reporting systems, FDA and CDC also utilize additional surveillance tools. This includes the CDC?s VSD which incorporates eight large Managed Care Organizations, and now has health records linked to over 450,000 doses of Gardasil, and focuses on several potential risks: thrombotic events (blood clots), seizures, syncope, appendicitis, anaphylaxis, and GBS. Thus far, the VSD studies have not found safety signals or concerns for any of these events. The manufacturer has also committed to conduct a large postmarketing study to further assess the vaccine?s safety.

Summary

Based on the review of available information by FDA and CDC, Gardasil continues to be safe and effective, and its benefits continue to outweigh its risks.

CDC has not changed its recommendations for use of Gardasil. FDA has not made any changes to the prescribing information for how the vaccine is used. In addition, FDA routinely reviews manufacturing information, and has not identified any issues affecting the safety, purity and potency of Gardasil.

Public health and safety are priorities for FDA and CDC. As with all licensed vaccines, we will continue to closely monitor the safety of Gardasil. FDA and CDC continue to find that Gardasil is a safe and effective vaccine that will potentially benefit the health of millions of women by providing protection against the types of HPV in the vaccine that cause cervical, vulvar and vaginal cancer, genital warts, and other HPV-related genital diseases in females.


US affirms benefit of Merck's Gardasil - (The Wall Street Journal)

Merck is Pleased the FDA and CDC Re-affirm the Safety Profile of GARDASIL [Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant]

Note to editors: The head of the clinical research program for GARDASIL is available for comment, including broadcast interviews.

WHITEHOUSE STATION, N.J., Aug. 20, 2009 - Merck is pleased that the US Food and Drug Administration (FDA) and US Centers for Disease Control and Prevention (CDC) reaffirmed this morning that, "based on the review of available information by FDA and CDC, GARDASIL continues to be safe and effective, and its benefits continue to outweigh its risks." The FDA's full statement is available here: (Gardasil Vaccine Safety, posted: 8/20/2009).

"We will continue our practice of effectively communicating the safety profile of GARDASIL -- it's a responsibility Merck takes very seriously," said Richard M. Haupt, MD, MPH, head of the GARDASIL clinical program.

"We hope that the many parents who may have been frightened this week by misleading reports understand that Merck people are parents, too. Our own children are vaccinated with GARDASIL. I am a father and a pediatrician who has worked on GARDASIL for six years, and all of my daughters have been vaccinated with GARDASIL.

"Parents should understand the extensive data supporting the safety profile of this vaccine, and we encourage them to look to CDC and FDA, and to the advice of their own physicians, to make an informed choice about something as important as a vaccine to help prevent cervical cancer.

"Nearly 500,000 women are diagnosed with cervical cancer each year around the world. Even 50 years after the advent of pap testing, an average of 30 American women are still diagnosed with cervical cancer each day. Now that there is a vaccine, we have an opportunity to not only impact this disease through early detection but also through a medical intervention."

GARDASIL is for use in girls and women 9 to 26 years of age for the prevention of cervical, vulvar, and vaginal cancers; precancerous or dysplastic lesions, and genital warts caused by HPV Types 6, 11, 16, and 18. HPV types 16 and 18 cause approximately 70 percent of cervical cancer cases.

Important information about GARDASIL GARDASIL does not substitute for routine cervical cancer screening, and women who receive GARDASIL should continue to undergo screening.

GARDASIL has not been demonstrated to provide protection against diseases from vaccine and non-vaccine HPV types to which a woman has previously been exposed through sexual activity. GARDASIL is not intended to be used for treatment of active genital warts; cervical, vulvar, and vaginal cancers; cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), or vaginal intraepithelial neoplasia (VaIN).

GARDASIL has not been demonstrated to protect against diseases due to HPV types not contained in the vaccine. Not all vulvar and vaginal cancers are caused by HPV, and GARDASIL protects only against those vulvar and vaginal cancers caused by HPV Types 16 and 18.

Select safety information GARDASIL is contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of GARDASIL.

Because vaccinees may develop syncope, sometimes resulting in falling with injury, observation for 15 minutes after administration is recommended. Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following vaccination with GARDASIL. When syncope is associated with tonic-clonic movements, the activity is usually transient and typically responds to restoring cerebral perfusion.

GARDASIL is not recommended for use in pregnant women.

The most common adverse reaction was headache. Common adverse reactions that were observed among recipients of GARDASIL at a frequency of at least 1.0 percent and greater than placebo were fever, nausea, dizziness; and injection-site pain, swelling, erythema, pruritus and bruising.

Dosage and Administration GARDASIL should be administered in three separate intramuscular injections in the deltoid region of the upper arm or in the higher anterolateral area of the thigh over a six-month period with the first dose at an elected date, the second dose two months after the first dose, and the third dose six months after the first dose.

Please see accompanying Prescribing Information and Patient Product Information for GARDASIL.

About Merck Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.

Forward-looking statement This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2008, and in any risk factors or cautionary statements contained in the Company's periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.

GARDASIL is a registered trademark of Merck & Co. Inc, Whitehouse Station, N.J., USA.


Study on Vaccine for Cervical Cancer Finds Benefits Despite Some Risks

NY Times
By RONI CARYN RABIN
Published: August 18, 2009

The new vaccine designed to protect girls and young women from cervical cancer has a safety record that appears to be in line with that of other vaccines, a government report has found. Some serious complications occurred, including at least 20 deaths and two cases of Lou Gehrig's disease, but they were not necessarily caused by the vaccine, the study said.

The most common serious complications after vaccination with Gardasil were fainting episodes and an increased risk for potentially fatal blood clots, possibly related to oral contraceptive use and obesity, the study found.

The vaccine has been given to more than seven million girls and young women nationwide and there is no way to prove that complications came from the vaccine.

But while the tone of the study, published in The Journal of the American Medical Association, was reassuring, the authors noted that the analysis was based on imperfect data drawn from reports made to a voluntary government surveillance database. The majority of adverse event reports were filed by Merck & Company, the vaccine's manufacturer, and most failed to provide enough information for further investigation.

