When 12-month-old Jimmy Flinton joined a clinical trial of a new immunization for chickenpox, measles, mumps and rubella, no one told his family it contained about 10 times the usual dose of live-virus chickenpox vaccine.
And no one considered whether his family's unusual chickenpox history -- including adolescent shingles and herpesvirus in the eyes -- might raise the risk of adverse reactions to the vaccine.
Now that Jimmy has been diagnosed with regressive autism, they wish someone had done so.
In 2002 Jimmy's mom, Jennifer Flinton, signed a seven-page "Research Subject Consent Form -- Vaccine Study (Children)" at the office of her pediatrician in Olympia, Wash.
"Your child is invited to be in a research study," reads the form, which lists Merck & Co. of Whitehouse Station, N.J., as the sponsor. "You need to decide whether or not you want your child to be in this study. Please take your time to make your decision."
The purpose was "to test the safety of the study vaccine, ProQuad refrigerated and to show that this vaccine provides a similar level of protection as compared to another study vaccine, ProQuad frozen." Both versions contained attenuated -- substantially weakened -- live viruses designed to trick the body into developing immunity to real-live measles, mumps, rubella (German measles) and chickenpox.
Previously, those first three vaccines were combined into one shot called the MMR, made by Merck; the chickenpox vaccine came in a separate shot called Varivax, also by Merck.
ProQuad was Merck's investigational vaccine designed to put all four in one shot.
Tests already had determined ProQuad required more chickenpox virus than Varivax to produce the same level of immunity. A phenomenon called immune interference, in which viruses interact and interfere with each other in the human body, rendered the dose from the standalone vaccine insufficient.
The consent form Jennifer Flinton signed did not say anything about more chickenpox virus. It simply said ProQuad was "a combination of two licensed vaccines," the MMR and Varivax.
Merck wouldn't confirm exactly how much more chickenpox virus is in ProQuad, characterizing it only as "higher." But in 2004, a Merck scientist said the amount in ProQuad was "about a log" -- 10 times -- higher, according to minutes of a meeting at the Centers for Disease Control and Prevention.
As already reported in this series, Jimmy Flinton's family is one of several in the same Olympia neighborhood who spotted a common thread: They had unusual histories of chickenpox and other herpesviruses in their families; their child got the chickenpox and MMR shots in close temporal proximity, often at the same 12-month office visit when both are first recommended; and the child subsequently was diagnosed with regressive autism.
Jimmy is one of two children who were in small trials at age 12 months of chickenpox and MMR vaccines. Jimmy's group had 33 participants, according to the Western Institutional Review Board in Olympia, which approved the protocol.
The second child was among 68 trialing Merck "process upgrade" chickenpox shots given with the standard MMR.
The local trials were part of Merck studies of the vaccines in the United States and abroad. Spokeswoman Christine Fanelle would not address whether any other cases of autism had been reported in the broader trials, but she emphasized that neither Merck not independent experts have found a relation between vaccines and autism.
"We don't see an association," she said, citing as confirmation a 2004 report by the widely respected Institute of Medicine, part of the National Academies. That report rejected a link between autism and either the MMR vaccine or the mercury-based vaccine preservative thimerosal, and it urged that research dollars be spent on "more promising" autism research.
"There will always be some people who say vaccines cause autism despite the lack of scientific evidence," Fanelle said.
Based on their admittedly anecdotal observations, however, the Olympia parents are concerned that inherited problems handling vaccine viruses may be an overlooked risk factor for autism in some children.
Jimmy Flinton's paternal grandmother, Mary Southon, had a routine case of chickenpox in kindergarten. Fifteen years later, in 1970, she developed shingles on her right leg -- painful, blister-like pustules at nerve endings caused by reactivated chickenpox virus.
That is decidedly not routine. Shingles usually occur in older people or those with immune suppression, such as cancer patients undergoing chemotherapy.
"I was a healthy 20-year-old woman," Southon said, recalling her surprise at the outbreak. The infection lasted several weeks and left her with permanent mild circulatory weakness in her leg and edema just above the ankle.
"I remember how painful it was and how it seemed to go on for the longest time," said Southon, who lives in Olympia. She was going through a divorce at the time and suspects stress might have triggered the outbreak. She also suffered from lifelong recurrent cold sores, another herpesvirus.
Twenty years later, in 1990, Southon made a painful mistake that reminded her of that vulnerability.
"What happened was, I stuck a hard contact (lens) in my mouth, not knowing I was getting a cold sore. I put it into my eye and did it with the other contact, too.
"I developed cold sores on both corneas. That was very painful and went on for several weeks before the doctors finally figured out what it was," she said. The doctor put her on medication for shingles and the problem cleared up, though not before doing damage she says will one day require cornea transplants.
Coincidentally or not, Southon said she has not had any cold sores since she took the shingles medicine.
