Vaccines and Autism: A Tale of Shifting Hypotheses

ResearchBlogging.orgA paper coming out in the next issue of the journal Clinical Infectious Diseases addresses the question of the link between vaccines and autism. This new review article examines three hypotheses linking vaccines to autism:

(1) the combination measlesâmumpsârubella vaccine causes autism by damaging the intestinal lining, which allows the entrance of encephalopathic proteins;

(2) thimerosal, an ethylmercuryâcontaining preservative in some vaccines, is toxic to the central nervous system; and

(3) the simultaneous administration of multiple vaccines overwhelms or weakens the immune system.

The MMR hypothesis was first advanced in a paper by Andrew Wakefield, in 1998. The present study suggests that Wakefield's MMR - Autism link was flawed for a number of reasons. Methodologically, the studied cohort was self selected among a large population. The MMR vaccine is given at about the same time autism is often diagnosed, exacerbating a confirmation bias effect. The MMR-Vaccine theory relies on an intestinal route for encephalopathic substances, which would be indicated by some kind of G.I. symptoms prior to the autism, but this was often not the aetiology of the disease. There are other problems with this study as well.

The paper examines other MMR-Vaccine link studies and finds them at fault as well.

The Thimerosal link hypothesis asserts that ethylmercury, an ingredient in Thimerosal, is the cause of autism. Thimerosal is an antibacterial that has been used for decades to preserve various vaccines, (not including MMR, which is a live vaccine). Although there are several reasons to not think that Thimerosal can cause autism, several studies have been conducted to test the relationship (probably not a bad idea given the importance of this problem) and all of these studies failed to link Thimerosal to autism. What is especially convincing are studies that show a complete discordance between Thimerosal use and autism.

In Sweden and Denmark, researchers found a relatively stable incidence of autism when thimerosalâcontaining vaccines were in use (1980-1990), including years when children were exposed to as much as 200 μg of ethylmercury (concentrations similar to peak US exposures) [22]. However, in 1990, a steady increase in the incidence of autism began in both countries and continued through the end of the study period in 2000, despite the removal of thimerosal from vaccines in 1992.

The third hypothesis .... that too many vaccines stress the patient and ultimately cause autism to develop ... was also found to be flawed.

Vaccines do not overwhelm the immune system. Although the infant immune system is relatively naive, it is immediately capable of generating a vast array of protective responses; even conservative estimates predict the capacity to respond to thousands of vaccines simultaneously... The immune response elicited from the vast antigen exposure of unattenuated viral replication supersedes that of even multiple, simultaneous vaccines.... Multiple vaccinations do not weaken the immune system. Vaccinated and unvaccinated children do not differ in their susceptibility to infections not prevented by vaccines ... Autism is not an immuneâmediated disease. Unlike autoimmune diseases such as multiple sclerosis, there is no evidence of immune activation or inflammatory lesions in the CNS of people with autism...

The present study is, essentially, a meta study of twenty or so other studies that in combination seem to force the conclusion that the three hypotheses mentioned at the outset do not explain an apparent increase in autism cases. The authors suggest that the apparent increase in cases is a matter of changes in reporting, although as we have seen in other studies, that is contested.

Full disclosure: One of the paper's authors is "...a coinventor and patent coholder of the rotavirus vaccine Rotateq and has served on a scientific advisory board to Merck."

Jeffrey S. Gerber, Paul A. Offit (2009). Vaccines and Autism: A Tale of Shifting Hypotheses Clinical Infectious Diseases, 48 (4), 456-461 DOI: 10.1086/596476


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A paper coming out in the next issue of the journal Clinical Infectious Diseases addresses the question of the link between vaccines and autism. This new review article examines three hypotheses linking vaccines to autism: (1) the combination measlesâmumpsârubella vaccine causes autism by damaging…
My name is Paul Offit. I'm the chief of the division of infectious diseases at the Children's Hospital of Philadelphia and my published expertise is in the area of vaccine safety and rotavirus-specific immune responses. (I'm the co-inventor of the rotavirus vaccine, RotaTeq). I've written a book…
As the hypotheses shift... It's now been about ten years since vaccines were first blamed to be the cause of autism. First, it was the MMR vaccine. The mechanism by which this vaccine was supposed to cause autism was ill conceived. Measles vaccine virus was proposed to replicate in the intestine…
The mercury militia and MMR scaremongers aren't going to like this, not one bit. What should greet my in box upon my arrival at work after a long Fourth of July weekend, but an alert of a new study of a large population of children in Canada that utterly failed to find an epidemiological link…

Still lagging the target, of course. I believe that there's been a schism in the Mercury Militia; the Old Guard (now mostly found on MHA and blog comments) still insists that it's the mercury, the mercury wasn't really removed, etc.