"We feel confident recommending people get the vaccine; the benefits still outweigh the risks," said Dr. Barbara A. Slade, the study's first author and medical officer with the Centers for Disease Control and Prevention, which did the study together with the Food and Drug Administration. She added, "This is the most complete picture we have."

Nevertheless, an accompanying editorial questioned whether any level of risk is acceptable when inoculating a healthy population against a disease that can be prevented through screening.

"There are not a huge number of side effects here, that's fairly certain," said the editorial writer, Dr. Charlotte Haug, an infectious disease expert from Norway, about the vaccine. "But you are giving this to perfectly healthy young girls, so even a rare thing may be too much of a risk.

"I wouldn't accept much risk of side effects at all in an 11-year-old girl, because if she gets screened when she's older, she'll never get cervical cancer," Dr. Haug said in an interview. "You don't have to die from cervical cancer if you have access to health care."

The vaccine was approved for girls and young women ages 9 to 26 and is recommended for routine vaccination of girls 11 and 12.

Merck officials said they were pleased with the findings of the new report.

"This confirms the very favorable safety profile we've seen in our extensive clinical trials," said Dr. Richard M. Haupt, executive director of clinical research for Merck Research Laboratories, adding that while screening is important, the vaccine can reduce the number of abnormal results and procedures, because it prevents infection with four strains of HPV, including two implicated in most cases of cervical cancer today.

"Pap screening alone is not the answer," Dr. Haupt said.

Another paper in JAMA described how Merck, whose sales of Gardasil totaled $1.4 billion last year, provided professional medical societies with grant money the organizations used to develop educational programs promoting the product. The lectures glossed over questions about the vaccine's effectiveness and whether booster shots would be needed, said Sheila M. Rothman, the paper's author.

"The message they were giving was really the drug company message," said Dr. Rothman, professor of sociomedical sciences at Mailman School of Public Health at Columbia. The marketing strategy overstated the risks of cervical cancer for American women, she said. "It was being marketed as if every girl were at equal risk for this disease and needed this vaccine, even though cervical cancer is not a disease of all women in the U.S. - it particularly affects girls who don't have access to health care and Pap tests," Dr. Rothman said.

The study on adverse events analyzed 12,424 reports of adverse events that occurred after immunization with the HPV vaccine from June 1, 2006, to Dec. 31, 2008, when more than 23 million doses of vaccine were distributed, enough to vaccinate more than seven million girls with all three required doses.

That was calculated as a rate of 53.9 adverse event reports to the Vaccine Adverse Event Reporting System for every 100,000 doses of vaccine distributed. Syncope, or fainting, occurred most frequently, with a rate of 8.2 reports per 100,000 vaccine doses, followed by 7.5 per 100,000 for local site reactions and 6.8 per 100,000 for dizziness.

Report rates were then compared with those of other vaccines given in similar populations of girls the same age, Dr. Slade explained.

Of the total number of reports, 6.2 percent, or 772 reports, were considered serious events, including 32 reports of death. Only 20 of the deaths could be verified; the others included four that were provided by the manufacturer without further information, and eight secondhand reports that could not be verified.

Of the 20, 14 of the deceased had only received the HPV vaccine, while others had received multiple vaccines. The average age of the girls who died was 18, and causes of death varied widely - including two cases of diabetic ketoacidosis, one case related to prescription drug abuse, one case of juvenile amyotrophic lateral sclerosis or Lou Gehrig's disease, one case of meningoencephalitis, three pulmonary embolisms or blood clots to the lung, six cardiac-related deaths, one case of sepsis related to influenza B and two because of seizure disorders. Four deaths were unexplained.

Dr. Slade said the disparate causes of death made it difficult to determine an underlying cause, or to determine if the vaccine played a causal role.

"We didn't see any patterns in the causes of death, any pattern in the time between vaccination and death, or the age of the people who died - there just didn't seem to be any real pattern that would cause us to have heightened concern," Dr. Slade said, adding that the number of deaths was "actually very similar to what we see after other vaccines in similar age groups." She said the A.L.S. cases were being investigated further.


"The Risks and Benefits of HPV Vaccination" EDITORIAL

Charlotte Haug, MD, PhD, MSc

JAMA. Aug 19 2009;302(7):795-796.

When do physicians know enough about the beneficial effects of a new medical intervention to start recommending or using it? When is the available information about harmful adverse effects sufficient to conclude that the risks outweigh the potential benefits? If in doubt, should physicians err on the side of caution or on the side of hope? These questions are at the core of all medical decision making. It is a complicated process because medical knowledge is typically incomplete and ambiguous. It is especially complex to make decisions about whether to use drugs that may prevent disease in the future, particularly when these drugs are given to otherwise healthy individuals. Vaccines are examples of such drugs, and the human papillomavirus (HPV) vaccine is a case in point.

zur Hausen, winner of the Nobel Prize in Physiology or Medicine in 2008, discovered that oncogenic HPV causes cervical cancer.1-4 His discovery led to characterization of the natural history of HPV infection, an understanding of mechanisms of HPV-induced carcinogenesis, and eventually to the development of prophylactic vaccines against HPV infection.

The theory behind the vaccine is sound: If HPV infection can be prevented, cancer will not occur. But in practice the issue is more complex. First, there are more than 100 different types of HPV and at least 15 of them are oncogenic. The current vaccines target only 2 oncogenic strains: HPV-16 and HPV-18. Second, the relationship between infection at a young age and development of cancer 20 to 40 years later is not known. HPV is the most prevalent sexually transmitted infection, with an estimated 79% infection rate over a lifetime5-6 The virus does not appear to be very harmful because almost all HPV infections are cleared by the immune system.7-8 In a few women, infection persists and some women may develop precancerous cervical lesions and eventually cervical cancer. It is currently impossible to predict in which women this will occur and why. Likewise, it is impossible to predict exactly what effect vaccination of young girls and women will have on the incidence of cervical cancer 20 to 40 years from now. The true effect of the vaccine can be determined only through clinical trials and long-term follow-up.

