Global Vaccine Safety

Human papillomavirus vaccines safety (HPV)

Extract from report of GACVS meeting of 11-12 December 2013, published in the WHO Weekly Epidemiological Record on 14 February 2014

GACVS reviewed evidence related to autoimmune disease and the HPV, with a focus on multiple sclerosis (MS). The last review was conducted in June 2013, when the Committee reviewed updated data from the USA, Australia, Japan, and the manufacturers of Cervarix (GlaxoSmithKline) and Gardasil (Merck). With >175 million doses distributed worldwide and more countries offering the vaccine through national immunization programmes, the Committee continued to be reassured by the safety profile of the available products. Serious adverse events that have been reported as potential signals have been investigated in more detail and were not confirmed, including Guillain-Barré syndrome, seizures, stroke, venous thromboembolism, anaphylaxis and other allergic reactions. Surveillance of pregnancy outcomes among women inadvertently vaccinated during pregnancy through spontaneous reports and registries has not detected any adverse outcomes above expected rates.

While surveillance data and epidemiologic studies on HPV vaccine have remained reassuring, allegations have continued to surface in the media and elsewhere about the safety of the vaccine. Epidemiologic studies before and after licensure showed no increased risk of autoimmune disease, including MS. Since the introduction of HPV vaccines, such diseases have been under particularly careful investigation given their correspondingly high age-specific background incidence.9, 10, 11

Examples of such studies include a register-based cohort study in Sweden and Finland that included almost 1 million girls aged 10–17 years, among whom almost 300 000 were vaccinated against HPV.12 The study investigated whether vaccination was associated with an increased risk of autoimmune, neurological or thromboembolic events. The study results did not show evidence of any association between exposure to HPV vaccine and autoimmune, neurological, and venous thromboembolic adverse events.

In the USA, an observational study involving almost 200 000 girls and young women who had received at least 1 dose of HPV vaccine found no increased incidence of 16 investigated autoimmune diseases in the vaccinated compared to the non-vaccinated group.13 The incidence of MS in the vaccinated cohort, for example, was not significantly higher than the non-vaccinated cohort (incidence rate ratio 1.37, 95% confidence interval 0.74–3.20). In a third study, a pooled analysis of data from 11 clinical trials involving nearly 30 000 participants aged >10 years, of which 16 142 received at least 1 dose of Cervarix and 13 811 received either a placebo containing aluminium hydroxide or 1 of 2 different hepatitis A vaccines. No increased risk for the onset of autoimmune diseases after administration of Cervarix was observed in comparison to the control group.14

The Committee was provided with an overview of cases that were the subject of concern in France. These included one case of MS that had been ajudicated by a French Regional Commission for Conciliation and Compensation. Another 14 cases of MS were reported through regional pharmacovigilance centres and/or the manufacturers to the European Medicines Agency. All 15 cases had been classified as being of “doubtful” causality, according to the French grading system. In addition, the overview from France included results of a cohort study involving 2 million girls aged 12–16 showing a lack of increase in hospitalization rates for autoimmune diseases among those who received the HPV vaccine (2.1/10 000 patients/year) compared to those who did not (2.09/10 000 patients/year).

In summary, GACVS was presented with a series of cases of adverse events following administration of the HPV vaccine. Multiple studies have demonstrated no increase in risk of autoimmune diseases, including MS, among girls who have received HPV vaccine compared to those who have not. The Committee remains reassured by the safety profile of the vaccine, but noted the importance of continued surveillance and epidemiological investigation with an emphasis on the collection of high quality data; such data are essential for interpretion of any adverse events which may occur following vaccination. Allegations of harm due to vaccination based on incomplete information may lead to unnecessary harm when effective vaccines are not used.

9 Siegrist CA. Autoimmune diseases after adolescent or adult immunization: what should we expect? CMAJ. 2007 Nov 20;177(11):1352-4.

10 Siegrist CA, Lewis EM, Eskola J, Evans SJ, Black SB. Human papilloma virus immunization in adolescent and young adults: a cohort study to illustrate what events might be mistaken for adverse reactions. Pediatr Infect Dis J. 2007 Nov;26(11):979-84.

11 Callréus T, et al. Human papillomavirus immunisation of adolescent girls and anticipated reporting of immune-mediated adverse events. Vaccine. 2009 May 14;27(22):2954-8.

12 Arnheim-Dahlström L, et al. Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study. BMJ. 2013 Oct 9; 347.

13 Chao C et al. Surveillance of autoimmune conditions following routine use of quadrivalent human papillomavirus vaccine. J Intern Med. 2012 Feb;271(2):193-203.

14 Descamps D, et al. Safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine for cervical cancer prevention: a pooled analysis of 11 clinical trials. Hum Vaccin. 2009 May;5(5):332-40.

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on 18 March 2014