Medscape's replacement Gardasil magic wand - Members only

Zosia Chustecka

Medscape Medical News 2008. © 2008 Medscape

Editor's note: This article replaces "HPV Vaccine Adverse Events Worrisome, Says Key Investigator," which was posted on July 26, 2008, and did not meet Medscape's editorial standards.

 

August 8, 2008 — Reports of adverse events after administration of the human papillomavirus (HPV) vaccine (Gardasil, Merck) have been making headlines, and questions over the safety of the vaccine have been raised by consumers, parents, healthcare professionals, and others, notes a recent joint statement from the US Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA). But having analyzed the available data, the agencies offer reassurance.

"Based on ongoing assessments of vaccine safety information, the FDA and CDC continue to find that Gardasil is a safe and effective vaccine," the agencies said in a statement released on July 22, 2008. "The benefits continue to outweigh the risks," they said. "This vaccine is an important cervical cancer prevention tool," they added.

The manufacturer also issued a statement, dated July 10, 2008, saying it too had analyzed available data and it "believes that no safety issue related to the vaccine has been identified. These types of events are events that could also be seen in the general population, even in the absence of vaccination."

Both statements were issued after several cases of damage allegedly caused by the vaccine were highly publicized in the lay media in the United States. One example is the case of a 13-year-old now almost completely paralyzed, as reported on CBS News. Another report described a 19-year-old who collapsed and died 2 weeks after receiving the first dose of Gardasil. This report first appeared in East Bay Express News (California) and was recycled on NaturalNews.com with the headline "Girl Dies after HPV Jab," although the report contained additional information that the woman had been taking an oral contraceptive, which the CDC thought contributed to her death.

Merck spokesperson Tracy Ogden told Medscape Oncology that the company has received many comments from physicians and from groups representing patients who are concerned about recent media reports about Gardasil and the detrimental effect they may have on vaccine uptake and protection against cervical cancer.

"There is a great deal of hype, lack of understanding, fear-mongering, and totally unrelated agendas surrounding this issue. It is distressing that these reports have absolutely nothing to do with objective science, and objective science is the process through which we should and must make our decisions related to the public welfare," said Maurie Markman, MD, professor of gynecologic medical oncology at the University of Texas MD Anderson Cancer Center, in Houston, who acts as an advisor to Medscape Oncology.

"In any large population, there are going to be events such as death and paralysis, and it is understandable from human point of view that when tragedy strikes, people will look around for an explanation as to why it may have happened. But the fact that an event happened after vaccination does not mean that it happened because of the vaccination," Dr. Markman emphasized.

Data Are "Overwhelmingly Positive"

"That is why we do randomized clinical trials," he continued, "and it is very important that 2 separate large clinical-trial programs with 2 different products have come to very similar conclusions." (The other HPV vaccine, Cervarix [GlaxoSmithKline], is not available in the United States but is marketed elsewhere in the world). Dr. Markman pointed out that he has no links with either manufacturer.

"The data are overwhelmingly positive that this is an extremely safe and extremely effective vaccine," he said.

However, Diane Harper, MD, professor of community and family medicine/obstetrics and gynecology at Dartmouth Medical School, in Hanover, New Hampshire, and director of the Gynecologic Cancer Prevention Research Group at the Norris Cotton Cancer Center, is more circumspect. Dr. Harper, who was involved in clinical trials with both HPV vaccines, commented during an interview, "Serious adverse events reported do happen, but in small numbers of women being vaccinated, and some of these events may be so rare that they will never be directly linked to the vaccine."

Dr. Harper notes that she has received money from both Merck and GlaxoSmithKline for consultation about and conducting clinical trials on the HPV vaccines. "This is a good vaccine and it is generally safe," she said.

Vaccine Is Only Part of the Story

 

However, there is also another very important part to the cervical cancer prevention story, Dr. Harper said, and that is regular Pap tests. Even women who are vaccinated need to have regular Pap testing, as otherwise they are still at risk of developing cervical cancer. And women who decide not to have the vaccine can still protect themselves by undergoing Pap testing.

