No Increase in Autoimmune Conditions From Use of HPV Vaccine

Daniel M. Keller, PhD

January 27, 2012

January 27, 2012 — In a large population of young women aged 9 to 26 years who received quadrivalent human papillomavirus vaccine (HPV4), researchers found no increase in new-onset autoimmune conditions. This observational safety study showed no cluster of disease onset according to vaccination timing, dose sequence, or patient age for the 16 prespecified autoimmune conditions examined, researchers reported in an article published in the February 2012 issue of the Journal of Internal Medicine.

Investigators led by Chun Chao, PhD, from the Department of Research and Evaluation at Kaiser Permanente Southern California in Pasadena, followed-up participants (n = 189,629) from 2 managed care organizations for 180 days after each HPV4 dose for new diagnoses of the autoimmune conditions. Participants received 1 to 3 doses over the course of 6 months between August 2006 and March 2008.

The 16 conditions included autoimmune disorders from the following categories: rheumatologic, such as immune thrombocytopenia, systemic lupus erythematosus, and rheumatoid arthritis; endocrine, such as type 1 diabetes, Hashimoto’s disease, and Graves’ disease; and neurologic/ophthalmic, including multiple sclerosis and other central nervous system demyelinating diseases. Potential new-onset cases were identified through review of electronic medical records (International Classification of Diseases, Ninth Revision, diagnosis codes; abnormal laboratory values; or pharmacy prescriptions) of women who had been members of the health plans for at least 12 months (n = 149,306). Any cases identified between January 2004 and the first dose of HPV4 were deemed to be preexisting and were excluded. Ninety-nine percent of the women were in the indicated age range.

The incidence of each condition among vaccinated women was compared with an estimated incidence for unvaccinated women, derived using multiple imputations, and was expressed as an incidence rate ratio (IRR).

Of 719 cases eligible for review, from 31% to 40% of the conditions found were confirmed as new-onset. No IRR was significantly elevated except that for Hashimoto's disease (IRR, 1.29; 95% confidence interval [CI], 1.08 - 1.56), but based on a lack of temporal clustering and biological plausibility of a relationship, the investigators concluded that there was "no consistent evidence for a safety signal for autoimmune thyroid conditions." Hashimoto's disease is "a relatively common autoimmune condition in young women," the authors note.

Compared with unvaccinated women, the incidence rates for vaccinated women were significantly lower for type 1 diabetes (IRR, 0.57; 95% CI, 0.47 - 0.73) and for juvenile rheumatoid arthritis (IRR, 0.48; 95% CI, 0.26 - 0.91).

A strength of the study is the strategies it used to account for a lag between symptom onset of autoimmune conditions and a correct diagnosis, including the 180-day observation period after each dose of vaccine, broad and highly sensitive case identification criteria, and expert panels to confirm diagnoses and dates of disease onset. Limitations are that the exact timing of symptom onset was not always clear, and that cases classified as new-onset may have preexisted.

A further strength of the study is that it was conducted using a large, ethnically and sociodemographically diverse population receiving routine care, making it likely that the findings apply to the usual groups of young women receiving HPV4. The authors said these safety results provide "important complementary knowledge" to data from clinical trials and from the Vaccine Adverse Event Reporting System.

This study was conducted as a postlicensure commitment to the US Food and Drug Administration, the European Medicines Agency, and other regulatory authorities.

William Schaffner, MD, chair of the Department of Preventive Medicine at Vanderbilt University School of Medicine in Nashville, Tennessee, and president of the National Foundation for Infectious Diseases, commented to Medscape Medical News that he is impressed with the study, which he said is "very well designed and executed...nicely written up, [and] very comprehensive" in its survey of a wide variety of immune disorders.

He said the results, which would be expected, are still comforting, and that such postmarketing studies are important. "There's no evidence that HPV precipitates or in any way enhances any autoimmune conditions, which is, of course, one of the kind of vaguely stated concerns of people who are vaccine skeptics," Dr. Schaffner said. "This is a relatively new vaccine, and it's reassuring...particularly so since this is given originally to young women[, and] now [is] also being given to young men. But young women have a higher rate of some of these autoimmune disorders than do young men."

In this era of vaccine skeptics, and even deniers, and in which "HPV has even entered the political discourse," he said, "I think it's very important that this sort of message be transmitted as widely as possible." He mentioned that publication in a more prominent journal may have given the study even more exposure.

One remaining potential issue is whether observing the medical records for just 6 months after the final dose is sufficient, but Dr. Schaffner said he would assume that if a vaccine were going to stimulate an autoimmune response, "you ought to see it within 6 months.... The farther out you go, the more coincidental events that you will pick up."

He revealed that the 2 manufacturers of HPV vaccines are considering expanding the repertoire of protection in a subsequent generation of vaccines by adding antigens from other HPV types.

The study was funded by Merck & Co. Dr. Chao received research funding for another study on HPV vaccine, as well as other research funding from Merck & Co, Pfizer, and Amgen for unrelated studies. Other authors received research funding from Merck & Co, GlaxoSmithKline, Novartis, Wyeth (Pfizer), and Sanofi Pasteur, and one author received funding as unpaid consultant to Merck & Co. Two of the authors are employees at Merck Research Laboratories. Merck & Co had significant input into the study design and analytic plan, all of which were prespecified in a US Food and Drug Administration–approved protocol, and took part in the review of analyses and drafting and revising of the manuscript. Kaiser Permanente collected and analyzed all data, and Kaiser Permanente authors had final decision power about all editorial suggestions. Dr. Schaffner serves on the Data Safety Monitoring Board for experimental vaccine trials for Merck and Sanofi Pasteur, but not for HPV vaccine trials. He is an occasional consultant to GlaxoSmithKline, Novartis, and Dynavax Technologies Corporation.

J Intern Med. 2012;271:193-203. Abstract

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