The first HPV vaccine was licensed for use in the United States in June 2006,9 and the Advisory Committee on Immunization Practices recommended routine vaccination of girls aged 11 to 12 years later that same month.10 However, the first phase 3 trials of the HPV vaccine with clinically relevant end points-cervical intraepithelial neoplasias grades 2 and 3 (CIN 2/3)-were not reported until May 2007.11 Previously only reduction in the prevalence of persistent infection and CIN from the 2 virus strains included in the vaccine had been reported. The results were promising, but serious questions regarding the overall effectiveness of the vaccine for protection against cervical cancer remained to be answered, and more long-term studies were called for.12 However, no longer-term results from such studies have been published since then.

So how should a parent, physician, politician, or anyone else decide whether it is a good thing to give young girls a vaccine that partly prevents infection caused by a sexually transmitted disease (HPV infection), an infection that in a few cases will cause cancer 20 to 40 years from now? Two articles in this issue of JAMA13-14 present important data that may influence, and probably already have influenced, such decisions about HPV vaccination.

The report by Rothman and Rothman13 demonstrates how the vaccine manufacturer funded educational programs sponsored by professional medical associations in the United States. The article illustrates how the Society of Gynecologic Oncology, the American Society for Colposcopy and Cervical Pathology, and American College Health Association helped market the vaccine and influenced decisions about vaccine policy with the help of ready-made presentations, slide sets, e-mails, and letters. It is of course reasonable for professional medical associations to promote medical interventions they believe in. But did these associations provide members with unbiased educational material and balanced recommendations? Did they ensure that marketing strategies did not compromise clinical recommendations? These educational programs strongly promoting HPV vaccination began in 2006, more than a year before the trials with clinically important end points were published. How could anyone be so certain about the effect of the vaccine? This matters because the voices of experts such as the professional medical associations are especially important with a complex issue such as this.

In another article, Slade and colleagues14 from the US Centers for Disease Control and Prevention and the US Food and Drug Administration describe the adverse events that occurred 2.5 years following the receipt of quadrivalent HPV vaccine that were reported through the US Vaccine Adverse Events Reporting System (VAERS). Even though most of the reported adverse events were not serious, there were some reports of hypersensitivity reactions including anaphylaxis, Guillain-Barre syndrome, transverse myelitis, pancreatitis, and venous thromboembolic events. VAERS is a passive, voluntary reporting system, and the authors call attention to its limitations. They point out that only systematic, prospective, controlled studies will be able to distinguish the true harmful effects of the HPV vaccine. These limitations work both ways: it is also difficult to conclude that a serious event is not caused by the vaccine.

Whether a risk is worth taking depends not only on the absolute risk, but on the relationship between the potential risk and the potential benefit. If the potential benefits are substantial, most individuals would be willing to accept the risks. But the net benefit of the HPV vaccine to a woman is uncertain. Even if persistently infected with HPV, a woman most likely will not develop cancer if she is regularly screened.15 So rationally she should be willing to accept only a small risk of harmful effects from the vaccine.

When weighing evidence about risks and benefits, it is also appropriate to ask who takes the risk, and who gets the benefit. Patients and the public logically expect that only medical and scientific evidence is put on the balance. If other matters weigh in, such as profit for a company or financial or professional gains for physicians or groups of physicians, the balance is easily skewed. The balance will also tilt if the adverse events are not calculated correctly.


"Postlicensure Safety Surveillance for Quadrivalent Human Papillomavirus Recombinant Vaccine"

Barbara A. Slade, MD, MS; Laura Leidel, RN, FNP-C, MPH; Claudia Vellozzi, MD, MPH; Emily Jane Woo, MD, MPH; Wei Hua, MD, PhD; Andrea Sutherland, MD, MSc, MPH; Hector S. Izurieta, MD, MPH; Robert Ball, MD, MPH; Nancy Miller, MD; M. Miles Braun, MD, MPH; Lauri E. Markowitz, MD; John Iskander, MD

JAMA. Aug 19 2009;302(7):750-757.

ABSTRACT

Context - In June 2006, the Food and Drug Administration licensed the quadrivalent human papillomavirus (types 6, 11, 16, and 18) recombinant vaccine (qHPV) in the United States for use in females aged 9 to 26 years; the Advisory Committee on Immunization Practices then recommended qHPV for routine vaccination of girls aged 11 to 12 years.

Objective - To summarize reports to the Vaccine Adverse Event Reporting System (VAERS) following receipt of qHPV.

Design, Setting, and Participants - Review and describe adverse events following immunization (AEFIs) reported to VAERS, a national, voluntary, passive surveillance system, from June 1, 2006, through December 31, 2008. Additional analyses were performed for some AEFIs in prelicensure trials, those of unusual severity, or those that had received public attention. Statistical data mining, including proportional reporting ratios (PRRs) and empirical Bayesian geometric mean methods, were used to detect disproportionality in reporting.

Main Outcome Measures - Numbers of reported AEFIs, reporting rates (reports per 100 000 doses of distributed vaccine or per person-years at risk), and comparisons with expected background rates.

Results - VAERS received 12 424 reports of AEFIs following qHPV distribution, a rate of 53.9 reports per 100 000 doses distributed. A total of 772 reports (6.2% of all reports) described serious AEFIs, including 32 reports of death. The reporting rates per 100 000 qHPV doses distributed were 8.2 for syncope; 7.5 for local site reactions; 6.8 for dizziness; 5.0 for nausea; 4.1 for headache; 3.1 for hypersensitivity reactions; 2.6 for urticaria; 0.2 for venous thromboembolic events, autoimmune disorders, and Guillain-Barre syndrome; 0.1 for anaphylaxis and death; 0.04 for transverse myelitis and pancreatitis; and 0.009 for motor neuron disease. Disproportional reporting of syncope and venous thromboembolic events was noted with data mining methods.

Conclusions - Most of the AEFI rates were not greater than the background rates compared with other vaccines, but there was disproportional reporting of syncope and venous thromboembolic events. The significance of these findings must be tempered with the limitations (possible underreporting) of a passive reporting system.

