by David Isaacs
More than 200,000 children in the Western and Midwestern United States had been given Cutter’s faulty vaccine, in which the live virus had not been killed. Of these, some 40,000 children developed polio, 200 were paralysed permanently and 10 died. Cutter promptly withdrew its vaccine.
The Cutter Incident (as it came to be called) was a major catastrophe. American immunisation expert Paul Offit has discussed its origins in great detail in his fascinating book The Cutter Incident. In 1998 and 1999, Offit spoke at length to Julius Youngner, who was a young member of Salk’s laboratory staff at the time of the incident.
The day after the contracts were signed, Youngner was rung by the Associate Director of Research at Cutter Laboratories to say they were having trouble inactivating poliovirus for their vaccine and the live virus was persisting for days. Youngner immediately visited their manufacturing plant in Berkeley, California. He was appalled to find an amateurish setup and had serious concerns about their ability to reliably inactivate live poliovirus. He later told Offit: ‘They looked like they didn’t know what the Hell they were doing.’ When he returned to Philadelphia, Youngner told Salk about his concerns and offered to write to the head of the Laboratory of Biologics Control. Salk said he would write, but never did.
This is Youngner’s memory of what happened, related over 40 years after the event. Salk is not alive to give his version, and the relationship between the two men after the Cutter Incident was far from cordial. However, Cutter Laboratories would not by any means be the last pharmaceutical company to cover up knowledge of safety concerns and risk lives in favour of profit.
Ben Goldacre is an Oxford doctor, academic and author. In his powerful book Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients, he describes the lengths to which some pharmaceutical companies will go to promote drugs they know are not only ineffective but frankly harmful. It is little wonder that vaccine sceptics are suspicious of the motives of vaccine companies, although improved safeguards make it incredibly unlikely we will ever have another Cutter Incident.
The small family firm of Cutter Laboratories was clearly culpable. Its vaccine was associated with far, far more cases of paralysis than the vaccines made by any of the four other well-established pharmaceutical companies. Three of these companies’ vaccines had not caused any increase in paralysis at all. But one batch of Wyeth vaccine was associated with considerably more cases of paralysis than any of Wyeth’s other batches. Did Wyeth immunise children with one vaccine batch that contained live virus? The figures were suggestive but not definitive. It might have been pure chance. For example, the children who received the suspect batch might have been coming down with polio already. The suspect batch was quietly removed from the shelves and the public was not informed. In late 1955 Neal Nathanson who worked at the Centers for Disease Control (CDC) co-authored a report called The Wyeth Problem, in which he raised his suspicion that children were indeed given a batch of Wyeth vaccine which inadvertently contained live poliovirus, although he does not mention a cover-up. Nathanson wrote many scientific papers about the Cutter Incident, but never published a paper expressing any concerns about the Wyeth vaccine. History does not relate whether he was advised by his superiors at the CDC, a federal public health agency, not to publish any further details for fear of worrying the public about the continuing IPV program. There was to be no Wyeth Incident. Was this a cover-up or a wise precautionary measure to allay public concern?
There was a government inquiry into the Cutter Incident, of course. A congressional hearing heard witnesses blame FDR’s National Foundation for Infantile Paralysis, which funded the trial; the Laboratory of Biologics Control, which controlled vaccine safety; and Jonas Salk, who they alleged had developed a faulty technique for killing the vaccine virus. Many people working in vaccine regulation were sacked, from the most senior to the most junior.
Politicians blamed politicians. Senator Wayne Morse of Oregon said: ‘The federal government inspects meat in the slaughterhouse more carefully than it has inspected the polio vaccine.’ Some tried to blame then Vice President Richard nixon for purportedly putting pressure on authorities to license the vaccine. He didn’t. Nixon might have been responsible for Watergate, but he didn’t cause the Cutter Incident.
Cutter Laboratories never admitted it was at fault. It said the problem was a general one that applied to all IPV, even though Cutter vaccines caused many more cases of paralysis than any of the other companies’ vaccines, including Wyeth’s. Mostly Cutter Laboratories blamed the government for inadequate testing. Walter Ward, the scientist who led Cutter’s IPV development program, asserted that Jonas Salk’s technique for killing the virus was the only cause of the disaster, which Ward always referred to as ‘the Salk Incident’.
