Last July, women claiming side effects from the cervical cancer vaccine sued Japan’s government.

The Yomiuri Shimbun via AP Images

Critics assail paper claiming harm from cancer vaccine

Alarmed by “pseudoscience” that may bring “devastating” health consequences, two groups of researchers have asked the journal Scientific Reports to retract a paper that they claim undermines confidence in the human papillomavirus (HPV) vaccine, given to girls to prevent cervical cancer.

The 11 November paper describes impaired mobility and brain damage in mice given an HPV vaccine. The mice received doses that were proportionally a thousand times greater than that given to people, along with a toxin that makes the blood-brain barrier leaky. That protocol, critics contend, does not mimic what happens in the human body.

“Basically, this is an utterly useless paper, a waste of precious animals,” David Gorski, a surgical oncologist at the Barbara Ann Karmanos Cancer Institute in Detroit, Michigan, wrote on his Orac blog at scienceblogs.com. In an email to Science, the paper’s corresponding author, Toshihiro Nakajima of Tokyo Medical University, defended the work, stating: “Our manuscript was formally published after an intensive scientific review done by reviewers and by the editorial board of Scientific Reports.”

The tussle is the latest salvo in a widen
ing global battle over the HPV vaccine. Originally licensed in 2006, the vaccine is now approved for use in more than 
120 countries. Studies show it is already starting to reduce HPV infections, which are blamed for 528,000 cervical cancer cases and 266,000 deaths each year, with the greatest burden in developing countries. (Boys are also now getting vaccinated, as HPV can cause genital warts and various cancers.) But in several countries, girls have complained of debilitating symptoms, reminiscent of chronic fatigue syndrome, 
after vaccination.

Off the cliff

After claims arose that the human papillomavirus vaccine could cause debilitating side effects, the vaccine rate among women in Japan plummeted.

(Graphic) J. You/Science; (Data) S. Hanley et al., The Lancet (27 JUNE 2015) © The Lancet

These claims have attracted media attention, spawned antivaccination campaigns, and cut vaccination rates. More than 90% of Danish girls born in 2000 received at least one vaccine dose, but that rate has dropped year by year. Ireland also saw a drop in vaccination rates in 2015 and 2016. The trend is “alarming,” says Heidi Larson, who heads the Vaccine Confidence Project at the London School of Hygiene & Tropical Medicine.

Japan is the prime battleground. As in many countries, the HPV vaccine got off to a promising start there. The first vaccine was licensed in 2009; in April 2013, the ministry added the vaccine to its recommended list and offered it for free. Uptake was robust. Sharon Hanley, a cancer epidemiologist at Hokkaido University in Sapporo, Japan, and colleagues reported in The Lancet in 2015 that roughly 70% of girls born between 1994 and 1998 completed the three-dose vaccination course.

In spring 2013, however, a number of media outlets in Japan reported on alleged side effects. These include difficulty walking, headache, fatigue, poor concentration, and pain. That June, the health ministry suspended its “proactive recommendation” for vaccination, pending an investigation.

The following January a ministry panel concluded that there is no evidence for a causal association between the HPV vaccine and the reported adverse events. The European Medicines Agency and the U.S. Centers for Disease Control and Prevention have come to similar conclusions. Epidemiological studies indicate that the symptoms reported by the vaccinated girls are found at equal rates in nonvaccinated populations. Yet Japan’s health ministry has never restored its proactive recommendation, which means that although the government pays for the shots, it has stopped urging local authorities to promote vaccination.

Vaccination rates have plummeted in Japan. Hanley says that in the city of Sapporo, the vaccination rate fell to just 0.6% of eligible girls, and she believes that nationwide, the rate is close to zero. (In a sign of growing trouble for vaccination, 63 women in July filed a class-action lawsuit against the government and vaccinemakers, seeking $125,000 each in compensation for the alleged side effects.) Larson notes that health ministries in other countries aggressively promoted vaccine safety after claims of side effects surfaced, keeping vaccination rates high. An official at Japan’s health ministry says a decision on restoring the proactive recommendation is under review.

Nakajima’s study is sure to inflame the debate. His group gave mice large doses of the HPV vaccine along with a pertussis toxin to help the vaccine slip into the central nervous system. The treatment, they found, impaired tail movement and locomotion. A postmortem revealed structural damage, increased cell death, and other abnormalities in the mice’s brains.

Critics assail the study in a pair of letters to Scientific Reports and its publisher, the Nature Publishing Group. One, signed by 
20 members of the HPV Prevention and Control Board at the University of Antwerp in Belgium, asserts: “This experimental setup in no way mimics the immunization with HPV vaccines but is gross over dosage and manipulation of membrane permeability.” A second letter, from David Hawkes, a viro
logist at the University of Melbourne in Australia, and two colleagues argues that the paper “lacks a clear methodology, adequate controls to control for bias, descriptions of results consistent with the data presented, or enough information for this study to 
be reproduced.”

Nakajima defends his group’s methodo
logy, stating that they adopted a strategy similar to that commonly used in studying autoimmune encephalitis in mice. As for the dose, he wrote, “This is just the first paper and dose-dependency could be one of the interesting experiments in the future.” He added that they are now preparing a detailed response to criticisms of their paper.

Vaccine proponents worry that the paper will embolden vaccine opponents. Nearly 200 tweets have mentioned it, with several mistakenly assuming it appeared in Nature. Both letters call on Scientific Reports to withdraw it. In an email to Science, a journal spokesperson confirmed having received the letters, and wrote, “We investigate every concern that is raised with us carefully and will take action where appropriate.”

Even as opposition to the HPV vaccine gains momentum, evidence of its efficacy is accumulating. But with its paltry vaccination rate, Japan is unlikely to see any reduction in its current 9000-plus cases of cervical cancer and 3000 deaths each year. Worse, says Larson, Japan’s suspension of the proactive recommendation “has been particularly applauded” by vaccine-critical groups in other countries. For women in Asian nations with weaker health infrastructure, Hanley adds, “The vaccine may be their only hope of prevention.”