Her son, Paul Flinton, also had chickenpox as a child. At age 15, Paul got shingles, too -- also remarkable, doubly so given his mother's similar history. The shingles spread along his neck, primarily on the right side, up to his jaw line; he even had a spot on his forehead.
"The doctor did diagnose it as shingles and was just amazed someone that young had developed it," Southon recalled. It was also a stressful period in Paul life's, she said, but the ongoing family pattern suggests unusual, inherited susceptibility to the virus.
"It just seems there is a genetic weakness towards it, a tendency to pick up the herpesvirus and run with it," Mary Southon said. Given that, they might not have enrolled Paul son's Jimmy in the ProQuad trial if they knew it had 10 times the standard dose of chickenpox virus.
She questioned why Merck would allow a child with Jimmy's family background to test any chickenpox vaccine.
"It's heartbreaking to think this could have been prevented if they (Merck) had done a little more research or had been a little more imaginative in (considering) what could have happened," she said.
"I just think the rush to develop the vaccine is criminal. Why would they want to give babies 10 times the amount of the virus? Where is the thinking on that?"
Several vaccine researchers who remain concerned abut a possible autism link told this column they find the Olympia cluster, and Jimmy's case in particular, deeply disturbing. The children's histories fit one of the major vaccine-autism hypotheses like a surgical glove: the idea that interference among live viruses in vaccines could warp the body's natural immune response, leading to persistent infection and delayed neurological problems.
After Age of Autism outlined the cases to him last month, British gastroenterologist Dr. Andrew Wakefield -- the chief proponent of that controversial theory -- met with several of the Olympia parents. He called their stories heartbreaking and likened the experience to "staring into an abyss" of unintended vaccination consequences that he fears are not confined to Olympia.
"The key to many of the problems you see with viral vaccines is interference," he said afterward.
"The host control of a viral infection is fundamentally mediated through an adequate immune response, and that immune response has been conditioned by tens of thousands of years of evolution," said Wakefield. "And the outcome of an infection is dependent on the pattern of exposure.
"So measles is innocuous when encountered under normal circumstances of dose and age of exposure. But when it's encountered under atypical circumstances early in life, particularly at high dose, then the outcome is very different. And the problem for these viruses is persistence and delayed disease," he said.
"So if they can establish persistent infection, elude the host immune response, then they can all come back and cause delayed disease later in life."
"And herpesviruses do exactly the same thing," he added.
"What alarms me about the cavalier approach of the industry and everybody else, the regulators, to these viruses is they presume the wild infection to be nasty and the vaccines to be innocuous -- that they can manipulate something that is biologically highly intelligent and exploit it to their advantage.
"And they can't. The viruses don't behave like that and they never will. They merely come back to haunt you as something different."
Wakefield, who left Britain in the wake of the controversy generated by his theories and now is conducting research in the United States, said it is well-established that problems coping with viruses can be inherited. His theories are based on research into the MMR vaccine; Britain does not give routine chickenpox immunizations.
The Institute of Medicine's 2004 report dismissed Wakefield's concerns as speculation untethered to any scientific foundation. It said "the body of epidemiological evidence favors rejection of a causal relationship between the MMR vaccine and autism. ... The committee further finds that potential biological mechanisms for vaccine-induced autism that have been generated to date are theoretical only."
"The overwhelming evidence from several well-designed studies indicates that childhood vaccines are not associated with autism," said Dr. Marie McCormick of the Harvard School of Public Health, who chaired the IOM's immunization review committee.
"We strongly support ongoing research to discover the cause or causes of this devastating disorder. Resources would be used most effectively if they were directed toward those avenues of inquiry that offer the greatest promise for answers. Without supporting evidence, the vaccine hypothesis does not hold such promise."
The CDC, whose Advisory Committee on Immunization Practices recommends the childhood vaccination schedule that states adopt, funded the Institute of Medicine study along with the National Institutes of Health.
"Groups of experts, including the American Academy of Pediatrics, agree that MMR vaccine is not responsible for recent increases in the number of children with autism," the CDC noted.
"The existing studies that suggest a causal relationship between MMR vaccine and autism have generated media attention," the CDC said. "However, these studies have significant weaknesses and are far outweighed by the epidemiologic studies that have consistently failed to show a causal relationship between MMR vaccine and autism."
On Oct. 30, 2002, James George Flinton had his blood drawn as a baseline for the clinical trial in Olympia. At the same office visit, he got the ProQuad shot -- the refrigerated version, as it turned out.
For his participation, Jimmy's family got a $50 gift certificate, with another to come at the end of a 42-day safety follow-up period when his blood would be drawn again to see if ProQuad worked.
Last September, the Food and Drug Administration approved frozen ProQuad for children 12 months to 12 years old. Merck said it is still working on the refrigerated version.
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Next: Downward spiral
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This ongoing series of columns on the roots and rise of autism welcomes reader response. Links to all the columns are available at theageofautism.com. E-mail: [email protected]