Several leading scientists, including Salk’s lifelong rival Albert Sabin and Nobel Prize laureate John Enders, advised Congress and the assembled media throng to stop the IPV immunisation program. During a less public government meeting, Enders told Salk pointedly: ‘It is quack medicine to pretend that this is a killed vaccine when you know that it has live virus in it. Every batch has live virus in it.’ The usually sanguine Salk was shaken. He later said he felt suicidal for the first time in his life.
But the United States Government, and indeed the public, had too much invested in the polio prevention program to stop now. The IPV immunisation program continued. Initially uptake was patchy. The American public was understandably confused by the mixed messages: the government and the vaccine companies were saying IPV was safe, whereas leading United States scientists including a Nobel Prize winner said it was not.
In a timely but tragic twist of fate, less than three months after the Cutter vaccine was withdrawn, the United States was hit by a nationwide polio epidemic. More than 1700 people were paralysed. There was no randomised control trial in place, but the outbreak provided ample evidence of vaccine efficacy. The rate of polio in unimmunised people was 20 per 1000. The rate in people who had received one dose of IPV was 10 in 1000, half as much. The rate after two doses was 5 per 1000, a quarter as much. The rate after the ideally recommended three doses was zero. That is why we now give three doses of polio vaccine.
One positive was that the Cutter Incident led to highly effective federal regulation of vaccine production. Regulations on vaccine safety were tightened, and the number of vaccine regulatory staff was increased from 10 in 1955 to 150 by 1956. The United States has had an incomparably unblemished safety record ever since. Vaccine regulation was moved to the United States Food and Drug Administration in 1972, which now has more than 250 staff dealing solely with vaccine safety. Because they are given to everyone, vaccines need to be even safer than pharmaceuticals, and indeed they now are.
In the longer term, the Cutter Incident did not have a lasting adverse effect on the uptake of polio vaccine in the United States or elsewhere. Polio was and is a truly terrible disease, and almost everyone in the 1950s and 1960s knew a family who had a paralysed child. Most people were prepared to accept that the Cutter Incident was an isolated accident, and that the Salk vaccine was subsequently made safe. Memory of infectious diseases, and particularly visible evidence of their ravages, are powerful drivers of vaccine acceptance.
The Cutter Incident had another less beneficial outcome, however. Cutter Laboratories was sued by the parents of a child with severe permanent paralysis, and this case acted as a test case for 60 other suits. In a confusing jury trial, it was found that Cutter Laboratories had not been negligent, but the company was still ordered to pay compensation to those injured by the vaccine. This was, without precedent, liability without fault. Americans have a long history of suing for anything and everything, but this was the start of a new saga. A pharmaceutical company could be sued successfully, despite following the regulations, if someone given a vaccine developed a rare, known side effect, even if they had been warned about it. The verdict precipitated a climate of litigation against vaccine companies, which had a detrimental effe
ct on vaccine production.
You don’t need to feel too sorry for Cutter Laboratories, though. The company paid the compensation and thrived, making pharmaceuticals as well as vaccines. By 1962 it had assets of over US$18 million, 80% more than in 1955. In 1978 it was bought by the German pharmaceutical company Bayer.
The losers were the children who developed polio, not Cutter.
The MMR–autism controversy
The United Kingdom whole-cell pertussis vaccine controversy in the 1970s, described in Chapter 1, was soon proved spectacularly and tragically wrong when whooping cough returned to the United Kingdom with a vengeance between 1977 and 1979. Even though concerns that the vaccine could cause brain damage proved unfounded, it is unlikely that the public was ever totally reassured.
This was fertile ground for another vaccine controversy, and one with even greater repercussions: the claim that there was a possible link between measles-mumps-rubella (MMR) vaccine and autism. The controversy started at the Royal Free Hospital in the London suburb of Hampstead, a major teaching hospital with a proud history. (I have personal links: I grew up in Hampstead, my eldest son, Ben, was born at the Royal Free, and a dear friend was until recently a consultant neurologist there. What is more, John Keats wrote ‘Ode to a Nightingale’ just down the hill from the Royal Free.)
