Gardasil Does Not Increase MS Risk

Pauline Anderson

January 06, 2015

There is no increased risk for multiple sclerosis (MS) or other demyelinating disease among girls and women in Denmark and Sweden who received the human papillomavirus (HPV) vaccine, a large new study confirms.

Because demyelinating diseases are relatively rare, previous controlled observational studies were unable to reliably confirm or refute a potential association with HPV vaccination.

The new results help support a favorable overall safety profile of the HPV vaccine, said Anders Hviid, DrMedSci, senior investigator, Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark.

"The study provides reassurance based on about 4 million study participants with almost 800,000 people who were vaccinated," said Dr Hviid.

Dr Anders Hviid

The study is published in the January 6 issue of JAMA.

National Vaccination Program

Researchers tapped into national health and demographic databases in Denmark and Sweden for information on vaccinations and demyelinating diseases. In addition to MS, these diseases included optic neuritis, neuromyelitis optica, transverse myelitis, and acute disseminated encephalomyelitis.

The analysis assessed the effect of receiving the quadrivalent HPV vaccine (Gardasil, Sanofi Pasteur MSD SNC; Merck in the United States), which was licensed in Europe in 2006 and recommended as a three-dose schedule.

In Denmark, this vaccine has been included in the national vaccination program since 2009 for 12-year-old girls, with catch-up vaccination at ages 13 to 15 from October 2008, and of women aged 20 to 27 from August 2012. In Sweden, the vaccine has been subsidized since May 2007 and was subsequently implemented in the national vaccination program for 10- to 12-year-olds in January 2012, together with catch-up vaccination of 13- to 17-year-old girls.

The study did not include the bivalent HPV vaccine because it is given to less than 1% of all vaccine recipients in Denmark and Sweden.

The cohort study included 3,983,824 Danish and Swedish girls and women (mean age, 25.5 years), almost 3.5 million of whom entered the study in 2006; the rest entered every year until 2013. Their mean age at the time of vaccination was 17.3 years (the Danish cohort was somewhat older: mean age, 18.5 years vs 15.3 years for the Swedish group).

Of these females, 789,082 were vaccinated during the study period (2006 - 2013), with 670,687 receiving at least two doses and 467,812 receiving four doses.

After exclusion of cases of prevalent MS, the MS cohort analysis included 3,978,271 persons, 788,986 of whom were vaccinated and 3,189,285 not vaccinated. And after removal of prevalent cases of other demyelinating diseases, that cohort analysis included 3,980,716 (788,931 vaccinated and 3,191,785 not vaccinated).

There were 73 cases of MS and 90 cases of other demyelinating disease during vaccinated periods in the cohort analysis, and 4208 cases of MS and 3154 cases of other demyelinating disease during the unvaccinated risk periods.

No Increased Risk

The data showed no increased risk for MS. The crude incidence rates in the main analysis were 6.12 events per 100,000 person-years (95% confidence interval [CI], 4.86 - 7.69) for the vaccinated period and 21.54 events/100,000 person-years (95% CI, 20.90 - 22.20) for the unvaccinated period. The adjusted rate ratio (RR) was 0.90 (95% CI, 0.70 -1.15).

In the main analysis for the composite outcome of other demyelinating disease, the crude incidence rates were 7.54 events/100,000 person-years (95% CI, 6.13 - 9.27) for the vaccinated period and 16.14 events/100,000 person-years (95% CI, 15.58 - 16.71) for the unvaccinated periods, for an adjusted RR of 1.00 (95% CI, 0.80 - 1.26).

Analyses by country, both Denmark and Sweden alone, by age, and with different risk windows corroborated the results.

The findings were also confirmed in a self-controlled case-series analysis in which time-independent factors, such as socioeconomic status and genetic predisposition, can't confound the estimates. This analysis uncovered 4322 cases of MS (339 vaccinated) and 3300 cases of other demyelinating diseases (370 vaccinated).

Consistent with the cohort study, this analysis showed no increased risk for MS (incident ratio [IR], 1.05; 95% CI, 0.79 - 1.38) or other demyelinating diseases (IR, 1.14; 95% CI, 0.88 - 1.47).

Further sensitivity analyses also corroborated the results. Excluding a prevaccination risk period of 30 days from the unexposed group did not significantly change the results, nor did using only exposed cases.

Calm Fears

The findings should calm fears that MS is caused by the HPV vaccination. A quick Google search will uncover numerous patients with MS convinced that their disease originated with being inoculated against HPV.

"The HPV vaccine has been linked to many serious chronic diseases on the Internet and in the press, and all these allegations contribute to insecurity among adolescent girls and their families," commented Dr Hviid. "To maintain public and professional confidence, it's important to take these allegations seriously with high-quality research."

He pointed out that unfortunately, some women will develop these debilitating diseases after being vaccinated, "not as a result of vaccination per se, but rather due to chance or other causes."

Dr Hviid noted that this is the largest and most comprehensive study to date on this subject. "The current evidence suggests that clinicians and patients should not fear demyelinating diseases as a result of HPV vaccination," he said.

The study results would apply to girls and women receiving the HPV vaccination in the United States, said Dr Hviid.

A limitation of the study was that information on ethnicity, socioeconomic status, lifestyle factors, and family history was not available. An "unmasking phenomenon" — in which vaccination in the setting of diseases, such as MS, that have obscure symptoms could uncover symptoms already present — may have resulted in a bias toward an association.

However, because a positive association was not found, this was not a factor in this study, said Dr Hviid.

Another possible limitation is that the study used date of diagnosis instead of date of disease onset, which wasn't available through the hospital registers. If onset and diagnosis didn't occur in the same exposure period, cases would have been misclassified. Random misclassification would bias results toward no association.

But the researchers used a 2-year risk period following the latest vaccination, and a US study found that the diagnostic delay has been estimated to be less than 1 year in more than 50% of cases occurring after 2000.

When asked to comment, Lily Jung Henson, MD, a neurologist at Swedish Neuroscience Institute, Seattle, Washington, said she's "grateful" that no association between MS and the HPV vaccine was identified in the study.

"The HPV vaccine is so important from a woman's perspective that any potential reluctance to pursue vaccination would have resulted in a lot more harm than benefit," she said.

However, she added, in her view the association "has not been on any of my patients' radar screens."

The study was funded by the Swedish Foundation for Strategic Research, Novo Nordisk Foundation, and the Danish Medical Research Council. Dr Hviid reported receiving a grant from the Novo Nordisk Foundation.

JAMA. 2015;313:54-61. Abstract


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.