The New Official Version, on the other hand, is blaming unspecified "toxins," including aluminum salts and glutamate ions.

By D. C. Sessions (not verified) on 30 Jan 2009 #permalink

I think we can expect the peer reviewed lit to always lag the blogosphere. For better or worse.

I don't think that the MMR vaccine ever contained thimerosol. It's a "live vaccine" and the use of an antimicrobial agent would ruin its effectiveness.

'Course that makes the link even more dubious...

I'll take "Shifting Goalposts for $1000, Alex."

No, it was used in a lot of other vaccines, but not MMR (or live vaccines generally). (I meant to say "not including" MMR .... thanks, I'll fix that)

All 3 of those hypotheses are being presented before the Vaccine Court, the Autism Omnibus "trial', using the same expert witnesses for all 3 speculations.

All 3 of those hypotheses are being presented before the Vaccine Court, the Autism Omnibus "trial', using the same expert witnesses for all 3 speculations.

Yes and no -- several of the original cast of plaintiff witnesses have withdrawn, and the Court has refused to recognize Wakefield and the Geiers.

By D. C. Sessions (not verified) on 30 Jan 2009 #permalink

I think that vaccines are target for anxious parents because if there is some more amorphous cause, for example something environmental, that is not only more complicated to discover but would require more of public and political will to resolve, ie clean-up and change of lifestyle re pollutants. Even though there have been a number of studies to disprove a link between autism and vaccines people continue to believe it. The problem is those people piggy-back on the families who do vaccinate children, keeping incidence of infectious childhood disease low. But those diseases do have mortality and risks of complications if they become more prevalent.

What of the following is worse? Not being able to have children, having cancer, having alterations to your DNA, or getting a vaccine?

Ding ding ding....getting a vaccine!!

For shame Dr. Laden, are you trying to drive up your hit counts? :^P

Yeah Dawn, all those vaccines I received in the military (24? I remember the g/d plague and cholera ones were given every 6 months, typhoid was a yearly dosage, and typhus, polio, MMR, DPT, were administered as well. Yellow fever was given on 10 year intervals.) endangered me as much as the bombs that were set off in front of the HQ building.

Seriously, every military member is pumped so full of goodies that they should all be dead if the Mercury Militia was right just one percent of the time. Then again, the problem in dealing with the stupid is that they are ignorant of their condition and so are unwilling to correct it.

By Onkel Bob (not verified) on 31 Jan 2009 #permalink

Greg's and Dawn's respective methods of arguing their claims differ in subtle ways. Can anyone spot them?

Dawn is an ignorant paranoid and Greg is a brilliant logician?

By Elizabeth (not verified) on 31 Jan 2009 #permalink

When I first read Dawn's blogs URL I thought it said "Vaccine Sex Posed". Now that would be a much more interesting thing to write about...

Hi Greg Laden -

"Unlike autoimmune diseases such as multiple sclerosis, there is no evidence of immune activation or inflammatory lesions in the CNS of people with autism."

Unfortunately for Mr. Offit's credibility, when you use five year old science in the area of autism, you are going to get some things wrong. His source for this particular quote is the 2004 IOM paper regarding vaccination and autism. The lack of an observations regarding immune activation in autism is referenced several times in the IOM report.

Here is something from the IOM paper on page 131:

Although a number of studies have suggested immune dysregulation in autism, there is as yet no evidence that these findings are directly related to the pathogenesis of autism. Unlike what is known about neuroimmunological disorders that affect the brain, such as multiple sclerosis and acute disseminated encephalomyelitis, there is no evidence of immune activation or an inflammatory process within the autistic brain. Neuropathological studies of autism have revealed no evidence of cerebral inflammatory lesions or microglial activation, which is a common feature in immune-mediated encephalitis (Bauman and Kemper, 1997). However, there are very few autopsy studies of brains from people with autism and this has not been fully investigated. Analysis of CSF from young children with autism, including screening for sensitive inflammatory markers such as quinolinic acid and neopterin, has also found no evidence of inflammation (Comi et al., 1999). The sample size in these studies is small, however.

