On Tuesday, the Federal Government's leading immunization advisory panel unanimously approved a sweeping list of vaccine safety research recommendations for the US Department of Health and Human Services, including several that are directly or indirectly linked to the vaccine-autism debate. The endorsement, from the highly influential National Vaccine Advisory Committee, will surely intensify the argument.
Proponents of continued research into possible relationships between vaccination and a wide variety of immunological, metabolic and neurodevelopmental disorders will be cheered by many of the recommendations, while their critics will take comfort in noting that the NVAC declared that the epidemiological evidence to date assured them there is no link between vaccines and autism, at least within "the general population."
Still, major gaps in research plague our complete understanding of vaccine safety, the committee seemed to be saying. We don't really know how our current immunization schedule might affect certain susceptible populations that might be at greater risk for vaccine injury. It is plausible that some children -- for a variety of reasons -- cannot handle the one-size-fits-all vaccine schedule and its many ingredients. Those subgroups should be separated out and studied on their own, the NVAC said.
Despite its rejection of vaccines as a general cause of autism, the panel nonetheless backed two vaccine-autism related measures -- plus a lengthy list of study ideas that mirror what autism and vaccine-safety advocates have been requesting for years. Many of those advocates had direct input into the formulation of the groundbreaking document.
Call it the "democratization of science." The very idea must drive some people to fits of apoplexy, but I see it as a healthy sign of a responsive -- and responsible -- government.
As a bit of background, the CDC's Immunization Safety Office (ISO) created a 5-year research agenda for vaccine safety issues and asked the NVAC to review and critique the plan -- and to propose new measures as the panel saw fit. The NVAC in turn reached out for public comment from around the country. To their credit, panelists listened very carefully.
A Controversial Vaccinated vs. Unvaccinated Study
Without influence from autism and vaccine safety groups, it is unlikely that the august NVAC (see roster of NVAC members, including experts from CDC, HHS, academia and the pharmaceutical industry) would have unanimously endorsed first-step measures to study and compare vaccinated, unvaccinated, and "alternatively vaccinated" groups of children for a number of immunological and neurological disorders -- including autism.
The controversial idea was not part of the CDC's original research agenda. But NVAC soon discovered that, "Members of the public, stakeholders, and the Interagency Autism Coordinating Committee (or IACC, the Federal Government's central autism research body) have articulated an interest in a study of vaccinated vs. unvaccinated children to determine if there are differences in health outcomes between groups with varying exposures to vaccines."
How and whether to conduct such studies -- which would be costly, complicated and subject to ethical questions -- is a hot-button question in itself. For example, prospective clinical trials, where children would be randomized into vaccinated and placebo groups, would be patently unethical, and therefore impossible.
But public participants in the NVAC process suggested an alternative plan: An "observational study" to look at "natural variation in vaccination schedules, including some children where vaccination is declined through parental intent," the NVAC wrote. In other words, if parents decided not to vaccinate their kids on time, or at all -- even after they had been strongly urged to do so -- then it would not be unethical to enroll their children in an observational study of health outcomes.
Some autism parents and others also lobbied hard to include comparison studies of vaccines and vaccine ingredients in test-tube and animal models, (for example, vaccine-vs-placebo clinical trials on infant primates), and NVAC concurred. "Consideration should be given to broad biomedical research including laboratory studies, and animal studies," the panel wrote.
But first, NVAC wants to study the feasibility of doing such studies, at least on kids.
An "external expert committee," such as the Institute of Medicine, the NVAC said, should consider "strengths and weaknesses, ethical issues and feasibility, including timelines and cost" of various ways to study vaccinated, unvaccinated and possibly, partially vaccinated children or "children vaccinated by alternative immunization schedules."
Such studies should look at outcomes like biomarkers for immune and metabolic dysfunction (for example, autoimmunity and mitochondrial problems) plus "neurodevelopmental outcomes, allergies, asthma, immune-mediated diseases, and other developmental disabilities such as epilepsy, intellectual disability and learning disabilities," the panelists said.
Most parents I know could not agree more with that assessment. But that was not all.
"The inclusion of autism as an outcome is desired," the NVAC declared, in what can only be described as a major victory for many ASD advocates.
Finally, in yet another nod to parents, the NVAC added: "This review should be conducted expeditiously, in a transparent manner, and involving broad public and stakeholder input."
A three-day-old request for an interview with someone at NVAC is still pending. Meanwhile, James Moody, an attorney for the mercury-autism group Safe Minds, called the unanimous vote a "huge win" for parents who want more vaccine research, but said the idea deserved more than just a commitment to a feasibility study.
"All the other recommendations are to actually do particular research projects, so why is this one singled out?" he told me. "Of course, all projects must be methodologically sound and ethical, etc., but why do we need a separate study for this? I think it is just kicking the can down the road, and I made that point in public comment at the NVAC."