INTRODUCTION

On June 8, 2006, the Food and Drug Administration (FDA) licensed the quadrivalent human papillomavirus recombinant vaccine (qHPV) (Gardasil; Merck & Co, Inc, Whitehouse Station, New Jersey) for females aged 9 to 26 years to prevent infection with genital human papillomavirus (HPV) types 6, 11, 16, and 18.1 Later that month, the Advisory Committee on Immunization Practices (ACIP) recommended routine vaccination of females aged 11 to 12 years with 3 doses of qHPV and catch-up vaccination for females aged 13 to 26 years. Doses are administered intramuscularly on a schedule of 0, 2, and 6 months.2 The viruses HPV-16 and HPV-18 can cause cervical cancer, other anogenital cancers, and precancerous or dysplastic lesions and are responsible for about 70% of cervical cancers worldwide.3 The viruses HPV-6 and HPV-11 are the most common causes of genital warts.

Prior to licensure, clinical trials were conducted in more than 21 000 women. Vaccination with qHPV was 90% to 100% effective in preventing precancerous cervical, vaginal, and vulvar lesions and genital warts caused by infection with the relevant HPV types (6, 11, 16, or 18) in women aged 15 to 26 years who were uninfected prior to vaccination.4-5 Additional immunogenicity and safety studies in 9- to 15-year-olds demonstrated high seropositivity postvaccination; geometric mean antibody titers were as high as those of women aged 16 to 23 years in the efficacy trials and, by postvaccination month 7, were 1.7- to 2.7-fold higher.6

In the clinical trials, the incidence of solicited systemic clinical adverse events following immunization (AEFIs) was similar in the vaccine group (59%) and the placebo group (60%). Headache was the most commonly reported systemic AEFI in both groups (qHPV, 28.2%; placebo, 28.4%). Proportions of fever (13.0% vs 11.2%) and nausea (6.7% vs 6.5%) were slightly higher in the vaccine recipients vs the placebo group. The rates of serious AEFIs were comparable between the 2 groups (<0.1%). There was a slightly higher number of severe injection site reactions in the vaccine group (n = 10, 2.2%) compared with the placebo group (n = 4, 0.9%) in the 5 days after vaccination.1

With more than 23 million qHPV doses distributed in the United States as of December 31, 2008 (number provided by manufacturer, http://www.cdc.gov/vaccinesafety/vaers/gardasil.htm), postlicensure safety monitoring can detect AEFIs too rare to have been detected during prelicensure trials. This article summarizes data from the US Vaccine Adverse Event Reporting System (VAERS) for the 2.5 years following licensure.

COMMENT

Our review of 12 424 reports of AEFIs following receipt of qHPV after licensure found that most did not meet the FDA definition of serious. The safety profile described by these data for frequent AEs is consistent with prelicensure data, with the exception of syncope and VTEs. This review summarizes passive surveillance data from more than 23 million doses distributed in the United States. Such postlicensure monitoring allows for the potential detection of rare AEFIs as more people are vaccinated. As expected with increased numbers of immunizations in the postlicensure setting, rare AEFIs were observed more often than in the prelicensure review.

Ongoing monitoring will help assess whether the serious reports to VAERS, as well as the few serious AEs identified during prelicensure trials, require further evaluation.22 The Vaccine Safety Datalink is providing additional surveillance through the use of rapid cycle analyses to monitor for seizures, syncope, anaphylaxis, appendicitis, GBS, and VTEs.23 Important identified concerns from either VAERS or the Vaccine Safety Datalink can be investigated using well-designed, systematic, hypothesis-driven studies.

Reported deaths with available records, autopsy reports, or death certificates describe causes other than recent vaccination. Two of 3 VTE death reports described the use of oral contraceptives, which can increase the risk of VTE 3- to 6-fold.24 Because the population of young women who frequently use hormonal contraceptives overlaps with those receiving the qHPV vaccine, coincidental occurrences of VTE among qHPV recipients may be anticipated. Nonetheless, close monitoring continues for VTE reports to VAERS following qHPV and other vaccines.

Vasovagal syncope is among the most frequently reported AEFIs following qHPV. When it results in falls, significant traumatic injuries can occur.25-26 The ACIP and Red Book have published guidelines to prevent vasovagal syncope and related injury following vaccination.27-28 After several newly licensed adolescent vaccines (qHPV; quadrivalent meningococcal conjugate vaccine; and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine) were added to the routine immunization schedule, the number of postvaccination syncope reports to VAERS increased, primarily among females aged 11 to 18 years.29 This age group also has a higher background rate of syncope than other age groups. The predominance of females could be related to an actual difference between the sexes or could represent reporting bias since the qHPV vaccine is currently licensed for females only. With the increased use of adolescent vaccines, we strongly urge vaccine providers to diligently implement the ACIP recommendations for a routine 15-minute waiting period following vaccination. There have been reports in the literature documenting seizure-like activity during syncope in children.30-31 Some reports to VAERS of seizures may be anoxic seizures resulting from syncopal episodes.

Reports of VTEs after qHPV immunization should be interpreted with caution due to the multiple limitations of a passive reporting system and the potential effect of widespread media coverage stimulating reporting. These cases occurred over a wide time interval after immunization, and 90% reported a known risk factor for VTEs. It is difficult to establish a potential window of biological plausibility since the time frame between risk factor exposure and clot formation is unknown. We did not detect any signal for VTEs through data mining or in the Vaccine Safety Datalink. Continued monitoring will be done for cases in VAERS, the Vaccine Safety Datalink, and potential future studies.

Our review of definite and possible GBS reports revealed a lower RR (0.3/100 000 estimated person-years based on dose distribution) than the background incidence rate of GBS in 9- to 26-year-old females (1.57/100 000 person-years). We did not detect any signal for GBS through data mining or in the Vaccine Safety Datalink, although the extent of underreporting to VAERS is not known.20

Because there are no adequate and well-controlled studies in pregnant women, and animal reproduction studies are not always predictive of human response, qHPV is not recommended for use in pregnant women.1 Exposures to qHPV during pregnancy have been identified in VAERS. As agreed with the FDA at the time of licensure, the vaccine manufacturer established a voluntary pregnancy registry to monitor outcomes among women vaccinated with qHPV during the month prior to conception or during pregnancy.1 This pregnancy registry is more complete than VAERS reporting and includes continued follow-up of cases.