When Andrew Wakefield came to work at the Royal Free Hospital as a consultant gastroenterologist in 1997, research there was in the doldrums. Wakefield arrived like a breath of fresh air. He was eloquent, with an infectious enthusiasm. He persuaded colleagues to join him in research that he said was at the cutting edge, and promised them their work would be published in high-powered journals. There were even whispers of a Nobel Prize. Wakefield had long been interested in a possible link between inflammatory diseases of the bowel, such as Crohn’s disease, and measles virus infection. In 1993, he had published research suggesting measles virus might cause Crohn’s disease and in 1995 a paper suggesting a link between measles vaccine and Crohn’s disease. These findings excited interest but could not be replicated by other researchers.
A year after he started at the Royal Free, Wakefield and his colleagues submitted a paper based on 12 children with autism whom they said had been referred consecutively (one after the other) to the gastroenterology department because of gut symptoms (diarrhoea, abdominal pain, bloating, food intolerance). The authors claimed that 8 of these 12 children displayed symptoms of autism soon after they were given MMR vaccine and one displayed symptoms soon after catching measles infection.
It was 1998. The day the paper was published in the prestigious British journal The Lancet, 41-year-old Wakefield transfixed a packed press conference with a startling video news release. He claimed to have found the cause of autism: MMR vaccine. He said he had discovered a new ‘bowel and brain’ syndrome. He proposed that the MMR vaccine virus travelled in the bloodstream to the muscle supplying the gut, where it could grow and cause inflammation. The inflammation could allow unidentified, harmful proteins to enter the bloodstream and travel to the brain, causing autism. At this stage, he had no evidence to support his theory, but he was sure he would find it. Wakefield was articulate and charismatic; his claims made headline news.
Wakefield’s assertion that MMR vaccine caused autism was outrageously bad science. The Royal Free team only studied 12 children already known to have autism. Their claim that eight of the children experienced a sudden onset of autism after MMR vaccine was puzzling, as autism is a chronic condition and had not previously been associated with a specific trauma. When trying to prove that a trauma actually causes a disease, it is essential that a study includes a control group, in case the association between the supposed trauma (in this case MMR vaccine) and the disease (autism) is just a chance association (in which case the disease would occur equally commonly in the control group). Wakefield and his colleagues had no control group for comparison.
Yet in the summary of their Lancet article the authors wrote: ‘We identified associated gastrointestinal disease and developmental regression in a group of previously normal children, which was generally associated in time with possible environmental triggers.’ ‘Developmental regression’ implies that the children’s development went backwards, and the paper unequivocally stated that the children were previously normal. The suggested ‘environmental triggers’ were MMR vaccine in eight children and measles infection in one. The paper quoted the parents as saying their children were developing normally until they were given MMR vaccine, but then within two weeks of MMR the child’s behaviour changed and they lost skills – for example, some stopped talking.
The claims about new bowel changes were also suspect. The authors claimed to have found bowel changes, to which they gave a new name, ‘autistic enterocolitis’. (Enterocolitis means ‘inflamed bowel’.) Experts would later throw doubt on the veracity of the bowel changes. Furthermore, to describe the changes, Wakefield and his fellow authors performed endoscopies on 8 of the 12 children. Such an endoscopy, which involves sedating the child and inserting a tube with a camera down the child’s throat and into the bowel, is quite invasive. As many as three people were occasionally needed to hold a patient down to perform endoscopy. The ethics of performing such procedures on children was also later called into question.
Wakefield proposed that instead of MMR vaccine, children should be immunised with measles vaccine, mumps vaccine and rubella vaccine separately, with at least a year between each vaccination. In his press conference, Wakefield said: ‘One more case of autism is too many. It’s a moral issue for me and I can’t support the continued use of these vaccines given in combination until this issue has been resolved.’ How ironic and, indeed, cynical that Wakefield, who would prove to have falsified most of the data in the paper for personal financial gain, would claim this was a moral issue for him.