And there is a serious risk of delay, he said. The IOM could take up to two years to do a feasibility study, and the idea could also "easily be buried or killed at IOM."
But, Moody added, the NVAC report is "a huge admission as to a crucial gap in necessary safety science -- and furthers the ethics point that the current vaccine schedule has not been shown to be minimally safe and therefore is unethical mass population human research."
"Plus," he said, "ignorance and uncertainty are the enemies of public confidence in vaccines."
Autism is "Appropriate" to Study as Clinical Outcome of Vaccination
As part of its 5-year plan, the CDC's Immunization Safety Office proposed looking at a number of possible "clinical outcomes" following vaccination. Many autism parents and others have been urging science and the government to investigate these same potential links for years.
The advocates will be pleased to learn that NVAC concurs with them and with CDC that such clinical outcomes are "appropriate" for study. The outcomes include:
Autoimmune diseases -- which might include asthma, diabetes and some ASD symptoms.
Central nervous system demyelinating disorders -- which might include MS and acute disseminated encephalomyelitis, or ADEM, which the federal Vaccine Injury Compensation Program, or vaccine court, recently said was a precursor to ASD in one child's case.
Encephalitis -- brain swelling, often seen in ASD.
Encephalopathy -- any type of brain disease or damage.
Complications from post-vaccine fever -- such as the autism case of Hannah Poling, from vaccine court.
Also on the list of clinical outcomes to study: "Neurodevelopmental disorders, including autism spectrum disorder."
The committee chose to comment specifically -- and only -- on the clinical outcome of ASD. "The relationship between vaccine exposure and autism/ASD is an area of intense public interest," the panelists said. But they were, "assured by the many epidemiological studies that have demonstrated no association between vaccination and autism spectrum disorders in the general population."
For example, in 2004 the IOM concluded that "the evidence favors rejection of a causal relationship at the population level between MMR vaccine (or thimerosal) and ASD."
On the other hand, as the NVAC rightfully acknowledged, the IOM included a very important caveat in its 2004 report: "Further research on the possible occurrence of ASD in a small number of children subsequent to MMR vaccination is warranted."
"Importance" of Studying the Mitochondria-Vaccine-Autism Link
The NVAC said that the conclusions of the 2004 IOM report "regarding the lack of a population-level relationship between MMR and thimerosal-containing vaccines and ASD risk remain sound." But, it added, "Recent developments around mitochondrial dysfunction reinforce the importance of studies of (vaccine injury) in rigorously defined subsets of the ASD spectrum."
And though vaccination, "almost certainly does not account for the recent rise in ASD diagnoses," public concerns over vaccines, and the fact that ASD is such a common and severe disorder warrant, "additional study in well defined subpopulations."
One reason for the "important" caveat about high-risk subgroups, the NVAC wrote, was "recent case studies and research reports around the incidence of mitochondrial dysfunction in children with ASD," which have been estimated at somewhere between 7%-to-30% of all ASD children, and possibly higher among children who regressed following normal development.
In December, researchers from Cleveland Clinic, Harvard and Johns Hopkins Univeristy wrote in PLoS Online that mitochondrial dysfunction "may be present in a substantial percentage of children with ASD." And they said there "might be no difference between the inflammatory or catabolic stress of vaccinations and that of common childhood diseases, which are known precipitants of mitochondrial regression."
"Large population-based studies will be needed to identify a possible relationship of vaccination with autistic regression in persons with mitochondrial cytopathies," the authors wrote, and it looks like members of the NVAC concur.
Mitochondrial dysfunction, "carries an established risk of brain damage subsequent to infectious disease," the NVAC wrote. "Thus, a small and specific subset of the general population (such as those with mitochondrial dysfunction) may be at elevated risk of reduced neurological functioning, possibly including developing ASD, subsequent to live virus vaccination."
The NVAC added that, "the size of the subpopulation is too small for population-level epidemiological studies to have sufficient power and precision to detect such a risk factor," which is exactly with what many autism parents and researchers have been saying for quite some time.
But just how "small" is that subpopulation? Is it only 1-in-5,000, as some research suggests?
The NVAC wrote that mitochondrial dysfunction is "rare at the population level." But recent investigations have suggested that genetic susceptibilities for mitochondrial dysfunction are far more common than anyone previously realized.
In August, the United Mitochondrial Disease Foundation announced a "landmark research finding" showing that at least one-in-200 healthy humans, "harbors a pathogenic mitochondrial mutation that potentially causes disease." The finding was published in the American Journal of Human Genetics.
And another autism researcher at the Kennedy Krieger Institute in Baltimore told me that between one-in-400 to one-in-50 people may have specific nuclear DNA mutations that could also confer risk for mitochondrial dysfunction.
