Safety Profile of HPV Vaccines Under Review in Europe

Zosia Chustecka

July 13, 2015

The European Medicines Agency has started a review of human papilloma virus (HPV) vaccines "to further clarify aspects of their safety profile," although the agency also points out that this review "does not question that the benefits of HPV vaccines outweigh their risks."

The agency also notes that while the review is being carried out, no change in the use of these products is recommended.

HPV vaccines are now routinely given in immunization programs in many countries, and worldwide are estimated to have been given to more than 72 million people. They are expected to protect against cervical cancer as well as other cancers and conditions that are associated with the virus, including anal cancer and genital warts.

The review was initiated at the request of Denmark and will look specifically at the data for two conditions that have been reported, rarely, with the vaccines:

  • complex regional pain syndrome (CRPS), a chronic pain condition affecting the limbs, and

  • postural orthostatic tachycardia syndrome (POTS), a condition in which the heart rate increases abnormally after sitting or standing up, causing symptoms such as dizziness and fainting, as well as headache, chest pain, and weakness.

Reports of these two conditions occurring in young women who have received an HPV vaccine have been previously considered during routine safety monitoring by the agency's Pharmacovigilance Risk Assessment Committee, but at that time, a causal link between them and the vaccines was not established.

The agency points out that "both conditions can occur in non-vaccinated individuals and it is considered important to further review if the number of cases reported with HPV vaccine is greater than would be expected."

The review will consider any research that could help clarify the frequency of the two conditions after vaccination or identify any causal link, and on completion of the review, it will decide whether changes to product information are needed.

Recent Reports

A recent report on these two syndromes, CRPS and POTS, occurring after HPV vaccination was published online May 20 and in the July issue of Clinical Rheumatology.

"The symptoms more often reported are chronic pain with paresthesias, headaches, fatigue, and orthostatic intolerance," writes Manuel Martínez-Lavín, MD, from the Rheumatology Department, Instituto Nacional de Cardiología Ignacio Chávez in Mexico City, Mexico. "Adverse reactions appear to be more frequent after HPV vaccination when compared to other type[s] of immunizations. Different isolated cases and small series have described the development of [CRPS], [POTS], and fibromyalgia after HPV vaccination."

These are illnesses often difficult to diagnose, and they have several overlapping clinical features, he writes. "Sympathetic nervous system dysfunction seems to play a major role in the pathogenesis of these syndromes. Also, small fiber neuropathy has been recently recognized in CRPS, POTS, and fibromyalgia."

In the article, Dr Martínez-Lavín proposes a hypothesis that small fiber neuropathy and dysautonomia could be the common underlying pathogenesis for this group of rare, but severe, reactions that follow HPV vaccination.

"Clinicians should be aware of the possible association between HPV vaccination and the development of these difficult to diagnose painful dysautonomic syndromes," he concludes.

Earlier this year, the Danish Medical Journal published a systematic review of 53 patients with symptoms of orthostatic intolerance and generalized dysautonomia as a suspected adverse effect of vaccination with the quadrivalent HPV vaccine, Gardasil.

The authors, Louise Brinth and colleagues, from the Frederiksberg Hospital, Denmark, say all the patients had been referred to their Syncope Unit. "All patients had symptoms consistent with pronounced autonomic dysfunction including different degrees of orthostatic intolerance, severe non-migraine-like headache, excessive fatigue, cognitive dysfunction, gastrointestinal discomfort and widespread pain of a neuropathic character," they write.

All patients underwent a 60-degree head-up tilt table test, and POTS was diagnosed according to current guidelines, the authors note. "We may have diagnosed more than half of these patients with POTS — but POTS should probably be looked upon as a symptom secondary to another yet unidentified condition rather than as a disease entity of its own," they write. "This is underscored by the fact that patients experienced the same degree and pattern of symptoms regardless of the POTS diagnosis. The underlying aetiology behind POTS is still somewhat elusive and the prevalence of POTS is most common in the same subset of the population that are receiving the HPV vaccine (young women), which complicates the aetiological discussion.

