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Cervical cancer is the third most common cancer of women [1]. Human Papillomavirus (HPV) is estimated to cause more than 0.5 million cancers globally – a majority of which are cervical cancers [2]. The World Health Organization (WHO) estimated that more than 250 000 deaths occurred in 2005 and 2.7 million years of life were lost in 2000 because of cervical cancer [2]. Vaccines for HPV provide an opportunity for reducing HPV infections, and hence, the global burden of cervical cancer.

Two vaccines are currently licensed and marketed for HPV – a quadrivalent vaccine (HPV4), first licensed in 2006, and a bivalent vaccine (HPV2), first licensed in 2007. Safety data from prelicensure trials and early postmarketing studies have contributed to a good safety profile of these vaccines. Like any newly introduced vaccine, it is important to develop a robust evidence base for safety of HPV vaccines to ensure safety of the vaccinees and to maintain public confidence in these vaccines. Autoimmunity is a concern for many vaccines. However, because of relatively low baseline incidence of many autoimmune conditions, large postmarketing studies are required to evaluate any increased risk of autoimmune conditions after vaccination.

In this issue of the Journal of Internal Medicine, investigators from two managed care organizations in California report results for surveillance of new-onset autoimmune conditions after HPV4 vaccination from a large postmarketing safety study [3]. In this study, potential cases of 16 prespecified autoimmune conditions were identified through electronic medical records and reviewed by clinicians for confirmation and for determining the date of onset. Eligible subjects were followed for 180 days after each dose of HPV4. The study included 189 629 women who received at least one dose of HPV4 between August 2006 and March 2008. The incidence of each of the conditions of interest was computed at one of the two managed care organizations and compared with the incidence in vaccinated females. This study did not identify any clusters for any of the evaluated conditions in terms of timing of vaccination, age or dose sequence. The incidence rate for Hishimoto’s disease was 29% higher in vaccinated females compared to unvaccinated females [incidence rate ratio (IRR): 1.29; 95% confidence interval: 1.08–1.56]. The incidence rate ratios for none of the other 15 autoimmune conditions were significantly elevated. The elevated IRR for Hashimoto’s disease was further reviewed by a multidisciplinary Safety Review Committee (SRC) -comprised of external experts. The SRC requested and interpreted additional graphical analysis of Hashimoto’s disease (and the other two autoimmune endocrine conditions evaluated in this study: type 1 diabetes and Graves disease). The onset of Hashimoto’s disease was mostly randomly distributed in terms of vaccination timing. The IRR for Graves disease – the other autoimmune thyroid condition evaluated – was not significantly elevated and many confirmed ‘new-onset’ events were likely pre-existing cases with the real onset date prior to vaccine receipt. Therefore, the SRC and the investigators determined that the Hashimoto’s disease-related signal was not a true association.

So far, HPV vaccines have had a good safety record. The safety and efficacy of HPV4 vaccine were evaluated in several clinical trials – with a cumulative enrolment of more than 29 000 women and men [4]. In clinical trials, the most common adverse event associated with the HPV4 vaccine was headache – followed by fever, nausea, dizziness, pain, swelling, erythema, pruritus and bruising at the injection site [4]. Vaccine-related serious adverse events were rare and occurred with a frequency of 0.4% [4]. The four most frequent serious adverse events (irrespective of causality) amongst HPV4 vaccine recipients were appendicitis (0.03%), (severe) headache (0.02%), gastroenteritis (0.02%) and pelvic inflammatory disease (0.02%). In clinical studies amongst 9- to 26-year-old females, the overall rates of incident systemic autoimmune conditions were the same amongst girls and women who received the HPV4 vaccine (2.3%) and the controls (2.3%). The rates of specific groups of autoimmune conditions were also similar between HPV4 recipient females and controls. Similarly, the risk of systemic autoimmune conditions was not elevated amongst 9- to 26-year-old males who received HPV4 vaccine compared with controls. During the trials, 40 deaths were reported in 29 323 individuals. Death rates were comparable to those expected in healthy adolescent and adult populations [5] and they were the same in the vaccine and the placebo arms [3].

