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Vaccine Medical Examiner

What the Gardasil Testing May Have Missed

There’s no evidence that the HPV vaccine causes serious harm, but an investigation shows the trials weren’t designed to properly assess safety.

Read a companion piece from Slate’s science editor on this investigation.

On a sunny autumn day three years ago, when Kesia Lyng was 30, she had a visit from her youngest sister, Eva. The two were close, and as they sat at the kitchen table in Lyng’s apartment, Eva confronted her chronically ill sibling with a painful fact: “You almost can’t take care of your own kids,” she told her. “You can’t keep pushing yourself so hard.”

Lyng, who was living with her husband and their two children in a lusterless part of Copenhagen, Denmark, had been struggling for years with inexplicable health problems: joint and muscle pains that came and left, powerful headaches, and a crushing exhaustion that even copious amounts of sleep could not cure. She was working part-time in the kitchen of her daughter’s kindergarten, the latest in a string of odd jobs. But her sick days had begun to multiply again. Often she would call her husband at work, sobbing from weariness, and ask to be picked up. At home, she was drained, with no energy to clean or cook or tuck the kids in bed. In her medical records, which she shared with me, her doctor noted that she was “having a very difficult time” and that she worried about losing her job if she asked for a sick leave.

On bad days, Lyng’s symptoms were incapacitating. “Your body is so tired you almost can’t move. Everything hurts. It hurts just to stretch, it hurts to get up. Your feet feel like big blocks. There’s this burning sensation in your body and the feeling that your muscles are about to cramp. Even small things, like having to go and buy milk, can be completely overwhelming,” she told me recently. “I’ve been incredibly frustrated at my body, because it’s so limiting.”

The trouble began in late 2002, just before Lyng turned 19. At first it felt like the flu, but there was no improvement. In the mornings, her body was stiff and achy and she found it increasingly hard to rise. When she was able to get up and go to school, she often fell asleep during class. If she ventured more than a few minutes away from home, she would nap on park benches or in cafes to summon the energy to get back. Eventually, she dropped out of school.

The abrupt transformation baffled people around the teenager. They saw a gregarious tomboy turn into someone who kept breaking dates, spent much of her time in bed, and used painkillers nonstop. “We thought it was a depression,” her friend Nanna Voltolina recalled. “She couldn’t do the same things as the rest of us. It was difficult for me to understand.”

Just before Lyng got sick, she had signed up to participate in a clinical trial of a then-experimental vaccine: Merck’s Gardasil was supposed to prevent infection from human papillomavirus, or HPV, a sexually transmitted disease. The virus causes no harm in the vast majority of people. But some HPV types can lead to genital warts, and others have been found to play a role in nearly all cases of cervical cancer, a malignancy that will affect 6 in 1,000 U.S. women at some point during their life. Lyng’s grandmother had died of cervical cancer the year before, so when a letter arrived offering her $500 to take part in a crucial international test of Gardasil, the decision was easy. She got her first shot of the vaccine at Hvidovre Hospital in Copenhagen on Sept. 19, 2002.

The symptoms snuck up on her shortly after her second shot on Nov. 14. They never abated. It wasn’t until 2016 that she received her diagnosis—chronic fatigue syndrome (CFS). The little-understood condition was once dismissed by many as a psychological problem, but is now recognized as a serious long-term illness that may have its roots in abnormal immune responses. There is no established treatment.

Kesia Lyng and her husband David.
David with wife Kesia Lyng. Kesia Lyng

In recent years, Lyng has become suspicious that there is a connection between her disease and her Gardasil immunization. Her ailments evoke descriptions found in hundreds of news stories from women who also received the vaccine, as well as several medical case reports from around the world. As these stories began to make headlines, HPV-vaccination rates in Denmark and elsewhere have tumbled and controversy has erupted. Many pointed out, rightly, that the accounts amounted to no more than anecdotal evidence, and that none of them cited data proving that the vaccine had actually caused any harm. The women might have gotten sick anyway, as Lyng might have; indeed, one recent epidemiological study found no increased risk of CFS in Norwegian girls following Gardasil vaccination.