Wakefield said autism did not follow measles vaccine when it was given alone in 1968, but did follow MMR when it was given in 1988, but this ignored the fact that diagnostic criteria had changed enormously and children were diagnosed with autism far more often in 1988 than in 1968. There was no credible scientific rationale for Wakefield’s claim that giving the same three vaccine viruses separately was safer than giving them combined in MMR vaccine.
In any case, measles, mumps and rubella vaccines were no longer made as separate vaccines in 1998. The effect of Wakefield’s suggestion to split the vaccines was that the public had to choose between MMR and no vaccine at all. When British Prime Minister Tony Blair was asked if he had given MMR vaccine to his youngest child, who was due for vaccination, he refused to answer. Everyone took that as a no. The public was confused. Officials were warning them of the danger of measles and Wakefield was warning them of the danger of the vaccine. Who were they to believe?
The MMR–autism link excited global interest, and Wakefield travelled abroad spreading his message. In 2000, Wakefield talked at United States autism conferences and appeared on the CBS network’s 60 Minutes program saying that MMR was linked to what he called an ‘epidemic of autism’. In 2003, more than five years after the Lancet paper, the United Kingdom’s Channel 5 broadcast a 90-minute film called Hear the Silence. Hugh Bonneville played Andrew Wakefield and Juliet Stevenson played the mother of an autistic child. In the film, the mother cannot convince doctors that her child’s autism started after the child was given MMR vaccine. But Dr Wakefield believes her. However, government officials decide they need to bring Wakefield down by portraying his research as flawed. They tap his phone and steal his files. But who is really behind Wakefield’s persecution? In the film it is Big Pharma. The mother of another autistic child portrayed in the film says: ‘It’s a multi-million-pound industry, so they’ll fight dirty.’ The film got a modest television audience and decidedly mixed reviews, and was pilloried by outraged doctors. But its portrayal of the pharmaceutical industry and the government as the villains played right into the hands of the vaccine sceptics.
The Lancet paper was very
bad science. But it took the persistence of one man, Brian Deer, to show that the research was fraudulent. Deer, an investigative journalist who specialised in inquiries into the pharmaceutical industry for the Sunday Times, was no respecter of reputations. He investigated Wakefield’s paper from 2003 onwards, and his concerns about the ethics of the research grew and grew. He wrote a series of articles for the Sunday Times and also published papers in the British Medical Journal (BMJ). He made a television documentary, MMR: What They Didn’t Tell You, shown on Channel 4 in Britain in November 2004. Wakefield sued Deer for libel over the documentary, but subsequently dropped the case and was ordered to pay costs.
As Deer accumulated even more worrying data suggesting that the paper in The Lancet might contain serious errors of fact and that aspects of the research might have been unethical, the United Kingdom General Medical Council (GMC) decided to investigate the paper in detail. The GMC is the official body that oversees doctors’ registration to practice. Wakefield and colleagues said it was unethical to investigate the 12 patients in the paper because it would infringe their privacy. But the GMC had the authority to look at the patients’ case records. The GMC hearing against Wakefield commenced in July 2007. What the GMC uncovered over the following three years would leave its verdict in no doubt.
When you publish a scientific paper you must declare any potential conflicts of interest. Wakefield had declared to The Lancet that he had none, but in truth he had major financial conflicts. Wakefield had in fact been working for two years with a Norfolk solicitor, Richard Barr, on a lawsuit against the MMR vaccine companies, on behalf of parents who claimed the vaccine had been the cause of their child’s autism. For this work, Wakefield was paid £150 (AU$265) an hour, and eventually earned a total of £435,643 (around AU$770,000) plus expenses. In addition, prior to the publication of his team’s paper in The Lancet, Wakefield had lodged a patent for a new measles vaccine he called Transfer Factor, which he also claimed could be used to treat inflammatory bowel disease (he gave Transfer Factor to one of the research patients). If successful, his unscientific recommendation to give measles, mumps and rubella vaccines as separate vaccines instead of MMR could have made him a fortune.