Vaccines and Regressive Autism Are "Of Particular Interest"
"In the context of vaccination research, the ASD clinical subset of particular interest is regressive autism" the NVAC wrote. The panelists said the regressive form of ASD was found in about 15% of all cases, though even some of the studies they cited seemed to refute this.
Last year, for example, Ambulatory Pediatrics reported that 15% of ASD children studied had lost both language and social skills. But another 41% lost either language or social skills. To the parents, at least, that meant that 56% of the ASD children had regressed in some form. As the authors of this study said, the percentage of regressive cases in ASD varies, "depending on the definition used." And, they concluded, "Requiring loss of language significantly underestimates the frequency of developmental regression."
And the PLoS Online article about mitochondrial autism stated that, of the 25 children in the chart review, 56% (14) had "regression of previously acquired skills." That rate was significantly above the roughly "one third of autistic children" who are reported to have regressed, the authors said.
The NVAC repeated the oft-quoted statement that, "the temporal occurrence of this regression and the vaccination schedule is not evidence of a causal relationship," but it added: "Regressive autism does fit the recommendations of the IOM (immunization) committee for further research in rigorously defined subsets of ASD."
Such studies might entail, "comparison of immune cytokine profiles between regressive and non-regressive ASD to screen for differential immune system profiles, or prospective vaccination response profiling in siblings of children with regressive ASD, a subpopulation who are at higher risk (somewhere between 3%-35% increased risk, depending on the study and number of siblings affected)," the NVAC wrote.
Most autism parents I know have been saying for years that their regressive ASD kids have very abnormal immune cytokine profiles.
"Worthwhile" to Study Vaccine Injuries and the Risk of Autism
Another autism subpopulation that should be included in vaccine studies is what the NVAC called "the intersection of ASD cases with (clearly defined vaccine outcomes) such as fever, febrile seizure, or hypotonic-hypo-responsive episode (HHE)."
Do these adverse effects correlate with ASD? "It would be worthwhile to assess," the NVAC wrote. "On a molecular level, it might be feasible to compare ASD cases with history of adverse events following immunization against cognitively normal controls with a similar history of adverse events, to assess whether there are significant differences in immune response profiles between groups."
The obvious place to do these analyses, it seems to me, is the Omnibus Autism Proceedings in vaccine court, where some 5,000 regressive cases are pending. And, more than 1,300 vaccine court cases were already paid out for encephalopathy and seizure disorders. We will soon learn how many of those children also have an ASD, though I can confirm now that it appears to be far, far higher than the1-in-150 rate reported by CDC.
Study At-Risk Subpopulations, Including Families With Autoimmunity and Prior Vaccine Injury
Are certain subpopulations at increased risk for vaccine injury? What are the potential biological mechanisms for those injuries? Are there certain "risk windows" in these groups, such as times when substantial neurodevelopment is occurring?"
Again, many parents and researchers have been asking these same questions for years - and now they are in official good company.
Both the CDC and the NVAC now agree that it is "important" to study vaccine injury susceptibility in "special populations," such as premature and low birth weight infants, pregnant women, adults over 65 years, people with immunodeficiency, people with autoimmune disorders, and children with "inborn errors of metabolism."
NVAC declared that "these groups are at increased risk for many adverse health outcomes" following immunization.
Autoimmunity, in particular, has been a big concern among advocates of vaccine-autism research. That's partly because children with ASD are five times more likely to come from families with a history of autoimmune disorders.
The NVAC now agrees with the CDC that autoimmunity and adverse events from vaccination "is appropriate to study in several contexts," including the "study of correlations between vaccine exposure and autoimmune disease onset, and the possibility that predisposition to autoimmune disease might indicate more global immune dysregulation and thereby increase risk of adverse events."
But NVAC went even further that the CDC agenda by recommending that children with "a well-documented family history of autoimmune disorders," be added to the list of potentially vulnerable subpopulations.
And there was more. The NVAC recommended adding other high-risk subpopulations to study for adverse events, including "children with siblings or parents who experienced an adverse event following immunization," and "children who have previously suffered an adverse event following immunization."
And, the NVAC added, results from such studies could provide, "opportunities to develop profiles that might be used to prevent AEFI by screening out children at elevated risk of AEFI.
Once again, these are many of the same things that thousands of autism parents and their supporters have been asking about for years. I imagine that most of them will be extremely grateful to the NVAC.
Study Multiple and Simultaneous Vaccination and "Alternative" Schedules
Many parents have questioned whether their child was adversely impacted by receiving too many vaccines -- either over time, or at once. This line of inquiry has earned them scorn and ridicule in some scientific circles - but not among some of the world's leading vaccine experts at the CDC and the National Vaccine Advisory Committee.
A 2002 IOM report determined that there was inadequate evidence to support or reject an association between multiple vaccinations and allergic diseases and asthma. "Since publication of that report, there are several new publications in the literature with respect to diabetes and asthma," the NVAC said.