It’s also true that more than 80 million girls and women have been vaccinated against HPV, and the vast majority have suffered no more than temporary discomfort at the injection site. In an emailed statement, Merck said it was “confident” in Gardasil’s safety profile, which “was established in clinical trials involving more than 25,000 females and males” and examined further in several surveillance studies. It also pointed out that regulators had found no scientific support for some of the most heavily publicized concerns, which focused on a couple of serious neurological disorders seen in vaccinated girls. Twice, the firm emphasized to me that according to the European Medicines Agency (EMA), the benefits of HPV vaccines “continue to outweigh their risks.” Health authorities across the globe share this view. Repeatedly, they have issued reassurances about the thorough randomized trials the vaccines were subjected to before approval. Such studies have long been researchers’ best yardstick to judge if something is a real risk or just a fluke. As the NIH’s National Cancer Institute notes on its website, all three HPV vaccines on the market today “have been tested in tens of thousands of people in the United States and many other countries. Thus far, no serious side effects have been shown to be caused by the vaccines.”

An eight-month investigation by Slate found the major Gardasil trials were flawed from the outset, however, and that regulators allowed unreliable methods to be used to test the vaccine’s safety. While these flaws do not mean Gardasil caused the rare crippling illnesses reported by the media, they are troubling. Public health officials use trials like these both to determine safety and, as evidenced by Merck’s statement above, to reassure the public when concerns like the ones about Gardasil arise. A flawed study design can complicate both tasks.

What is special about Lyng’s case is that she got sick during a clinical test—indeed, the largest-ever randomized placebo-controlled trial of Gardasil—years before the vaccine was approved (which it was, in 2006, in both Europe and the U.S.). Drug regulators tend to look much more seriously at potential side effects that surface during a pre-licensure study, which is what Lyng participated in, rather than after a product has already been found to be safe and been put on the market. But regulators never learned of Lyng’s plight. In fact, her repeated complaints of debilitating symptoms were not even registered in the study as potential side effects (“adverse events,” in medical parlance).

Lyng’s experience was not unique. Interviews with five study participants and more than 2,300 pages of documents obtained through freedom-of-information requests from hospitals and health authorities suggest inadequacies built into Merck’s major clinical tests of Gardasil. To track the safety of its product, the drugmaker used a convoluted method that made objective evaluation and reporting of potential side effects impossible during all but a few weeks of its yearslong trials. At all other times, individual trial investigators used their personal judgment to decide whether or not to report any medical problem as an adverse event—essentially, as a potential side effect worth evaluating further. Other health issues went on a worksheet for “new medical history,” reserved for conditions that bore no relation to the vaccine. This study design put the cart before the horse, asking investigators to decide which symptoms might be side effects, rather than tracking everything in the same way. While the company now says otherwise, there is no indication in the confidential study protocol that it submitted to regulators for approval that it would use new medical history as a safety metric. And it hardly would have qualified as such: The worksheet allotted just one line per entry, with no measurement of symptom severity, duration, outcome, or overall seriousness. Even if the company then used the data in subsequent safety assessments, the lack of detail would have hampered meaningful analysis.

European health regulators worried about Merck’s methods during a review of the company’s marketing application for Gardasil 9, the latest version of the vaccine, but have not made their concerns public. In an internal 2014 EMA report about Gardasil 9 obtained through a freedom-of-information request, senior experts called the company’s approach “unconventional and suboptimal” and said it left some “uncertainty” about the safety results. EMA trial inspectors made similar observations in another report, noting that Merck’s procedure was “not an optimal method of collecting safety data, especially not systemic side effects that could appear long after the vaccinations were given.”

“If I were a research subject, I would feel betrayed,” Trudo Lemmens, a bioethicist and professor of health law and policy at the University of Toronto, told me. “If the purpose of a clinical trial is to establish the safety and efficacy of a new product, whether it’s a vaccine or something else, I would expect that they gathered all relevant data, including whether it had side effects or not.”