Although VAERS shares inherent limitations of all passive surveillance systems, it is national in scope and can provide important signals that may require further attention.8 However, VAERS data need to be interpreted with caution, because not all reported events are systematically validated, and many may have only coincidentally followed vaccination. In addition, data limitations include underreporting, inconsistency in the quality and completeness of reported data, stimulated reporting due to extensive news coverage, and reporting biases.7 The VAERS reporting rate for qHPV is triple the rate for all other vaccines combined, perhaps reflecting greater public attention to HPV than the usual increased reporting following licensure of a new product ("Weber effect").32-33 AEFI reporting rates also need cautious interpretation, because vaccine distribution data do not allow calculation of age-specific reporting rates and do not provide the numbers of doses actually administered.

A further limitation of VAERS reports after qHPV is that a large proportion (68%) come from the manufacturer and most of these reports (89%) do not include sufficient identifying information to allow medical review of the individual cases. For example, when additional clinical information was available for review, approximately one-half of the cases of GBS and transverse myelitis were not confirmed.

Postlicensure safety surveillance of qHPV supplements data from the prelicensure randomized clinical trials. Ongoing VAERS monitoring also complements 2 large ongoing postlicensure observational safety studies: the CDC-sponsored Vaccine Safety Datalink "rapid cycle analysis" and a phase IV study agreed on by the manufacturer and the FDA at the time of vaccine licensure.1, 34 The latter study will provide data on the safety of simultaneous use of qHPV with other recommended vaccines, as well as autoimmune and serious AEFIs reported after qHPV vaccination. The pregnancy registry will continue for at least 5 years.

CONCLUSION

Vaccination with qHPV has the potential to decrease the global morbidity and mortality of HPV-associated diseases, including cervical cancer. After hepatitis B vaccine, which can prevent liver cancer, qHPV is only the second vaccine licensed with an indication to prevent cancer. The postlicensure safety profile presented here is broadly consistent with safety data from prelicensure trials. Because VAERS data must be interpreted cautiously and cannot generally be used to infer causal associations between vaccines and AEFIs, postlicensure monitoring will continue, and identified signals may be evaluated using epidemiologic observational studies.

RESULTS

From June 1, 2006, through December 31, 2008, VAERS received 12 424 reports of AEFIs following receipt of qHPV (Table 1), an overall reporting rate of 53.9 reports per 100 000 vaccine doses distributed. The majority of reports (8471/12 424, or 68%) were submitted by the manufacturer, compared with an overall rate of 40% for VAERS reports on other vaccines. During the same time period, manufacturer reports accounted for 14.5% of the meningococcal conjugate vaccine reports and 7.5% of the reports for tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine submitted to VAERS. Of the 8471 manufacturer reports for qHPV AEFIs, 7561 (89%) had insufficient identifying information to permit clinical follow-up or review. Additional sources of reporting included providers (17%), patients or parents (4%), state health clinics (1%), and "others" (11%).

In 9910 of 12 424 reports (80%), qHPV was the only vaccine identified. Patients received qHPV and quadrivalent meningococcal conjugate vaccine simultaneously in 775 of the AEFI reports (6%); the remaining 14% of reports described a variety of other vaccine combinations. Of the 8247 reports that included onset interval, 4393 (40%) occurred on the day of vaccination. Females accounted for 97% (12 039/12 424) of the patients for whom an AEFI was reported; the remaining 3% included males and reports with unspecified gender. Of 47 reports of qHPV administered to males, 25 (53%) were unintentional (medical errors with wrong vaccine administered), 17 (36%) were identified as off-label use, and 5 were from male HPV study participants. Among 9396 reports (77%) with dose information, 5772 (61%) followed the first dose, 2380 (25%) followed the second dose, and 1183 (13%) followed the third dose of qHPV. In addition, 61 (1%) inadvertently received 4 or more doses.

The most frequently reported AEFIs included syncope (n = 1847, 15%), dizziness (n = 1763, 14%), nausea (n = 1170, 9%), headache (n = 957, 8%), and injection site reactions (n = 926, 7.5%). These overall aggregate numbers must be interpreted with caution since each VAERS report usually includes multiple codes; thus, there were 46 932 total codes for 12 424 reports, for an average of 3.7 codes per report (range, 2-10). Also, review of individual reports revealed coding errors and occasional duplicate coding.

Serious Reports

Among the 12 424 AEFI reports, 772 (6.2%) were serious, including 32 reports of death, 20 of which had medical records, autopsy, or death certificates available for evaluation. Sources of serious VAERS reports included manufacturer (66%), patient/parent (11%), clinician (10%), state health clinic (1%), and "other" (12%). The most frequent serious symptom/MedDRA preferred-term codes included 159 reports of headache (21%), 119 nausea (16%), 113 dizziness (15%), 102 vomiting (13%), 102 pyrexia (13%), 102 fatigue (13%), and 98 syncope (13%). Medically important serious events included 8 reports of anaphylactic reaction (1%), 9 deep vein thrombosis (1.2%), 31 GBS (4%), 25 hypersensitivity (2.5%), 10 transverse myelitis (1.3%), 6 pancreatitis (0.8%), 14 pulmonary embolism (1.8%), 23 death (3%), 68 convulsion (8.8%), 30 urticaria (3.9%), and 9 autoimmune disorder (1.2%).

Local Injection Site Reactions

There were 1741 reports with at least 1 of the MedDRA coding terms for local reactions (Table 2); 684 (39%) occurred on the day of vaccination. The median onset interval was 0 days after vaccination (same day as vaccination) with a range of 0 to 408 days; 1338 reports (77%) identified qHPV alone. The most common local reaction reports included injection site pain (n = 926, 53%), injection site erythema (n = 490, 28%), and injection site swelling (n = 385, 22%). Forty-one reports (2%) involving local reactions were classified as serious. Review of these cases showed that 20 reports did not meet the FDA definition of serious; all of these were reported by the manufacturer. There were 4 cases reported as cellulitis and 1 case reported as an intra-articular injection. In the other 15 reports, local reactions were incidental and not the primary AEFIs contributing to severity.