So, it would seem, in 2004 anyways, that we hadn't really looked all for immune activation in the brains of children with autism very much. Strange that this little tidbit didn't make it into Mr. Offit's analysis. If I hadn't gone out to the IOM report myself, and read parts of it, I'd never have known that such strong qualifiers were in place regarding our knowledge of immune activation in the brains of children with autism. I wonder why Mr. Offit didn't acknowledge that our information set was incomplete, and in fact, seemed to be based on studies from 1999 or 1997? [Although, looking at some of the dates on his other references might explain that somewhat.]

But anyways, what a difference five years makes! It just so happens, anyone paying attention to the findings in autism research over the past five years will find that, in fact, we have lots of evidence that we didn't have in 2004.

For example, in 2005, Vargas reported chronically activated microglia and immune activation in the brains of people with autism in "Neuroglial activation and neuroinflammation in the brain of patients with autism" Fancy that, evidence of exactly what the IOM defines as "a common feature in immune-mediated encephalitis " in autism! It reported highly increased levels of pro-inflammatory cytokines like tnf-alpha, IL-6, and MCP-1; as well as chronically activated microglia.

In 2007, Chez reported highly increased levels of tnf-alpha in the CSF of children with autism, "Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children". And so again, long after the IOM report we have evidence of immune activation in the CNS of children with autism. How strange that these studies seem to have escaped Mr. Offit's keen eye.

In 2009, it happened again. Li reported that children with autism had a highly pro-inflammatory cytokine set in their brains when compared to normal children. "Elevated immune response in the brain of autistic patients."

If I didn't know any better; I'd think that either Mr. Offit either hasn't been paying attention to autism science, or is intentionally giving us a highly selective view of our availbable information in such a way that benifits his case.

Since 2004, we also have at least three studies that directly correlate abberant circulating values of immune system modulators with autism severity. For example, you might take a look at "Decreased transforming growth factor beta1 in autism: a potential link between immune dysregulation and impairment in clinical behavioral outcomes.", "Macrophage migration inhibitory factor and autism spectrum disorders", and "Serum levels of P-selectin in men with high-functioning autism.". There are many, many other studies of abberant values, but these are the ones I know of with correlations to severity.

Mr. Offit goes on to say: "In fact, current data suggest that genetic variation in neuronal circuitry that affects synaptic development might in part account for autistic behavior" In fact, he is correct. But that by no means exhonerates immune system dysfunction.

Over the past two years, several papers have come out regarding the association of a downregulated allele to the MET gene and interactions with HGF, with functions in synapse formation, immune system functioning, and gastro intestinal repair. In 2006, "Dynamic Gene and Protein Expression Patterns of the Autism-Associated Met Receptor Tyrosine Kinase in the Developing Mouse Forebrain" was published.

"Met protein appears to be principally located in axon tracts. Temporally, peak expression of transcript and protein occurs during the second postnatal week. This period is characterized by extensive neurite outgrowth and synaptogenesis, supporting a role for the receptor in these processes. Collectively, these data suggest that Met signaling may be necessary for the appropriate wiring of forebrain circuits, with particular relevance to the social and emotional dimensions of behavior."

The singalling factor critical towards MET interactions, HGF, is particularly interferred with by TNF-alpha (Sugano 2008). It just so happens, children with autism have been shown to create more tnf-alpha than their undiagnosed peers in response to a vareity of stimulants, including LPS, common environmental pollutants, and some boogeyman dietary proteins that some folks are keeping out of their childrens diets. (Ashwood 2008, Jyonouchi 2005, Jyonouchi 2002). So, take a set of children known to produce tnf-alpha at exaggerated rates, and induce immune responses right after birth, a time that is characterized by "extensive neurite outgrowth and synaptogenesis" by a set of operations known to be hindered by tnf-alpha. Great stuff.

The reason we shouldn't worry about any of this? A 2004 IOM report that (when read) acknowledges a dearth of underlying evaluations, and a series of studies about thimerosal or the MMR. As scientists, I would think that when you get more information, you might consider a new hypothesis, but that would disqualify that catchy title of the 'paper'. Tough call.

- pD

By passionlessDrone (not verified) on 12 Mar 2009 #permalink

Drone, what do you think is provoking the neuroinflammation in these cases of autism?

Hi Dillon -

It seems likely that there are many different mechanisms by which this can be happening from case to case; and indeed, it is probable there are many contributory factors in any individual child. Detangling the mess is a daunting task; assuming we even want to start looking.

We do have some evidence, however, that early life insults, even transient ones, are capable of causing changes that last into adulthood and include physiological characteristics of autism, such as chronically activated microglia as found by the 2005 Vargas paper.