Merck, which is known as Merck Sharp & Dohme outside the U.S. and Canada, did not address the EMA’s safety concerns. But it said its clinical trials follow “laws, regulations and guidelines” wherever they take place, and proceed only after approval by regulators and ethics committees. The company also stressed that “collection of New Medical History occurred at each study visit and was mandatory for all study subjects. New Medical History includes the collection of non-serious adverse events.”

When I asked the EMA to expand on its confidential observations, I was told by email that the concerned inspectors had, after all, considered the trial data to be usable. The company had successfully mollified the agency during preapproval discussions. “The clarification from the applicant that collection of new medical history data was mandatory for all subjects, and did not appear to be passively collected, but for at each study visit [sic], was found to be reassuring,” the EMA informed me. “Therefore, it appeared that the safety surveillance in the studies captured all medically relevant events.” The agency did not comment on the limitations of relying on “new medical history” instead of straightforward reporting of adverse events.

Underreporting of adverse events, to the extent that it occurred here, is nothing new to medicine. Trial investigators often miss participants’ symptoms, researchers say, and the data they do collect may not always see the light of day. A review out in 2016 found “strong evidence that much of the information on adverse events remains unpublished and that the number and range of adverse events is higher in unpublished than in published versions of the same study.” In 2009, Dr. John Ioannidis of Stanford University put the problem succinctly in an Archives of Internal Medicine editorial titled “Adverse Events in Randomized Trials: Neglected, Restricted, Distorted, and Silenced.”

Much less clear is how adverse events are handled during the actual conduct of clinical trials, and what the impact is. Are symptoms recorded as separate entities when they are really part of a larger constellation of health problems? Do they appear as innocuous one-time occurrences when in fact they are, or may become, chronic? And how many safety problems are simply missed because of short follow-up?

Lyng’s was no isolated case: At least five other Danish women say they developed chronic health problems during the trial. Future 2, as it is known, enrolled more than 12,000 young women from 13 countries, including the U.S. It was the larger of the two major randomized, placebo-controlled Gardasil trials—technically known as pivotal trials—that Merck conducted to support its marketing application for the vaccine. (The other study, less than half the size, was called Future 1.) Together, the two trials account for a large portion of the data that drug regulators in both the U.S. and Europe used to judge Gardasil’s safety before it was approved.

At Aalborg University Hospital, one of the Future 2 trial sites in Denmark, Miam Donslund began to experience persistent flu-like symptoms as well as two infections, one of which required hospitalization, shortly after immunization. These incidents were recorded, but again only as new medical history, meaning they were not processed as adverse events.

Donslund, now 38, told me she became so tired during the trial that at one point she was accused of being a drug addict. The year after she was vaccinated, she developed severe pains that forced her to use a wheelchair for a while; today she regularly uses crutches. Doctors have told her she might have psoriatic arthritis, but she never received a definite diagnosis. More than a dozen years later, “I work two days a week and the rest of the time I’m at home in bed and I can’t do the most basic things,” she said.

Stine Sørensen, 34, got her first shot of Gardasil a few months after Lyng, also at Hvidovre Hospital. Around this time, she began to experience general discomfort, headaches, and a profound fatigue that often made her miss school. “My mom and dad asked me, ‘Stine, are you on drugs?’ And I clearly remember that I got so angry,” she told me. Sørensen, who is currently employed under a special agreement for people with chronic illness, says she told study personnel about her problems during the trial; her records mention none of them. (All three women received the vaccine in the trial.)

The trial investigator who dealt with both Lyng and Sørensen, Dr. Anette Kjærbye-Thygesen, an OB-GYN at Hvidovre, declined to be interviewed for this story. In an email, a hospital press officer told me, “Regarding registration of various symptoms and health data, the doctor states that she has followed the trial protocol.” The hospital also declined to address my questions.