Syncope, Dizziness, and Nausea

There were 1896 reports with the coding term syncope or syncope vasovagal, 1572 with dizziness, and 1164 with nausea (Table 2). Only 62 reports described all 3 events in the same individual. The qHPV was the only vaccine given in 74% of the syncope/vasovagal syncope reports, 73% of the dizziness reports, and 78% of the nausea reports. Of the reports describing syncope/vasovagal syncope, dizziness, or nausea, 94%, 90%, and 95%, respectively, were classified as nonserious. Among reports with known onset intervals, the event occurred on the same day as vaccination for 90% (1107/1228) of syncopal reports, 75% (930/1233) of dizziness reports, and 63% (610/970) of nausea reports. Of the events that occurred on the day of vaccination and where a more specific time frame was given, more than half immediately (≤15 minutes) followed vaccination. Among the 1896 syncopal reports, 293 (15%) resulted in a fall and 200 falls (68%) resulted in a head injury. Head injuries included 9 fractures (6 nose, 2 skull, and 1 maxillary), 18 dental injuries, 9 concussions, 17 contusions, 5 intracranial hemorrhages (1 subdural hematoma, 1 subarachnoid hemorrhage, 3 not otherwise specified), and 45 lacerations (38 of which required sutures). In addition, there were 7 reports of contusions on elbows or knees. The EB05 (2.28) for syncope was the only positive signal identified with EBGM methods.

Headaches

There were 937 reports of headaches after qHPV vaccination (Table 2). These accounted for 7.7% of the total AEFIs reported. One hundred fifty of these reports (16%) were coded as serious. The most common reason for being classified as a "serious" report was hospitalization for neurologic evaluation after a syncope-related fall.

Hypersensitivity Reactions

There were 725 reports with a coding term indicative of hypersensitivity (Table 2). Review of the reports showed that 31 reports were coded incorrectly. In addition, there was 1 hearsay case that could be not evaluated, leaving 693 total hypersensitivity cases. Of the 693 hypersensitivity reports, 416 (60%) were from the manufacturer, 178 (26%) were from the health care professional, 24 (3%) were from a parent or patient, and 75 (11%) were from an "other" source.

Hypersensitivity reports included 600 of urticaria (87%); 95 rash (14%); 95 pruritus (14%); 42 arthralgia (6%); 28 anaphylactic reaction (4%); 23 generalized rash (3%); 22 pruritic rash (3%); and rare reports (<1%) of angioedema, dermatographism, serum sickness, bronchospasm, and eye swelling. Five hundred fifty-six reports (80%) were attributed to qHPV alone.

The time interval between vaccination and onset of symptoms could not be calculated for 150 reports. For the reports where time interval was available, more than half of the cases were reported on the same day as (n = 246, 35%) or the next day after (n = 126, 18%) vaccination. The median onset interval was 1 day with a range of 0 to 271 days. No dose information was provided in 106 reports; 82 of these (77%) were manufacturer reports. Most hypersensitivity reports (n = 393, 78%) occurred after dose 1, 160 (23%) occurred after dose 2, and 53 (8%) occurred after dose 3. The overall RR was 3.1 of 100 000 doses distributed.

There were 600 reports of urticaria to VAERS, including 178 reports (30%) of generalized urticaria, 33 reports (5.5%) associated with the injection site or arm, 114 (19%) on localized sites (including 42 on the upper body, 3 on the lower body, 18 on the torso, 11 on the arms and legs, 8 on the legs bilaterally, 10 on the arms bilaterally, and 22 on the face/head), and 8 reports (1%) of fewer than 10 hives scattered over the body. There were 267 reports (44.5%) that did not specify the location of the urticaria. Most reports of urticaria (n = 329, 55%) occurred after dose 1, 135 (22%) occurred after dose 2, and 46 (8%) occurred after dose 3. No dose information was provided in 90 reports; 69 of these (77%) were manufacturer reports. The median time interval from immunization to onset of symptoms was 17 days, with a range of 8 to 49 days. The overall RR was 2.6 cases per 100 000 doses distributed.

There were 28 reports coded as anaphylaxis after qHPV (Table 2). Two cases were hearsay reports without any medical information, leaving 26 cases for review. Seventeen of these cases (65%) occurred after dose 1, 4 (15%) occurred after dose 2, 1 case (4%) occurred after dose 3, and the dose number was unknown for 4 cases (15%). Review using the Brighton classification criteria found that 7 (27%) did not meet the criteria for anaphylaxis, 9 (35%) had insufficient information, and 10 (38%) met the Brighton anaphylaxis definition. Only 4 cases were of sufficient concern to be referred to an allergist. Twenty-five cases occurred on the same day as immunization. One case occurred 5 days after immunization; while this case met the Brighton case definition, it was thought unlikely to be vaccine related due to the prolonged time between immunization and onset of symptoms. The overall RR was 0.1 case per 100 000 doses distributed.

Guillain-Barre Syndrome

There were 42 cases of GBS reported to VAERS (Table 2). Twenty-six of the reports were made by the manufacturer with no identifying information to enable clinical review of the cases. After FDA contact of the manufacturer to request information on these cases of interest, additional medical information was obtained on 13 cases (50%). One reporter refused to provide the manufacturer with any identifying information. Six cases were hearsay reports and no further information could be obtained. No further identifying information was provided on 5 cases. Review of the 21 cases with available clinical information showed that 12 cases (57%) met the Brighton case definition, 1 case (5%) initially thought to be an atypical case of GBS was diagnosed as amyotropic lateral sclerosis at autopsy, 2 cases (10%) lacked sufficient detail for complete evaluation, 5 (24%) reported events did not meet the Brighton case definition, and 1 case (5%) occurred prior to vaccination. Medical records are still being collected for the 11 recent cases.