 

Dr. Harper feels this message has not been made clear to the general public and that it has been overshadowed by what she considers to be aggressive and inappropriate promotion of Gardasil. As a gynecologist dealing with the general population, her advice on the HPV vaccine is that "if you are at all concerned, then don't have the vaccine — have regular Pap smears and you will be equally protected from cervical cancer."

She continued, "Whether or not to get vaccinated with Gardasil is a personal choice by each girl/woman and/or her parents." Each individual must weigh her family health history and whether it may put her at any possible risk for an adverse event that Gardasil might trigger (not even necessarily cause). As examples, Dr. Harper mentioned family history of motor neuron disease or autoimmune diseases, which could affect how the person reacts to the vaccine. She illustrated this point by saying: "Salt does not usually kill anybody, but for a person with congestive heart failure, it could lead to fatal pulmonary edema, so you could say that salt caused their death, as it was the last straw that broke the camel's back."

Details of the Adverse-Events Reports

Gardasil is 1 of the "most heavily studied and intensively monitored vaccines," commented John Iskander, MD, acting director of the Immunization Safety Office at the CDC in Atlanta, Georgia. So far the available data suggest that it is safe, he said in an interview, although he added that "there are no medical products, including vaccines, that are completely safe and effective."

"We have drawn attention to the possibly increased risk of fainting after Gardasil, again not saying that this is a property of the vaccine, and that precautions should be taken to avoid injury," he said. "But there has been nothing that has warranted a change in the recommendation for its use."

Dr. Iskander has been heading the postlicensure safety monitoring of the vaccine. The CDC and FDA monitor the safety of all vaccines through the Vaccine Adverse Event Reporting System (VAERS). This system collects unconfirmed reports of events occurring after vaccination, and anyone can file such a report.

As of June 30, 2008, the VAERS system had received 9749 reports of adverse events after Gardasil vaccination, of which the great majority (94%) were classified as nonserious and the remaining 6% classified as serious.

Merck said that as of June 2008, it has distributed more than 30 million doses of Gardasil worldwide, including nearly 18 million doses in the United States. The company says it cannot determine the exact number of doses that have been administered, but, based on private insurance claims data and a broad estimate of public-sector use, it estimates that at least 8 million US women have received at least 1 dose. Gardasil has been available in the United States since June 2006.

Dr. Iskander commented that, of the 9749 adverse events reported, the 6% to 7% serious adverse event rate for Gardasil compares with a serious adverse event rate of about 10% to 15% reported for all vaccines (including Gardasil) in the VAERS system.

However, Dr. Harper counters that a direct comparison of these percentages is an invalid metric to use, as the population may not have been as motivated to report less serious events in other vaccines (eg, targeted at infants or the elderly) that have been less actively promoted, and this could artificially elevate the proportion of serious adverse events reported.

The nonserious adverse event reports include syncope, pain at the injection site, headache, nausea, and fever. The agencies note in their statement that fainting is common after injections and vaccinations, especially in adolescents, and say that they have reminded immunization providers about the recommendation to watch individuals carefully for 15 minutes after vaccination. Falls after fainting can cause injury and can be prevented by keeping the individual seated during the observation period, they add. This recommendation was added to the Gardasil prescribing information, and so far this is the only change that has been made to the product's labeling.

The serious adverse event reports were death, Guillain-Barré syndrome (GBS), and thromboembolic disorders.

Most of the individuals in whom thromboembolic disorders have been reported already had risk factors such as the use of oral contraceptives, which are known to increase the risk of clotting, the agencies comment.

Incidence of Guillain-Barré Syndrome

GBS occurs spontaneously in the general population, and Dr. Iskander noted that there is a baseline occurrence of this disorder among adolescents of about 1 to 2 per 100,000 persons per year. The CDC and FDA say the available data do not suggest an association with the vaccine: "To date, there is no evidence that Gardasil has increased the rate of GBS above that expected in the population."

