The HPV Vaccine (Gardasil) Safety Revisited

Gardasil (qHPV) was licensed in 2006 as a vaccine against four types of Human Papillomavirus (HPV) and marketed as, “The first vaccine targeted to prevent cancer.”  From its inception it has been one of the more controversial vaccines.  Some religious groups feared that the reduced threat of a sexually transmitted disease would lead to increased sexual promiscuity.  Other groups were concerned about its safety.  Some have questioned whether its high financial cost would make it a cost-effective intervention, while others have questioned the marketing tactics of its manufacturer Merck.

Most of these concerns bear consideration (though I have no time for those who advocate using the threat of disease and death to force conformation to their religious beliefs), and were in large part addressed by David Gorski in a SBM article last year.  If you’ve not read his post, I strongly suggest you do so.  Now that a large post-licensure study on qHPV has been published, it seems a good time to revisit the issue of greatest concern to me as a pediatrician and to most parents, namely qHPV’s safety and efficacy profile.


Infection with HPV is a common problem, infecting 79% of the population over their lifetime, and holding the dubious honor of being the most common sexually transmitted disease. In addition to genital warts, HPV infection has been clearly shown to be responsible for a large percentage of cancers in areas that contract HPV, including the vulva, vagina, and penis (40%), anus (90%), and oropharynx (12%), but the most common site of HPV-caused cancer is the cervix.  Cervical cancer is diagnosed in 7.9/100,000 women per year, amounting to approximately 11,000 cases in 2008 and 3900 deaths in the US.  Worldwide, the WHO estimates 500,000 cases of cervical cancer and 260,000 related deaths.

We have largely failed in preventing HPV infection.  Infections are not always obvious and are thus hard for sexual partners to identify and avoid.  Barrier devices like condoms don’t cover all the potential infected areas (see the list above) and are thus helpful but of limited utility. Education and abstinence are clearly inadequate to fully address the problem.

In spite of our limited ability to prevent HPV infection, gynecologists have made significant progress in reducing the number of women who suffer from cervical cancer, in large part through regular screening with Pap-smears.  The ability to identify and treat pre-cancerous lesions on the cervix or to identify cervical cancer early in its course has lead to a marked reduction in deaths from cervical cancer in the US.  It has been so effective that one of the highest risk factors for developing cervical cancer is now a failure to obtain routine Pap-smears.

Yet in spite of the success of Pap-smear screening, we were still faced with 11,000 cases of cervical cancer and 3900 deaths last year.  Through sustained effort and eternal vigilance on the part of patients and physicians we can reduce the impact of HPV induced malignancy, but the population at risk remains unchanged.  And let’s be honest, humans suck at eternal vigilance.  If we could prevent the infection, we could prevent its complications and reduce the impact of the inevitable lapse in our eternal vigilance.  Vaccines allow us to do exactly that.


qHPV is a vaccine against the two most common causes of genital warts (types 6 and 11) and the two leading causes of cervical cancer (types 16 and 18).  Its antigen is a virus-like particle with no genetic material, so it is not a live-virus vaccine and cannot cause infection.  It has an excellent response rate, inducing an adequate antibody response to all four types of HPV in 99.5% of women after the third dose that has been shown to persist for at least five years.

Regarding efficacy, most cervical cancer occurs decades after the infection, so it will be quite some time before we can demonstrate the effect qHPV should have on the incidence of cervical cancer.  However, lesions identified on Pap smear and known to precede cervical cancer occur far earlier, and have served as a surrogate in pre and post-licensure studies.  In trials to date, qHPV is 94-100% effective at preventing pre-cancerous changes from these four HPV types.


qHPV is effective, but what of its safety? When it was submitted for licensure, over 20,000 women between the ages of 16 and 26 (the peak ages during which most women are infected) were enrolled in phase 3 trials.  Potential adverse events were solicited from all participants were nearly identical between the test and control groups.  The only reactions that stood out when compared to the control group were fever (13% vs 11.2%), nausea (6.7% vs 6.5%) and injection site reactions (2.2% vs 0.9%).  No serious reactions were seen.  Based upon this information, qHPV was considered to be safe and approved by the FDA.

Since its release, however, there have been reports of serious adverse reactions following qHPV injection.  Many articles voicing concerns about its safety cite the VAERS database. These reports have generated headlines in the mainstream media, not to mention being perpetual fodder for crank sites like NaturalNews and, and have been a if not the major source of the concern expressed by parents.

As a part of routine post-licensure follow-up and to address these very concerns, “Postlicensure Safety Surveillance for HPV Vaccine” was funded by the FDA and CDC and published last month in JAMA. This article is the largest attempt to evaluate the adverse events seen since qHPV was released.  In it, the authors compared the adverse events reported to VAERS to the expected background rate of reported events in the unvaccinated general population of women aged 9-26, re-evaluating the previously reported adverse events known from licensure as well as the reports of more serious events that have gained public attention.  The results are reassuring.

Over the first 2.5 years since its release, 23 million doses of qHPV were administered, and VAERS received 12,424 reports of adverse events.  Of these, only 772 (6.2%) were classified as serious or life-threatening. These are summarized in the table below, taken from the article:

VAERS reported adverse events for Gardasil

Of all of these events, only two are above what one should expect from their respective baseline rates and not previously identified by the original licensure studies.  The first is Venous Thromboembolic Events (VTEs).  These are blood clots within the blood vessels that can be quite serious; these occurred in 0.2/100,000 doses.  The second was syncope, or loss of consciousness, which occurred in 8.2/100,000 doses.  This does not establish that qHPV causes these events; remember that this study and the VAERS in general are not designed to establish causation.  Nevertheless, further studies are certainly warranted to confirm or refute qHPV’s role in these rare events, and physicians should bear the correlation in mind when considering the administration of qHPV.

Notice, however, that the rates of major events of concern, namely Guillain-Barre syndrome, autoimmune disorders, transverse myelitis, and death, were all exceedingly rare, and not above what one would expect to occur in the normal unvaccinated population.  In spite of the clear limitations inherent in the use of the VAERS database, this study should strongly reinforce the confidence of physicians and parents regarding the safety of HPV vaccination.

Gardasil (qHPV) is a new vaccine.  Recommendations regarding its use are likely to continue to change as we learn to optimize its use.  Just last week, an FDA advisory panel recommended that qHPV be approved for use in males age 9-26, and Merck is likely to seek approval to broaden the approved ages of administration.  Whether these developments should alter the current practice is a point of open debate.  And of course, as with any new medical intervention qHPV warrants close surveillance for any unexpected adverse effects. Though uncertainties remain regarding this vaccine’s use in the sphere of public health, for a parent who desires to reduce the risk of HPV infection and HPV induced malignancies for their child, we can confidently say that qHPV is a safe and effective option.

Posted in: Public Health, Vaccines

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