Eleven of 12 confirmed cases were patients aged between 13 and 30 years. Six patients had received qHPV alone; 4 received qHPV and quadrivalent meningococcal conjugate vaccine; 1 received qHPV, quadrivalent meningococcal conjugate vaccine, and hepatitis A vaccine; and 1 received qHPV, quadrivalent meningococcal conjugate vaccine, and varicella vaccine. Onset intervals for the 12 definite cases ranged from 0 to 145 days. Only 8 of the confirmed cases were within the 4- to 42-day window of biological plausibility.18 The RR of GBS following qHPV was 0.3 confirmed cases per 100 000 person-years. The PRR for GBS after qHPV in 6- to 29-year-olds compared with all other vaccines in 6- to 29-year-olds was 0.4. This PRR did not meet the screening criteria for signal detection.

Transverse Myelitis

There were 10 cases of transverse myelitis reported to VAERS (Table 2). Two cases had insufficient information for adequate clinical review and 1 case was diagnosed as multiple sclerosis. All 7 confirmed transverse myelitis cases were found after qHPV vaccine alone. The age distribution of cases was 13 to 26 years. One case occurred after dose 1, and 6 cases occurred after dose 2. Only 1 case occurred within the theoretical 4- to 42-day window of biological plausibility.18

Motor Neuron Disease

There were 3 reports to VAERS of young females who presented with a rapidly progressing neurologic disorder occurring some months after receipt of the qHPV vaccine. One of these reports was a hearsay report (a fifth-hand report) that could not be identified and might represent 1 of the other 2 cases. Autopsy confirmed a diagnosis of amyotropic lateral sclerosis (anterior motor neuron disease) in 1 case. The other young female died in 2009. The autopsy findings on this case are still pending.

Venous Thromboembolic Events

Based on MedDRA search terms of venous thrombosis, thrombosis, embolism, pulmonary embolism, deep vein thrombosis, pulmonary thrombosis, and embolic stroke, there were 56 reports of VTEs after qHPV, for an RR of 0.2 case per 100 000 doses. Ten cases were hearsay reports that could not be confirmed or clinically evaluated, 9 reports were related to "clots with menses" and were not VTEs, 5 were manufacturer reports with no identifying information for follow-up, 1 report had insufficient information available for adequate evaluation, and 31 reports had sufficient information for clinical review. There were 5 reports of deep vein thrombosis alone, 7 reports of deep vein thrombosis with pulmonary embolism, 12 reports of pulmonary embolism without deep vein thrombosis, 4 reports of cerebrovascular accidents, 1 report of superior mesenteric vein thrombosis, and 2 reports of superior sagittal venous thrombosis. There were 4 deaths reported among the 19 pulmonary embolism cases (21%).

Thirty of 31 reports (97%) were associated with qHPV immunization alone. The mean age of individuals reported to have VTEs after qHPV immunization was 21 years (median, 20 years; range, 15-39 years). The number of doses preceding the diagnosis of a VTE included 9 cases after dose 1, 11 cases after dose 2, and 10 cases after dose 3; dose number was unknown for 1 case. The mean time between qHPV immunization and diagnosis was 41.5 days (median, 23 days; range, 0-306 days).

Risk factors included estrogen-containing birth control (n = 20), family history (n = 10), history of smoking (n = 2), immobility (n = 7), overweight (n = 6), increased triglycerides (n = 1), history of surgery (n = 1), pregnancy (n = 2), trauma from surfing (n = 1), and hyperviscosity from diabetic ketoacidosis (n = 1). Twenty-eight of 31 cases (90%) had a known risk factor for VTEs. Twenty-two of 31 cases (71%) were tested for hypercoagulability; 10 were positive, including 2 cases with factor V Leiden deficiency, 2 cases with methylenetetrahydrofolate reductase deficiency, 1 case with methylenetetrahydrofolate reductase deficiency with increased homocysteine levels, 1 case with the prothrombin gene mutation with methylenetetrahydrofolate reductase deficiency, 1 case with a prothrombin mutation and increased homocysteine levels, and 2 cases of antiphospholipid syndrome. All 10 cases with hypercoagulability had a known risk factor for VTEs, including 7 with a history of taking estrogen-containing birth control medications.

The PRR for 6- to 17-year-olds was 4.8 ({chi}2 = 4.16, P = .04). The PRR for 18- to 29-year-olds was 6.7 ({chi}2 = 7.48, P = .006). Both of these age groups met the screening criteria for signal detection.

Pancreatitis

There were 10 reports coded as pancreatitis in VAERS. One case was ultimately diagnosed with multiple ovarian cysts as the cause of the patient's right lower quadrant pain, leaving 9 reports of pancreatitis. All of the cases had risk factors for pancreatitis, including gallstones (n = 2), alcohol use (n = 1), increased triglycerides (n = 1), viral infection (Coxsackie) (n = 1), estrogen use (n = 2), and mild obesity (n = 2). All cases were hospitalized, meeting the FDA definition of a serious AEFI. Three cases presented after dose 1, 3 after dose 2, and 3 after dose 3. Two of the individuals who presented after dose 1 had resolution of symptoms but experienced subsequent exacerbations after doses 2 and 3. It was not possible to do any statistical comparisons because of low numbers.

Autoimmune Disorders

There were 51 reports of autoimmune disorders to the VAERS system, including 26 reports of autoimmune disorder (not otherwise specified), 1 report of scleroderma, 1 report of dermatomyositis, 18 reports of systemic lupus erythematosus, 13 reports of rheumatoid arthritis, 1 report of Sjogren syndrome, and 4 reports of mixed connective tissue disease. Fifty-one of these reports (88%) were associated with qHPV vaccine alone.

Pregnancy

There were 236 VAERS reports of qHPV given shortly before or during pregnancy. Twelve of the AEFI reports were coded as serious; 10 required hospitalization due to miscarriage and 2 cases included a life-threatening illness (1 deep vein thrombosis and 1 severe vaginal hemorrhage after emergency dilation and curettage). Two hundred twenty-eight reports (97%) were received from the manufacturer through the Merck Pregnancy Registry.