Dr. Iskander said more definitive data on the incidence of GBS, as well as other adverse events, should be available within the next few months from the Vaccine Safety Datalink (VSD) Project. A large, controlled study is almost complete that is comparing a vaccinated population (360,000 doses of Gardasil) and an unvaccinated population and looking at 9 very specific important outcomes, including GBS, blood clots, and seizures. "We are working feverishly to complete this study," Dr. Iskander said, "and then we will be able to say whether any of these events are occurring at a higher incidence in the vaccinated population."

With circumspection, Dr. Harper added: "It is unlikely that there will ever be a statistically associated relationship between peripheral neuropathies (GBS, etc) and Gardasil because the occurrence is rare — this does not mean that Gardasil is not involved in triggering these diseases; it means that we will never have enough evidence to prove absolutely no association in any subgroup of the population."

Dr. Harper noted that GBS has been associated with the meningococcal vaccine Menactra (Sanofi Pasteur). "This vaccine is no longer recommended in Canada because the incidence of GBS after Menactra is higher than the general Canadian population incidence," she commented. In the United States, promotion materials for Menactra state: "There is a potential for an increased chance of getting Guillain-Barré syndrome following vaccination."

The CDC recommends meningococcal vaccine for children aged 11 to 18 years, which overlaps with the age group that is approved to receive Gardasil. "The administration of Menactra with Gardasil (on the same day, different arms) is probably not wise," Dr. Harper commented, although she added that there is no CDC contraindication against coadministration of multiple vaccines.

Adverse-Event Reports on Watchdog Web Sites

The actual reports collected by VAERS have been made available on the Web site of the watchdog organization JudicialWatch, which obtained the records from the FDA under the Freedom of Information Act. A compact disc containing 8864 records was sent by the FDA on June 10, 2008.

JudicialWatch says the adverse event reports "read like a catalog of horrors," and it questions the safety of the vaccine, but the group also questions its efficacy in preventing cervical cancer and criticizes Merck's promotion of the product. "Given all of the questions about Gardasil, the best public health policy would be to reevaluate its safety and prohibit its distribution to minors," it says. "In the least, governments should rethink any efforts to mandate or promote this vaccine for children," JudicialWatch concludes in a special report on the vaccine, published on its Web site on June 30, 2008.

The VAERS records of adverse events after Gardasil vaccination on the JudicialWatch Web site have been used by other groups to highlight concerns over safety of the product.

Part of the problem stems from an ignorance about the VAERS system, says Kenneth Alexander, MD, PhD, chief of pediatric infectious disease at the University of Chicago, in Illinois. He has acted as a paid speaker for both Merck and GlaxoSmithKline, but he pointed out that he has been researching HPV since 1992, long before the vaccines came along.

"There is a lack of understanding that temporal relationships do not prove causality," he said in an interview. "In scientific terms, this is a very sensitive assay, but it is entirely nonspecific. It is not designed to pick up cause-and-effect relationships, and so it picks up a lot of noncausal events."

Consumer Concerns Not Assuaged

Consumer concerns over safety have not been assuaged by "reassurances from the government," said Barbara Loe Fisher, cofounder of the National Vaccine Information Center (NVIC). "We have heard reassurances about safety before — for example, with the whole-cell pertussis (diphtheria-pertussis-tetanus [DPT]) vaccine in the 1980s," she said, noting that this was subsequently withdrawn and replaced by an acellular version in the United States in the 1990s.

 

Ms. Fisher has a son whom she believes was damaged by the DPT vaccine 28 years ago, and she has worked ever since as an activist in the vaccine safety field in various capacities, including a 4-year stint as a consumer member of the FDA Vaccines and Related Biological Products Advisory Committee.

 

The NVIC, self-billed as "America's Vaccine Safety Watchdog," has also accessed VAERS reports and made them available in a searchable database on its Web site. These data show that during 2008, reports about Gardasil have accounted for 20% to 25% of all VAERS reports on all vaccines, Ms. Fisher said. "This is striking, as Gardasil isn't a mandatory vaccine while many other childhood vaccines are, but we don't know what this means."