The authors note that they "found a close chronologic association to the vaccination, but are well aware that this does not necessarily imply a causal relationship." In the 53 cases they report, the mean time between vaccination and onset of symptoms was 11.1 ± 12.5 days (range, 0 - 58 days), and symptoms were reported to appear after the first vaccination in 21 patients (40%), after the second vaccination in 19 patients (36%), and after the third vaccination in 13 patients (25%).

"Our findings do not confirm or dismiss a causal link to the HPV vaccine," the authors emphasize, "but they do suggest that further research is urgently warranted in order to clarify the pathophysiology of the symptoms experienced, to evaluate the possible link to the vaccine and to establish targeted treatment options for the affected patients."

They conclude, "Establishing a relevant and coherent diagnosis and treatment for these patients would contribute to maintaining the trust and credibility in this vaccine which is important as a preventive measure against HPV-related cancer."

The authors also comment that the symptoms they report as a potential adverse effect of HPV vaccination are similar to those that have been reported previously by Japanese researchers. Two reports appeared last year: Kinoshita and colleagues reported on "peripheral sympathetic nerve dysfunction in adolescent Japanese girls following immunization with the human papillomavirus vaccine" in an article that detailed 44 cases ( Intern Med. 2014;53:2185-2200), and Nishioka and colleagues report on clinical features and preliminary diagnostic criteria of human papillomavirus vaccination associated with neuroimmunopathic syndrome ( Int J Rheum Dis. 2014;17(Suppl 2):6-29).

POTS after HPV vaccination has also been reported in the United States. Writing in an article posted online September 16, 2013, and in the January 2014 issue of the European Journal of Neurology (2014;21:135-139), Svetlana Blitshteyn, MD, a neurologist at the State University of New York at Buffalo School of Medicine and Biomedical Sciences, described six patients who developed new-onset POTS from 6 days to 2 months after HPV vaccination.

"Three patients also had neurocardiogenic syncope, and three patients were diagnosed with possible small fiber neuropathy," Dr Blitshteyn writes. "Symptoms in all patients improved over 3 years with pharmacotherapy and non-pharmacological measures but residual symptoms persisted."

New-onset POTS after immunization could arise as a result of "[m]olecular mimicry with formation of cross-reacting autoantibodies to the potential targets of the autonomic ganglia, neurons, cardiac proteins or vascular receptors," she suggests.

Widespread Use of Vaccines

There are now three HPV vaccines available in Europe.

They include the original Gardasil vaccine (Merck; also marketed under the trade name Silgard), which was approved in Europe in September 2006 and offers protection against four types of HPV (6, 11, 16, and 19), and a newer version of this vaccine, approved in Europe in June 2015, known as Gardasil 9, which protects against nine types of the virus (6, 11, 16, 18, 31, 33, 45, 52, and 58). Both these vaccines are approved for use in both females and males for preventing precancerous growths and cancer in the cervix and anus, as well as genital warts.

Also available is Cervarix (GlaxoSmithKline), which was approved in Europe in September 2007 and offers protection against two virus types (16 and 18, which together are thought to account for about 70% of all cervical cancers). This vaccine is approved for use in girls and women to protect against precancerous growths and cancer in the cervix and genital area.

Oncologists voted HPV vaccines for preventing cervical cancer one of the five top advances in modern oncology in a recent survey conducted by the American Society of Clinical Oncology.

In the United States, HPV vaccination is recommended by many leading medical societies, including the Advisory Committee on Immunization Practices and the American College of Obstetricians and Gynecologists.

Australia has also been recommending HPV vaccination and was the first country to also recommend vaccination of boys as well as girls.

However, in June 2013, the Japanese Ministry of Health, Labor, and Welfare withdrew its recommendation for HPV vaccination in girls. According to local press reports, the ministry did not suspend vaccination but has instructed local governments not to promote the use of the medicine while analyses are conducted about adverse effects, such as long-term pain and numbness.


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