Imagining a link between HPV vaccination and CFS is not all that far-fetched, according to Dr. Jose Montoya, a professor of medicine at Stanford University and a CFS expert. The condition usually starts with an insult to the immune system—a severe infection, a car crash, a pregnancy. The first symptoms are flu-like, but months go by and the patient realizes she isn’t getting better. In a few genetically predisposed individuals, Montoya told me, it is “biologically plausible” that the vaccine, which mimics a natural infection, could also trigger an immune response powerful enough to lead to CFS. To find out if that is the case, trial investigators would need to carefully track participants’ symptoms “for at least one year,” he said.

Montoya was also quick to tell me that he is “pro-vaccine,” and he doesn’t think people should stop getting them. His eagerness to make that point underscores a larger issue with unpacking the shortcomings of Merck’s research: Acknowledging any uncertainty around the safety of vaccination can be a difficult exercise for health authorities, not least because of the debunked autism scare that continues to stoke anti-vax sentiments among parents. In today’s polarized conversation, either you believe vaccines are categorically safe, or you think they are so dangerous that you avoid them at significant personal risk.

But this is a false dichotomy that belies the complexity of medicine. Safety is not an absolute. Like drugs, vaccines are a varied lot, each with its own set of risks and benefits that relate to its particular use in particular individuals. And unfortunately, our knowledge about side effects is often woefully incomplete. To Lemmens, the University of Toronto bioethicist, the reluctance to have a frank discussion about the safety of Gardasil is counterproductive. “We do a disservice to science, and we play into the hand of the anti-vaxxers, if we’re not publicly discussing potential problems,” he told me.

Before I sent them to her, Lyng had never seen her trial records, which are owned by Merck. As we looked through them together, on a balmy day in August, she grew visibly upset. “What’s the use of testing a vaccine if you don’t register everything properly?” said Lyng, a pale and reedy woman with light-blue eyes. “It had enormous consequences for my life.”

We were sitting outside the house that she and her husband had recently bought on the outskirts of a small town near Copenhagen. There are fields at the end of their street, and a school just opposite their house that the children now attend. Lyng had been fired from her job as a kitchen helper in late 2014, but her sickness benefits and her husband’s salary kept the family afloat. The extra time to herself and her CFS diagnosis also gave her some peace of mind. Over the years, she had been diagnosed with attention-deficit disorder, depression, even “soft” bipolar.
None of these diagnoses fully explained her problems, she felt. Why would she get sudden fevers and rashes that would disappear again just as suddenly? Why would her body hurt on some days and not others? Why would she need to rest for two weeks if she had volunteered to plan the menu for her church’s New Year’s Eve party? The diagnosis gave her at least one answer.

In Lyng’s records from Future 2, we discovered, there was no mention of fatigue, one of her most debilitating symptoms. Meanwhile, her family doctor began documenting the problem on March 20, 2003, nine days after she got her third and final shot of Gardasil. In 2004, after several lab tests and specialist consultations had come up empty, he noted that Lyng continued to have “periods of headache, fatigue, pain in large and small joints, poor concentration and sleep problems. Her mood is fluctuating. There has been no suspicion of depression.”

Lyng told me she brought up her symptoms with study personnel at every visit during the four-year trial. (Trial subjects met with investigators regularly over four years, but the later visits were meant to monitor the vaccine’s efficacy—in this case, whether it prevented HPV-linked cell changes.) She even told them her illness had forced her to quit school. But no one seemed to take her seriously: “They keep saying, ‘This is not the kind of side effects we see with this vaccine.’ ”

Kjærbye-Thygesen, the trial investigator who saw Lyng, and a staffer with the initials “BW,” presumably a nurse, did report the headache and the joint pain, and also gastroenteritis and influenza, but not as adverse events. Instead, they used the worksheet for medical history, which directed investigators to list “Any new background or concomitant conditions, drug allergies and surgeries/procedures.” A note in the records, initialed by Kjærbye-Thygesen, said the vaccine was “hardly” to blame for Lyng’s joint pains, offering no further explanation.

