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Death After Cervarix Propels HPV Vaccination Into Headlines Again

Posted Oct 14 2009 10:02pm
From Medscape Medical News

September 30, 2009 (updated October 1, 2009) — The sudden death of a 14-year-old British girl shortly after she received Cervarix, a vaccine against human papillomavirus (HPV) to prevent cervical cancer, hit headlines worldwide yesterday. Today, however, the death is being reported as unlikely to have been related to the vaccine. The next day, a postmortem revealed that the girl had a large tumor in her chest cavity.

This is not the first time that a death has been reported after HPV vaccination; many of the other cases have been reported after inoculation with Gardasil in the United States, although there has been no proof of causality. Some of these deaths have also received wide media attention, and last month a mother who lost her daughter after HPV vaccination testified before a US Food and Drug Administration (FDA) advisory committee meeting.

In the latest incident, Natalie Morton, of Coventry in the United Kingdom, died on the same day that she received the vaccine at school as part of a national HPV vaccination program. She collapsed less than 2 hours after the injection, which was the first dose of a planned 3-dose course.

A preliminary postmortem revealed that she had "a serious underlying medical condition which was likely to have caused death," according to Caron Grainger, MD, joint director of public health in Coventry.

"We are awaiting further test results. However, indications are that it is most unlikely that the vaccination was the cause of death," Dr. Grainger said in a statement.

In response to the news of the death, several health authorities in the United Kingdom announced that they were temporarily suspending their HPV vaccination programs.

The Department of Health said all vaccines from the same batch (HPV1 Cervarix AHP VA04 3BB) would be quarantined as a precaution.

"No link can be made between the death and the vaccine until all the facts are known and a postmortem takes place," the Department wrote in a letter to health professionals. "As a purely precautionary measure, it is important that all stocks of Cervarix vaccine from the above batch are quarantined until the above incident has been fully investigated."

Further details were revealed the following day at a hearing at Coventry Magistrates' Court. Deputy coroner Louise Hunt said the postmortem revealed a large tumor that had "heavily infiltrated" the heart and had extended into the left lung. A pathologist told the inquest that the condition was "so severe that death could have arisen at any point," according to a report on BBC News.

Cervarix in UK, But Gardasil Elsewhere

The UK national program of HPV vaccination began last year, offering the vaccine through schools to all girls in the 12- to 13-year-old age range. A catch-up program for older girls, up to 18 years, was launched just recently, with the aim of covering all girls under 18 years by 2011. An estimated 1.4 million girls in the United Kingdom have already received the vaccine.

The United Kingdom chose to use Cervarix, manufactured by GlaxoSmithKline, for its national program, whereas many other countries — including the United States and Australia — chose to use Gardasil from Merck & Co. In fact, Cervarix is not available in the United States, and may not be for some time yet, it now appears.

Yesterday, the FDA announced that it was postponing its decision on approval of Cervarix, saying that it needed more time to consider the data, even though an FDA advisory committee meeting recently voted overwhelmingly for approval, as previously reported by Medscape Oncology.

The UK decision to choose Cervarix and not Gardasil has been questioned in the British press, with newspapers pointing out that the reasons behind the choice were never revealed, but is widely speculated to have been based on cost, with Cervarix being cheaper.

But the 2 vaccines also differ from each other in a key aspect.

Cervarix protects against 2 types of HPV virus (types 16 and 18), which together account for about 70% of all cervical cancer. Gardasil also protects against these, but in addition offers protection against HPV types 6 and 11, which cause genital warts. This extra activity means that Gardasil is also indicated for the prevention of genital warts in girls and women, and could be used for this indication in boys and men (it was recommended for approval for this use at the recent FDA advisory committee meeting).

However, the main purpose behind the development of these vaccines was to prevent cervical cancer, and for this indication, Cervarix is the better of the 2 vaccines, according to expert Diane Harper, MD, from the University of Missouri–Kansas City School of Medicine.

Dr. Harper has been involved in clinical trials with both vaccines, and was approached by Medscape Oncology for comment. As previously reported, Dr. Harper said that Cervarix was longer lasting, resulted in higher antibody titers, and offered wider cross protection against other HPV types than Gardasil.

But Dr. Harper has also been very vocal in emphasizing that these vaccines are not the only way to protect against cervical cancer, and she has repeatedly stressed that even when they are used, it remains vital to screen for cervical cancer with regular Pap tests.

She has joined in with questions over the benefit–risk analysis of HPV vaccination that have been raised, most recently in an editorial in the Journal of the American Medical Association (JAMA), as reported by Medscape Oncology.

That August 19 issue of JAMA also published details of adverse events that have been reported with Gardasil during its 2.5 years on the market (JAMA. 2009;302:750-757). These reports were made to the US Vaccine Adverse Event Reporting System, which is operated jointly by the FDA and the Centers for Disease Control and Prevention (CDC). The authors emphasized that a report of an adverse event does not necessarily mean there is a causal link. The paper noted that 12,424 reports of adverse events had been received, of which 772 (6.2%) were for serious adverse events, including 32 deaths.

This is a sobering reality.
In the United States, the death rate from cervical cancer (3 of 100,000 women, according to statistics from the CDC) is currently similar to the rate of reported serious adverse events from Gardasil (3.4 of 100,000 doses distributed), Dr. Harper pointed out. "This is a sobering reality," she said. "Would a parent accept such a rate of serious adverse events if the same cancer prevention can occur with continued Pap screening? Is there any acceptable level of risk of serious adverse events, including death, to prevent genital warts?"

A debate about the HPV vaccine is running on Medscape's Green Mountain Doc blog, written by Katharine Hikel, MD, who specializes in writing about women's health issues. Her post, entitled "'One Less Sucker' — Gardasil," criticized the marketing of this product, questioned whether it was medically necessary, and highlighted its adverse event rate.

"The rush-to-market approach for this questionable product, with billions spent on promotion, has completely [over-ridden] good judgment, critical analysis, and clear thinking on the part of providers," Dr. Hikel writes. She asserts that this has put millions of women "needlessly at risk."

In contrast, many cervical cancer specialists have spoken up in favor of HPV vaccination, as previously reported by Medscape Oncology. Maurie Markman, MD, professor of gynecologic medical oncology at the University of Texas MD Anderson Cancer Center in Houston, and an editorial advisor to Medscape Oncology, has repeatedly emphasized the benefits of the vaccine and the unique opportunity that it offers for protection from cervical cancer. He has spoken reassuringly about the safety of the vaccine, most recently in his videoblog "How Safe Is the HPV Vaccine?"

This view was echoed recently by the Society of Gynecologic Oncologists (SOG), which said that HPV vaccination represented a "paradigm-shifting prevention strategy for cervical cancer." In a statement released to the recent FDA advisory committee meeting, the SOG said: "The public-health value of the protection afforded by HPV vaccination overwhelmingly outweighs the self-limiting local side effects and even the rare but more serious effects that may or may not be vaccine-related."

Dr. Harper reports having received honoraria from Merck & Co and GlaxoSmithKline, and institutions at which she has worked have received funding from both companies to support clinical trials on HPV vaccines. Dr. Markman reports having received grants for educational activities from Eli Lilly and serving as an advisor or consultant for Genentech, Celgene Corporation, Tibotec, and Boehringer Ingelheim.
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