 

In addition, the NVIC has been running its own private vaccine reaction registry for the past 26 years, and it currently has about 140 reports on Gardasil, Ms. Fisher said. "These include reports of injury and death, and we are seeing a pattern of what we have termed 'atypical collapse,' " she commented. "These include cases where a girl suddenly passes into unconsciousness either immediately or within 24 hours of vaccination and then revives feeling weak and unable to speak properly or exhibiting other neurological signs. What we are concerned about is that girls are not aware of this possibility and could be crossing the road or driving a car and suddenly pass out."

Ms. Fisher also outlined concerns about how Gardasil has been studied. She pointed out that very few of the participants in the clinical trials were aged 11 to 12 years, which is the recommended target age for the vaccine. The New York Times reported in 2006 that of the 20,000 trial participants, 1200 were younger than 16 years.

Ms. Fisher added that the fact that the placebo used was aluminum based, and so the results may not give a true picture of the events associated with the vaccine, and noted the lack of any prelicensure data on administration of Gardasil simultaneously with other vaccines, in particular the meningococcal vaccine, which is targeted at a similar age range. She suggested that the vaccine was recommended for preadolescent girls prematurely.

"A lot of people reading these VAERS reports are shaking the pepper shaker to try to find salt," Dr. Alexander told Medscape Oncology. He is especially concerned that a small number of people, and he mentioned specifically JudicialWatch and the NVIC, "may have another agenda and may have an axe to grind."

Dealing With Safety Concerns Is Part of Patient Education

Dealing with concerns over safety is part of patient education, although it can become "a little onerous to explain all of the time," said Kevin Ault, MD, associate professor of gynecology and obstetrics at Emory University, in Atlanta, Georgia, and with the Winship Cancer Institute. He has been administering Gardasil to the "catch-up" population at the university clinic and said that by the time he sees these young women, they have usually already decided that they want the vaccine, but even so, there are lots of questions about safety, some which are unfounded. For example, he has been surprised at how many times he has been asked about mercury in vaccines and autism (after publicity over the measles-mumps-rubella vaccine) and has had to explain that no vaccine in the US now contains mercury and that, anyway, autism is not a risk for an individual in their 20s.

There has been a steady, low-level rate of "agitation" over the safety question for about a year now, Dr. Ault told Medscape Oncology in an interview, but he has not noticed any increase over the past month or so. His position is that the data available so far show that the vaccine is safe; the serious adverse events that have been reported are very rare, and there has been no consistent association between the vaccine and any particular serious adverse event. "It comes down to patient education," he said.

Improving the Health of Young People

Dr. Alexander said that reassuring about safety is only part of the story, and educating about the benefits of HPV vaccination is very important. He is a strong advocate for HPV vaccination: "Do I think this is going to prevent people from dying from cervical cancer? Absolutely.

"In the end, we all want to improve the health of our young people," Dr. Alexander commented. "The question is, is HPV immunization a good way to do it? From my perspective, we have the proven benefits that these vaccines prevent HPV infections and cervical precancers. These real and proven benefits of HPV immunization must be balanced against the potential but rare and entirely unproven associations of the vaccine with serious adverse effects. As I add things up, the proven benefits far, far outweigh the theoretical, rare, and unproven risks."

However, Dr. Harper said: "In developed countries where Pap screening systems have been effective for decades, the biggest value of the HPV vaccine will not be in preventing deaths from cervical cancer. The true value of the HPV vaccine will be to provide women with a greater reassurance that their future Pap screens will more likely be normal.

"Pap screening is still the only proven method we have for cervical cancer prevention," Dr. Harper pointed out. "We don't know how long the vaccine will protect a woman from HPV infection, and the vaccine does not protect against all types of HPV infection that cause cervical cancer." She said that the data so far show that vaccination is effective for 5 years, but it is still unknown whether boosters may be needed. Gardasil protects against 4 types of HPV, 2 of which are responsible for about 70% of cervical cancer, and the other 2 for about 90% of genital warts.

"In the end, regardless of whether a woman chooses to be vaccinated or not, the take-home message is to start and continue Pap screening throughout your life," Dr. Harper said.