New Medical History
Kesia Lyng’s new medical history (highlighting mine), six months into trial. Shown with Lyng’s permission.

Despite the oxymoronic instruction to list new conditions as history, this was no mistake. Merck’s study protocol shows that for participants outside the U.S. and the U.K., who made up the majority of the trial, only adverse events that investigators considered serious were to be reported. Other health complaints would be registered in much less detail as new medical history. (In the U.S. and the U.K., both serious and nonserious events were reportable.)

In all the trial locations, Merck also chose to restrict the reporting of adverse events—what the study protocol calls the “clinical follow-up for safety”—to just 14 days following each of the three Gardasil injections in the trial. Illness occurring outside these narrow time slots again was relegated to a single line on the medical-history worksheet, whereas for each adverse event, several assessments would need to be carried out and reported. There was an exception: Deaths or serious adverse events brought to the investigator’s attention and felt to be related to the vaccine or a study procedure were to be reported at any time. This design put individual investigators in charge of deciding, for most of the trial’s duration, what would be assessed and reported as a potential side effect.

(Future 1 did report nonserious adverse events for all, but it relied on the same short follow-up as Future 2 and also labeled many adverse events as new medical history.)

Experts I talked to were baffled by the way Merck handled safety data in its trials. According to Dr. Yoon Loke, a professor at the University of East Anglia who studies side effects, letting investigators judge whether adverse events should be reported is “not a very safe method of doing things, because it allows bias to creep in.” In essence, this feature meant that if you started out thinking the vaccine was safe, you would be less likely to find potential side effects. Of the short follow-up, Loke told me, “It’s not going to pick up serious long-term issues, which is a pity. Presumably, the regulators believe that the vaccine is so safe that they don’t need to worry beyond 14 days.”

A drug-safety adviser at a multinational pharmaceutical company told me, “Everything from the first injection to the last plus a follow-up period is what we call treatment-emergent adverse events.” She puzzled over the brief, interrupted follow-up periods in the Gardasil trials, as well as Merck’s choice not to report nonserious adverse events for all participants and its dismissal of many events as medical history. “This is completely bonkers,” she said, requesting not to be named for fear of compromising her position in the industry. “They’ve set up a protocol that seems very poorly thought through from a medical and safety perspective.”

According to the EMA’s emailed statement, “The scope of adverse experience collection in the clinical program for Gardasil reflected the standard across vaccine programs of this company.” It added, “The standard follow-up for a non-replicating vaccine [such as Gardasil] has been 14 days (Days 1 to 15) following each vaccination.”

There are no rules dictating the exact duration of adverse-event reporting in vaccine trials. For some studies, it can be measured in days; for others, it runs from start to finish, with all events recorded the same way regardless of their possible link to the vaccine. Indeed, reviews from 2005 and 2013 found striking variation in how vaccine researchers collected, analyzed, and presented safety data. The field has since seen efforts toward standardization, and health authorities are increasingly recognizing that some side effects may occur late. In guidelines published this year, the World Health Organization noted that while most vaccine side effects occur within two weeks, there may be “reasons to suspect that illnesses with onset many months after the last dose could be related to prior vaccination.”

Serious adverse experiences, six months into trial.
Serious adverse experiences (highlighting mine) six months into Gardasil trial. Shown with Lyng’s permission.

Lyng and I also read the definition of “serious adverse experience” on the worksheets that investigators had to fill out at each visit following a vaccination. It included events resulting in “persistent or significant disability/incapacity,” meaning a “substantial disruption of a person’s ability to conduct normal life functions.” On all the forms, the only checked box was the one that said “None.” Was this an error? Arguably not, because Lyng’s symptoms, as recorded by the study personnel, began three to four weeks after her second shot—outside the protocol’s mandatory follow-up for safety.

A press officer from the Danish Medicines Agency, which approved Future 2 in 2002, pointed out that Merck’s study protocol contained no mention of “new medical history” or “new medical conditions.” In an email, she wrote, “We are also not aware of whether this category has been used in other clinical trials with drugs, as these are not terms that are used according to guidelines.”