One hundred forty-three of the reports were coded as miscarriage (spontaneous abortion), including 1 molar pregnancy. There were 75 reports of elective termination of pregnancy following administration of qHPV. None of the reports described receipt of qHPV having influenced the decision to terminate the pregnancy. There were 13 deliveries of normal, healthy infants; 3 ectopic pregnancies; and 2 unknown pregnancy outcomes.

Deaths

There were 32 VAERS reports of death following qHPV vaccination (Table 2). Eight of the reports were second-hand reports that could not be verified. Four were manufacturer reports with no identifying information for confirmation or medical review. Twenty of the reports (62.5%) could be verified through clinical review of medical records and autopsy reports. Of these cases, 14 (70%) were after qHPV alone. The other 6 cases reported qHPV as well as a variety of other vaccines. Nine cases occurred after dose 1, 5 after dose 2, and 6 after dose 3.

Mean age was 18 years (median, 17 years; range, 12-26 years). There was no clustering by age. The mean time from last qHPV immunization to AEFI onset was 39 days (median, 14.5 days; range, 2-288 days). The mean time from last qHPV immunization to death was 47 days (median, 14.5 days; range, 2 to 405 days).

Causes of death included 4 unexplained deaths, 2 cases of diabetic ketoacidosis (1 complicated by pulmonary embolism), 1 case related to prescription drug abuse, 1 case of juvenile amyotropic lateral sclerosis, 1 case of meningoencephalitis (Neisseria meningitidis serogroup B), 1 case of influenza B viral sepsis, 3 cases of pulmonary embolism (1 associated with hyperviscosity due to diabetic ketoacidosis), 6 cardiac-related deaths (4 arrhythmias and 2 cases of myocarditis), and 2 cases due to idiopathic seizure disorder.

The PRR for deaths in 6- to 17-year-olds was 1.4 ({chi}2 = 0.42, P = .52). The PRR for deaths in 8- to 29-year-olds was 1.2 ({chi}2 = 0.01, P = .92). Neither of these met the screening criteria for signal detection.

METHODS

We analyzed qHPV reports received by VAERS from June 1, 2006, through December 31, 2008. This voluntary, national, passive surveillance system was established in 1990 and is operated jointly by the US Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC). Manufacturers, health care workers, patients or their parents, and others submit reports to VAERS.7 Although manufacturer reporting to VAERS is required, most information comes from physicians, patients, or other primary reporters.8 This analysis included only US reports to VAERS, which usually have more complete information and more feasible follow-up review of medical records than foreign reports. In addition, we had only US dose distribution data for calculation of reporting rates (RRs).

To code reported symptoms, VAERS uses a clinically validated, internationally standardized terminology, the Medical Dictionary for Regulatory Activities (MedDRA).9 Each report may have several assigned MedDRA codes. We searched the VAERS database using MedDRA codes for specific AEFIs of interest and predefined groups of MedDRA codes for local reactions and hypersensitivity reactions.

We classified VAERS reports as serious according to the FDA regulatory definition (21 CFR 314.80) of a serious AEFI as one that is life threatening; results in death, permanent disability, congenital anomaly, hospitalization, or prolonged hospitalization; or necessitates medical or surgical intervention to preclude one of these outcomes.10 We reviewed serious reports to identify primary AEs that needed further study. Onset interval is the number of days from the time of vaccination to the onset of earliest reported symptoms. The number of doses distributed in the United States (23 051 336), obtained from the vaccine manufacturer (number provided by manufacturer, http://www.cdc.gov/vaccinesafety/vaers/gardasil.htm), provided the denominator to estimate RRs.

Based on prelicensure safety data and the severity of or public attention to reported AEFIs, we performed detailed case reviews and separate analyses for syncope, dizziness, nausea, headache, local injection site reactions, hypersensitivity reactions including anaphylaxis, Guillain-Barre syndrome (GBS), transverse myelitis, pancreatitis, venous thromboembolic events (VTEs), deaths, and pregnancy outcomes.

Disproportionality screening with the empirical Bayesian geometric mean (EBGM) method, using Empirica WebVDME software (Phase Forward, Waltham, Massachusetts), identified AEFIs reported during the first year of licensure that were more frequent than expected.11-12 We used the lower 5% bound of the 90% confidence interval for the EBGM (EB05) of 2 or higher, following criteria outlined by Szarfman et al,13 to select AEFIs for further review. We also used proportional reporting ratio (PRR), another method to detect potential associations between reported AEFIs and a drug or vaccine, to compare the proportion of selected AEFI reports for qHPV with the proportion of selected AEFI reports for all other vaccines by age group and sex.14-15 We applied the PRR screening criteria that Evans15 proposed: number of cases of 3 or more, PRR of 2 or more, and {chi}2 of 4 or more.

Given the association of GBS with the 1976 swine influenza vaccine and more recently with quadrivalent meningococcal conjugate vaccine,16 there has been concern regarding the possibility of an association between GBS and other vaccines, including qHPV.17-18 Clinical subject matter experts from the CDC Clinical Immunization Safety Assessment Network reviewed reports coded with the MedDRA term GBS or with text containing GBS or Guillain-Barre. Cases were classified as confirmed GBS if they met the proposed Brighton Collaboration GBS case definition.19 Reports with insufficient information could not be classified. We used Healthcare Cost and Utilization Project data for 2000 through 2004 to estimate a background rate of GBS among 9- to 26-year-old females.20

The GBS reporting rate to VAERS was calculated as the number of reported GBS cases divided by the estimated person-time at risk, based on 6 weeks after each dose. This GBS reporting rate was compared with the background rate among females aged 9 to 26 years. From June 1, 2006, through December 31, 2008, there were 23 051 336 doses of qHPV distributed in the United States. Based on a 6-week window of biological plausibility after immunization, this gives a total of 2 650 667 person-years at risk.

Potential anaphylaxis reports were selected using the MedDRA terms anaphylaxis and anaphylactic reaction. Clinical subject matter experts from the CDC Clinical Immunization Safety Assessment Network reviewed reports to confirm the diagnosis of anaphylaxis. Reports were classified as anaphylaxis if they met the Brighton case definition.21

Because VAERS is a legally mandated, government-sponsored surveillance system, institutional review board approval and informed consent were not required.

 
 
 
 
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