As for simultaneous vaccination, the NVAC said the following: "Although the compatibility of candidate vaccines with routinely used vaccines is evaluated during development, the potential exists for complex interactions amongst vaccines that may not be apparent until large scale use post-licensure, such as with the use of MMRV." The quadruple-combo MMRV vaccine -- measles, mumps, rubella plus varicella (chicken pox) -- was found post-licensure to double the risk of seizures.
And, in a move sure to hearten some parents and displease some doctors -- the NVAC suggested that the CDC, "consider studies to examine more alternative immunization schedules vs. the current one."
And given the fact that parents are ALREADY deviating from the recommended schedule, this may have an unintended benefit: "to study immune system disorders and other relevant vaccine safety outcomes" due to multiple vaccination.
The same may hold true for simultaneous vaccination, the NVAC speculated, by asking: "Is there sufficient variation in the sequence in which vaccines are administered in practice to allow for an assessment of the safety of simultaneous vaccination?" Likewise, "if there is sufficient variation in the timing of vaccine administration," then CDC "should consider outcomes of interest and consider appropriate studies," the panel wrote.
Study Cumulative Exposures to Vaccine Components and Adverse Events
Many people who reject any vaccine-autism link often state that the number of antigens per vaccine has fallen substantially over time, so they could not implicated in any vaccine injury. But what about non-antigen components?
The NVAC said these were "appropriate to study" and recommended that CDC "evaluate cumulative levels of non-antigen component exposure possible through the schedule of recommended vaccinations."
"The determination of which ingredients have a higher priority for study should be based both on the intrinsic nature of the compound and potential levels of exposure," the panel wrote.
And, in another move that was in line with many parents' and scientists' wishes, the NVAC wrote:
"Risk assessment should consider other environmental exposures. Cumulative exposures should be considered when environmental exposures are comparable to vaccine ingredient exposures. For a cumulative assessment, exposures in the ambient environment should be considered, including the same substance or substances that are structurally similar and may possibly share a similar mode of action. There may also be situations where consideration of interactions between vaccine ingredients and environmental exposures is worthwhile."
This is particularly true for thimerosal. In fact, the CDC 5-Year agenda proposed studying nearly ALL non-antigen components -- except for thimerosal.
But the NVAC recommended that the study of thimerosal and adverse vaccine events should continue.
Don't Stop Looking at Thimerosal and Neurodevelopmental Disorders
Again, the NVAC said it was assured that epidemiological studies to date, "have demonstrated that thimerosal in vaccines is not associated with autism spectrum disorders in the general population."
But there have been "a few studies that have suggested that thimerosal exposure may be a risk factor for tics. First there was the 2003 CDC Verstraeten study, "in which there were inconclusive findings," the NVAC said, adding that, "This study has been criticized for its methods."
But a second study, based on the same CDC data, "with improved methods," showed statistically significant associations not only with tics, but also speech and language delays. "Protective associations" with thimerosal were detected for other neuropsychological disorders, however. And a third study in the UK also suggested a relationship between thimerosal and tics, the NVAC said.
The CDC had proposed looking at thimerosal and tics and/or Tourette syndrome (the presence of both phonic and motor tics) and the NVAC agreed that this was appropriate.
But the vaccine experts at NVAC added: "Because two of the studies above also found associations between thimerosal and speech and language delay," these were also valid outcomes to study, and should be included.
Finally, in a move that surprised thimerosal critics, the NVAC called for a reanalysis of the most recent CDC study, "Early thimerosal exposure and neuropsychological outcomes at 7 to 10 years," published in the New England Journal of Medicine.
That study found that prenatal and postnatal thimerosal exposure had no "consistent pattern of effect." Even so, the NVAC wrote that, "further evidence on whether any associations suggested are real, spurious, or artificial is needed."
The NVAC also questioned certain "methodological considerations" on data collection and analysis in the NEJM study, including the "failure to evaluate the cumulative exposure to thimerosal and methyl mercury prenatally and thimerosal after birth, and cumulative prenatal and infant exposure." Yet again, this is an issue that groups like Safe Minds have insisted should be investigated.
"The (CDC) Immunization Safety Office (should) sponsor an external and multidisciplinary reanalysis" of the study, the NVAC wrote. It also called for a reassessment of the children selected for the study, to "examine who did and did not agree to participate, in order to assess the potential for selection bias." The study had a very low response rate of just 30%.
It will be very interesting, to say the least, to see how the Obama Administration responds to this comprehensive and thoughtful list of vaccine safety issues -- including the lingering billion-dollar question about vaccines and autism in a small subgroup of children.
NOTE: A draft of the recommendations, which have been approved "with minor modifications," can be found here- The final report will be posted shortly.