She added that there had been no concerns at her agency over the safety testing in Future 2. “The safety measurements complied with applicable guidelines for vaccines,” she told me, adding that the 14-day follow-up “is in accordance with EMA’s scientific guidelines for vaccines.”

It was a description of a 15-year-old Colombian girl with neurological problems that first caught the attention of Dr. Rebecca Chandler, an American expat working at Läkemedelsverket, the Swedish Medical Products Agency.

Sweden is an EMA rapporteur for Gardasil and Gardasil 9, meaning that it was tasked with evaluating the marketing applications for the two vaccines on behalf of the European Union. As a clinical safety assessor at Läkemedelsverket, Chandler had been looking into post-marketing reports from Denmark and Japan about two serious, little-known neurological disorders in girls and young women vaccinated with Gardasil. In both countries, these cases had ignited vitriolic national debates that sent vaccination rates plummeting. When the application for Gardasil 9 arrived, Chandler decided to scrutinize the trial data to see if she found any references to the two conditions, known as postural orthostatic tachycardia syndrome (POTS) and complex regional pain syndrome (CRPS). The syndromes overlap to some extent, and also share a number of features with CFS.

At first, she found nothing—no instance of either disease was listed in the company’s application. But the Colombian teenager’s symptoms, as described in the clinical trial data, made her suspect POTS, and she asked the drugmaker to comb through its database for similar cases. Three girls vaccinated with Gardasil 9 had been diagnosed with POTS, it turned out, and one with CRPS. There were also several cases of neurological disorders “of interest,” Chandler wrote in her 2014 assessment. But none of them had been reported by the company as adverse events; rather, they were all labeled as new medical history in accordance with Merck’s study protocols.

Chandler, who now works at the Uppsala Monitoring Centre, a leading drug-safety research institution in Sweden, told me she “argued quite much” about her findings at the agency, “because I was very concerned that the study design was not appropriate to pick up these things.” Her regulatory colleagues apparently shared her apprehension, laying out their misgivings in a series of confidential EMA reports leading up to the approval of Gardasil 9. (I obtained these reports from Läkemedelsverket through several freedom-of-information requests.) One confidential EMA report from 2014 called Merck’s approach to safety “an unconventional and suboptimal study procedure”; another observed that the design “brings some degree of uncertainty into the overall safety assessment.”

Chandler found Merck’s data bolstered concerns about an association between the vaccine and POTS, but she was overridden by her agency colleagues. Later, a contested EMA review from 2015 and a U.S. study based on post-marketing data also found no support for a link.

Officials inspecting a Gardasil 9 trial for the EMA also felt compelled to spotlight how Merck dealt with safety, despite considering it “a systemic issue related to study design and as such not an inspection finding.” The unorthodox design “complicated” the reporting of adverse events, the inspectors wrote, in part because the information on “new medical events” was “limited, as only symptoms were collected and no further medical assessments were made and no outcome was recorded.”

In their final report recommending conditional approval of Gardasil 9, the EMA rapporteurs asked the drugmaker to “discuss the impact of [its] unconventional and potentially suboptimal method of reporting adverse events and provide reassurance on the overall completeness and accuracy of safety data provided in the application.” Läkemedelsverket refused to share the company’s response. In the EMA’s public assessment of Gardasil 9, all mention of the safety concerns has been scrubbed.

In response to my questions, the EMA pointed out that its experts, in a public assessment of the original Gardasil vaccine from 2006, found Merck’s way of evaluating safety “established and appropriate.” But the agency failed to explain how that opinion squares with its unpublicized reservations about the Gardasil 9 research, which handled safety essentially the same way.

Dr. Susanne Krüger Kjær, a professor of gynecological cancer epidemiology at the University of Copenhagen who oversaw the Danish part of Future 2, declined to address the safety concerns. “I can’t answer any of those questions because I didn’t design the trial,” she told me. She is one of the authors on the main scientific publication from the trial, which appeared in 2007 in the New England Journal of Medicine and contains no mention of new medical history.

