WASHINGTON, May 15 (UPI) -- In a clinical trial of an investigational drug, two questions are front-and-center: "Does it work?" and "Is it safe?"
In two clinical trials of Merck vaccines in Olympia, Wash., the study protocols called for drawing the child's blood; giving the shots; waiting 42 days, and then drawing blood again to see if antibodies developed.
That would show whether the drugs -- in this case, attenuated or weakened live-virus vaccines against chickenpox, measles, mumps and rubella -- were effective.
To answer the safety question, parents were asked to keep a log of any unusual events that occurred during the 42 days.
About halfway through that six-week "study window" a 1-year-old child in Olympia named Timothy Baltzley became quite ill. As outlined earlier in this series, Timothy got an investigational "process upgrade" chickenpox shot in January of 2001, along with the routine MMR immunization.
Timothy developed a fever that spiked to 102, and he was listless and sick to his stomach, his mother, Kimberly, recalled.
"He was just laying in one place," she said. "We had to carry him down the stairs and things like that. He wound up after a couple of days being a little better," and he appeared to completely recover.
But over the next few months, Timothy's behavior became increasingly odd and his development stalled; eventually, he was diagnosed with full-syndrome autism. The clinical trial and the illness lingered in Kimberly's mind.
Kimberly said Timothy's trial was explained to her as a step in the development of a four-in-one chickenpox-measles-mumps-rubella vaccine -- that's why the chickenpox and MMR shots were given at the same. For the same reason, the chickenpox shot Timothy got had a much higher dose of virus than the standard shot, she recalls being told, although the consent form did not mention any increase.
A higher dose was necessary because when viruses are combined, they can interfere in ways that undercut the effectiveness of individual vaccines, she was told. Merck studies already had shown more chickenpox would be needed to overcome such interference in a four-in-one immunization.
Kimberly's concerns were not assuaged when she met Jennifer Flinton, whose son, Jimmy, was diagnosed with autism after being in a subsequent trial nearly two years later at the same pediatrician's office.
The shot Jimmy got was the four-in-one vaccine Kimberly had been told was under development in Timothy's trial. Called ProQuad, it was approved by the Food and Drug Administration last September. ProQuad has about 10 times as much chickenpox virus as the standalone chickenpox shot. The consent form Jennifer Flinton signed for the ProQuad trial made no mention of that.
Merck said the trials Timothy and Jimmy participated in were unrelated; a spokesman did not respond to a question from UPI about how much chickenpox virus was in any of the shots.
Jennifer Flinton said she has a "very vague" recollection that Jimmy, like Timothy, had a temperature during his 42-day study window. "Because I was recording it every day, I did notice that it got close to 100 or at 100."
The temperature was short-lived and not alarming because a slight fever was listed as a possible side effect of the shot. But four months later, Jimmy got acutely ill.
"He was laying there with his head drooped over," she recalls, running a 102-103 temperature. The illness started on a Friday and was fading by Sunday -- physically, that is.
"He came out of it and stopped pointing, clapping, speaking, eye contact, joint attention, the whole bit -- everything that you'd write as a typical kid all went away." The abruptness of the change did not immediately register with the Flintons; they thought he might simply be slow in recovering from the physical illness.
But two months later at his 18-month checkup, she told pediatrician Dr. Carl Lindgren, who had conducted both trials, about Jimmy's loss of skills and the words he had been saying excitedly just a few months before.
"He seems to have stagnated," she told Lindgren, broaching her concern that Jimmy had developed autism. "He had emerging skills and they were gone all of a sudden."
Lindgren referred Jimmy to specialists at the Olympia School District, and by age 2 he had been diagnosed with full-syndrome autism. Jennifer said Lindgren told her after the diagnosis, "'You're probably going to hear something about vaccines being related to it.' I think he just said, 'Don't be alarmed if you hear that.'"
Lindgren referred UPI's questions about the trials to Merck. Although Jimmy's physical illness occurred well outside the 42-day study window for the ProQuad vaccine, a company spokesman told UPI it reported both Jimmy's and Timothy's autism diagnoses to the FDA in March. That was when UPI first raised the issue with Merck and the federal agency.
Merck said it alerted the FDA after the parents reported the cases; Kimberly Baltzley and Jennifer Flinton said they never contacted the company. Kimberly said Lindgren told her in September 2001 he would report Timothy's diagnosis to the study even though he did not believe there was a connection; Jennifer called the federal government's Vaccine Adverse Event Reporting System last summer and attributed Jimmy's autism to the cumulative effect of his vaccinations.
Jimmy and Timothy each have family histories of problematic reactions to chickenpox and other herpesviruses, raising concern they might have been unusually vulnerable to the high-dose chickenpox vaccines. Parents of other autistic children the same age who lived in the same Olympia neighborhood say they saw a similar pattern: problems with those viruses in their families; separate but in most cases simultaneous MMR and chickenpox shots by 15 months; and the onset of regressive autism in their children prior to 18 months of age.
Both Kimberly Baltzley and Jennifer Flinton said they do not know if the trial, the physical illnesses and the subsequent autism diagnoses are related in any way. They are concerned, though, that both cases fit with a controversial theory: because of immune interference, combination live-virus vaccines might warp the body's normal immune response, trigger persistent infection by one or more of the viruses and cause delayed but devastating damage to the child's developing brain -- namely, regressive autism.
Federal health authorities and Merck said there is no evidence of such a biological mechanism -- calling it "theoretical only" -- or any link between vaccinations and the disorder. There is no dispute, however, that vaccines can trigger physical and neurological problems.
Merck is conducting an ongoing study of fever-related seizures following ProQuad immunization, a study the FDA cited when it approved ProQuad last September.
"Merck will conduct a large-scale observational post-licensure safety study to evaluate the rate of febrile seizures in recipients of ProQuad in 25,000 subjects," the FDA's Norman W. Baylor, director of the Office of Vaccines Research and Review, wrote Merck in the approval letter.
The study was to begin in January and be completed by June 2008, the approval letter said.
"A seizure is an abnormal electrical discharge from the brain," according to the pediatric neurology Web site childbrain.com.
As Jennifer Flinton thought back over Jimmy's ProQuad clinical trial, she realized something. There had been no second blood draw to test for immunity, despite the protocol detailed on the consent form:
"At the second visit the study doctor or staff will draw a blood sample ... to determine if your child has responded to the vaccination. ... If the study vaccine works for your child, it may protect your child against developing meales, mumps, rubella, and chickenpox. On the other hand, it may not work for your child and there may be no benefit."
Jennifer recently asked the doctor about that and says she was told the study already had enough data when it came time to draw Jimmy's blood; the information was no longer needed for the clinical trial.
So along with concern the vaccine might not have been safe for Jimmy, no one knows if it worked, either.
Next: Ryan's reaction
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