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VACCINE SAFETY: UPDATE ON HUMAN PAPILLOMAVIRUS VACCINES

Sunday, 21st of July 2013

• UPDATE ON HUMAN PAPILLOMAVIRUS VACCINES

The Committee reviewed updated information about the safety of human papillomavirus vaccines (HPV) vaccines. The last review was conducted in June 2009,4 and GACVS noted at the time that accumulating evidence on the safety of HPV vaccines was reassuring and that studies on HPV immunization had been initiated, along with capacity-building for adverse events monitoring. GACVS continues to place a high priority on the ongoing collection of high-quality safety data in settings where the vaccine is being introduced.

In the past 4 years, safety data continued to accumulate as countries have initiated or expanded their immunization programmes. The GAVI Alliance has also begun taking steps to make HPV vaccine available to women in developing countries where the burden of cervical cancer is considerable. To date, some 175 million doses of HPV vaccines have been distributed. A review of adverse events reported to the US Vaccine Adverse Event Reporting System following the distribution of >23 million doses was published in 2009.5 Both manufacturers have developed pregnancy registries and are maintaining long term safety studies in conjunction with efficacy.

The Committee reviewed data from the United States, Australia, Japan and the manufacturers of Cervarix® (GlaxoSmithKline) and Gardasil® (Merck). Updates from the United States included an extension of the spontaneous reports to VAERS since the published review in 2009 as well as completed and planned studies from the Vaccine Safety Datalink. In Australia, a new programme targeting males started in February 2013 and data are starting to become available. Data from all sources continue to be reassuring about the safety of both vaccines.

The data from VAERS now includes >50 million doses distributed and the profile has not changed since the review in 2009. Reported adverse events not identified at the time of the first review, namely syncope and venous thromboembolism (VTE), were further investigated. Syncope continues to be reported but remains an event with a plausible relationship given the population and settings in which HPV vaccine is used. Adherence to a 15-minute observation period following vaccination has thus been strengthened as a recommendation. For VTE, while a rapid cycle analysis in the VSD did not find an increased risk, this is being further investigated with appropriate control for confounders such as oral contraceptive use, smoking and other risk factors in this population. Similarly, the VSD did not find any increased risk of Guillain-Barré syndrome or stroke. In Australia, safety surveillance has been enhanced and an expert group evaluated early reported events, including a signal regarding anaphylaxis. To date, with almost 7 million doses distributed, the previously investigated concern of increased anaphylaxis was not confirmed.

Following the extension of the vaccination programme in males and enhanced surveillance since 1 February 2013, preliminary results show the safety profile of Gardasil® to be similar to the profile among females.

Finally, there have been no further concerns regarding demyelinating disease or other chronic conditions also investigated earlier by the expert group.

Surveillance from the 2 manufacturers found no signals suggesting any necessary revisions to product labelling. Both have maintained surveillance of pregnancy outcomes following inadvertent vaccination during pregnancy. Detailed analyses of results have not found any new adverse outcomes related to HPV vaccination. For Gardasil®, long term follow-up has now extended to >8 years in the longest cohort, and no significant increase in newly diagnosed health events have been identified among those vaccinees. Updated analyses of the pregnancy registry have also been reassuring in that no adverse pregnancy outcomes have been observed beyond background expected rates. For Cervarix®, the data have been similarly reassuring regarding pregnancy outcomes and specific events of interest such as immune mediated diseases. Risk of syncope and anaphylaxis have been added to the label to warn of these potential events, the former being also possibly related to conditions around the vaccination experience itself.

Cases initially resembling complex regional pain syndrome (CPRS) were reported from Japan where >8 million doses of HPV vaccines have been distributed. CPRS is a painful condition that emerges in a limb usually following trauma. Cases have been reported following injury or surgical procedures. It remains of unknown etiology and may occur in the absence of any documented injury. CPRS following HPV vaccines has received media attention in Japan and the number of reported cases has risen to 24, only 7 of which were reported through usual post-marketing surveillance channels. Review by an expert advisory committee could not ascertain a causal relationship to vaccination given lack of sufficient case information and inability to reach a definitive diagnosis in many cases. While these are under investigation, Japan has continued to provide HPV vaccine in their national programme but is not actively recommending its use.

In summary, 4 years after the last review of HPV vaccine safety and with >175 million doses distributed worldwide and more countries offering the vaccine through national immunization programmes, the Committee continues to be reassured by the safety profile of the available products. Anaphylaxis and syncope, outcomes previously identified as concerns, have been addressed through further studies and appropriate revisions were made to the product labelling. Serious adverse events that have been reported as potential signals have been investigated in more detail, including Guillain-Barré syndrome, seizures, stroke, venous thromboembolism, anaphylaxis, and other allergic reactions – many using rapid cycle analysis in the VSD in the United States.

Surveillance of pregnancy outcomes among women inadvertently vaccinated during pregnancy through spontaneous reports and registries have not detected any adverse outcomes above expected rates.

 

The cases of chronic pain being reported from Japan deserve specific mention. To date there is little reason to suspect the HPV vaccine, given its growing use worldwide, in the absence of a similar signal from elsewhere. Recognizing the public concerns voiced, the Committee urges careful documentation of each case and a thorough search for a definitive diagnosis by medical specialists in order to best guide treatment. A timely clinical assessment and diagnosis of each case followed by appropriate treatment is therefore essential.