In its statement, Merck said that using the “new medical history” category “allowed broad collection of potential safety events including new conditions, symptoms, and laboratory or imaging tests thereby allowing comprehensive safety assessment.” It cited a study from 2010 that analyzed new medical history and found “comparable” rates in trial participants given vaccine and placebo, respectively.

On a rainy day in September, I flew with Lyng to Berlin to visit Gerd Wallukat, a scientist at the biotech startup Berlin Cures. Wallukat, a heavyset man in his mid-70s, has pioneered research into a special class of autoantibodies—proteins made by the immune system that attack the body’s own cells instead of foreign invaders like viruses or bacteria. Researchers have been finding these “agonistic autoantibodies” in people with different diseases, including CFS, POTS, and CRPS, but their role is not fully understood. Berlin Cures is in the middle of early-stage trials to see if neutralizing them could have a therapeutic effect.

One of Lyng’s doctors in Denmark had been working with Wallukat to look for autoantibodies in girls and women who fell ill following Gardasil vaccination. Their preliminary, unpublished findings suggested that nearly all of these women harbor one or more agonistic autoantibodies, and Wallukat had offered to test Lyng, too. On the plane, she was nervous and chatty. She didn’t want to be sick, she explained, but it was taxing having to convince people around her—her caseworker, her family, even her husband—that she was physically sick while one test after another came up empty. She dreaded the thought of receiving yet another negative result.

Gerd Wallukat
Gerd Wallukat, a scientist at Berlin Cures and one of the pioneers of the agonistic autoantibodies, talking to Lyng. Frederik Joelving

She didn’t. “You have beta-2, nociceptin, muscarinic,” Wallukat told her, referring to three types of autoantibodies, “the classical pattern I’ve seen in patients after vaccination.” From a coffee shop, Lyng called her husband. “I’m completely overwhelmed. It’s the first time I’ve had a positive result,” she told him. “This means it’s not just in my head—all those doctors who’ve asked if it could be psychological.”

But Lyng’s positive test triggers more questions than it answers: What induced those autoantibodies, and how? Did they cause her symptoms, as her doctor speculated? And would neutralizing them bring about improvement, as Berlin Cures wagered? The test brought another piece to the puzzle that is Lyng’s case; but as so often happens in science, it did not bring certainty, and it proved nothing in the way of causality. Should it turn out that Gardasil does have serious side effects, it’s apparent that they must be rare. What’s more, the vaccine might still be worth that hypothetical risk—cervical cancer, though uncommon, is a terrible disease.

If there’s one clear lesson from Lyng’s experience, it’s that science is a work in progress. To borrow the words of the American psychologist Brian Nosek, “Science isn’t about truth and falsity, it’s about reducing uncertainty.” Not owning up to that uncertainty, when it is legitimate, likely will only slow scientific progress. In the controversial realm of vaccines, it will also create fodder for conspiracy theorists spreading overblown or unfounded fears among an already distrustful public.

One way to respond to public concerns is to acknowledge the limits of our current body of research and to welcome discussion about what we know and don’t know, according to Lemmens, the bioethicist.
“Transparency and open debate around side effects are essential to safeguard trust in the provision of medication and public-health planning,” he told me. Instead, as confidence in Gardasil nosedived in Denmark, regulators doubled down on the simplistic message that the vaccine has been thoroughly tested and is unquestionably safe.

At a press conference in May, Dr. Søren Brostrøm, the director general of the Danish Health Authority and an OB-GYN, told journalists that “for us, as authorities, there is no doubt about this vaccine’s efficacy and safety.” This seems to contradict the EMA’s own deliberations about the way Merck reported safety data in its trials. As Dr. Christian Gluud, who heads the Copenhagen Trial Unit, a research center at Copenhagen University Hospital, told me recently, “If we had tested our vaccines properly, we wouldn’t be having the discussion we’re having now.”

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