As of 22 June 2011, approximately 35 million doses of HPV4 had been distributed in the United States [6], and the postmarketing safety data for HPV4 vaccine have been reassuring. An analysis was conducted of adverse events reported from 1 June 2006 through 31 December 2008 to the Vaccine Adverse Event Reporting System (VAERS) – a passive, voluntary surveillance system in the United States maintained by the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration [7]. Because reliable denominator data are not available for VAERS, comparison of reporting rates of a certain adverse event for various vaccines is often used to analyse VAERS data. In the reporting period, 12 424 adverse events – including 772 (6%) serious adverse events – following HPV4 receipt were reported to VAERS [6]. Most of the adverse events did not have higher reporting rates for HPV4 than the background rates of reporting after other vaccines. There was disproportional reporting of syncope and venous thromboembolic events (VTE). The VTE cases occurred over a wide period after vaccination and 90% had a known risk factor. Moreover, because many young women who are eligible for HPV4 vaccine also use hormonal contraceptives (a substantial risk factor for VTE), possibility of confounding cannot be ruled out. Although a signal for VTE could not be identified in the Vaccine Safety Datalink (a national-level large linked database project for assessing vaccine safety in the United States), CDC continues to conduct monitoring and surveillance of VTE after HPV4 vaccine using various data systems at its disposal [8].

The study by Chao et al., in this issue of the journal, makes a valuable contribution towards the HPV vaccine safety literature. It is important to continue postmarketing surveillance for HPV vaccine safety – particularly through large, adequately powered studies. In addition to the CDC’s ongoing safety surveillance, there are at least nine additional ongoing HPV4 studies with safety end-points being conducted in various countries [9].

Human Papillomavirus vaccine coverage remains relatively low in populations where this vaccine has been introduced [10]. Concerns about vaccine safety are amongst the reasons cited for refusing HPV vaccine. The expanding evidence base in favour of HPV vaccine safety, if properly synthesized into appropriate communications messages, should contribute to reassuring the public about the safety of HPV vaccines.

Conflict of interest statement

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  2. Conflict of interest statement
  3. References

Dr Omer was awarded the Maurice R. Hillerman Early-stage Career Investigator Award by the National Foundation for Infectious Diseases in 2009. The award is funded by an unrestricted educational Grant to the National Foundation for Infectious Diseases from Merck and Co., Inc. However, Dr Omer has no interaction with Merck and Co., Inc. related to this award.

References

  1. Top of page
  2. Conflict of interest statement
  3. References
  • 1
    Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion. Cancer Among Women. Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, 2011. 2-10-2011, 10-20-2011. Accessed on 15 November 2011 at http://www.cdc.gov/cancer/dcpc/data/women.htm.
  • 2
    World Health Organization. Human Papillomavirus and HPV Vaccines: Technical Information for Policy-Makers and Health Professionals. Geneva: World Health Organization, 2007.
  • 3
    Chao C, Klein NP, Velicer CM et al. Surveillance of autoimmune conditions following routine use of quadrivalent human papillomavirus vaccine. J Int Med 2011 October 4. doi:10.1111/j.1365-2796.2011.02467.x. (Epub ahead of print).
  • 4
    Merck & Co., Inc. GARDASIL Package Insert. 11. Whitehouse Station: Merck & Co., Inc, 2011.
  • 5
    CDC/National Center for Health Statistics. Death Rates by 10-Year Age Groups: United States and Each State, 1999–2007. Atlanta: CDC/National Center for Health Statistics, 2011. 10-8-2010, 10-20-2011.
  • 6
    Centers for Disease Control and Prevention National Center for Emerging and Zoonotic Infectious Diseases (NCEZID) & Division of Healthcare Quality Promotion (DHQP). Frequently Asked Questions about HPV Vaccine Safety. Atlanta: Centers for Disease Control and Prevention National Center for Emerging and Zoonotic Infectious Diseases (NCEZID) & Division of Healthcare Quality Promotion (DHQP), 2011. 8-8-2011, 10-20-2011.
  • 7
    Slade BA, Leidel L, Vellozzi C et al. Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA 2009; 302: 7507.
  • 8
    Markowitz LE, Hariri S, Unger ER, Saraiya M, Datta SD, Dunne EF. Post-licensure monitoring of HPV vaccine in the United States. Vaccine 2010; 28: 47317.
  • 9
    Bonanni P, Cohet C, Kjaer SK et al. A summary of the post-licensure surveillance initiatives for GARDASIL/SILGARD. Vaccine 2010; 28: 471930.
  • 10
    National and state vaccination coverage among adolescents aged 13 through 17 years – United States, 2010. MMWR Morb Mortal Wkly Rep 2011; 60: 111723.