For example, the same group, in 2007 published, "Neuroinflammation and behavioral abnormalities after neonatal terbutaline treatment in rats: implications for autism." Using an agent that has been found to increase rates of autism in twins, an animal model was used and they discovered that administration of terbutaline during very specific postnatal timeframes was sufficient to cause the same physiological changes (i.e., activated microglia), as well as 'behavioral abnormalities', in so much as you can tell if a rat has autism. But the key was, if you gave the rats the agent postnatal day 2 - 5, you observed changes. If you gave the agent on postnatal day 11 - 14, you didn't observe any changes. In this case, the poison was not in the dose.

Startlingly, we have similar evidence of long term, synaptic change by invocation of an immune response, but again, only if it happens during critical windows of development. Here is a neat study: Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats

Here is a snipet from the discussion section, with my emphasis:

The most exciting finding of the present study is that a mild inflammatory response evoked by LPS during a critical period of development causes a long-lasting increase in hippocampal excitability in vitro, and enhanced seizure susceptibility to the convulsants LI-PILO, KA, and PTZ in vivo. The latter effect was observed over a range of mildly inflammatory doses of LPS and was only evident if administered during the second postnatal week (P7 and P14), and not before (P1) or after (P20) this time. Importantly, inactivation of the proinflammatory cytokine TNF with an intracerebroventricular TNF antibody blocked the long-term changes to seizure susceptibility induced by LPS, whereas intracerebroventricular administration of rrTNF alone mimicked the effect of LPS on seizure susceptibility. These novel results indicate that a single transient inflammatory episode during development can modify the brain through a TNF-dependant mechanism, making it more susceptible to generate seizures in adulthood.

A tnf-alpha dependent mechanism by which having an immune response, a fake one, causes the animals to be more succeptible to seizures for forever. Administration of tnf-alpha antibodies prevents changes. Remember that our particular cohort of children has been found to create tnf-alpha at exaggerated rates compared to their non diagnosed peers, in response to LPS, dietary proteins, and environmental pollutants (Jyonouchi 2002, Jyonouchi 2005, Ashwood 2008). Children with autism have also been found to grow into adulthood with with epilepsy at rates between 20 - 40% and have abnormal EEGS without clinical seizures at rates approaching 60% (Chez 2007).

Winding back to neuroinflammation, we find that having early life seizures results in increased microglial activation, and unsurprizingly, increased succeptibility to seizures into adulthood. Glial activation links early-life seizures and long-term neurologic dysfunction: evidence using a small molecule inhibitor of proinflammatory cytokine upregulation. Note again, in this case, these effects could be ameliorated by inhibition of the inflammatory immune response; a regulatory mechanism we know to be highly abberant in children with autism.

It isn't all about the early life, though. We also have evidence that peripheral inflammation can cause changes to brain chemistry consistent with higher levels of inflammation through some still poorly understood interactions between the immune system and the brain. Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. Here we see that animals with induced liver inflammation showed increased levels of MCP-1 in the brain; one of the differences found in the 2005 Vargas study. And again, these changes were blocked when tnf-alpha was inhibited; something children with autism produce in spades compared to children without autism.

Theres plenty more, but this ought to get you started.

What we should be able to take from all of this is that the immune response is what is critical towards a veritable spectrum of outcomes that have been associated with autism. That doesn't mean that vaccines cause autism; but the fact is, we just haven't performed any analysis, at all, as to the result of invoking our immune system at earlier and earlier ages on our children. I suppose each person much use their discretion to determine if any hypothesis should be changed or not.

- pD

By passionlessDrone (not verified) on 14 Mar 2009 #permalink

Thank you for the response. It seems that the earlier the "insult", the greater the possible consequences. Presumably intrauterine stimuli can provoke these also, but perhaps the fetus/infant has to have an immune system that is mature enough to react, but not too developed to cope (making the early neonatal period the critical time).
Presumably a variety of triggers/stimuli could help induce these changes (if they are indeed a significant factor).

There is nothing unique about vaccines that cause immune system stimulation. There is nothing "immature" about the immune system response that produces these effects.

The intrauterine responses are due to maternal immune system stimulation, not due to immune system stimulation of the fetus. The fetus remains isolated from the maternal immune system by the placenta.

PD is incorrect in stating that there has been no analysis of what happens when the immune system is stimulated earlier and earlier. These effects have been studied. The effects of vaccines are small compared to the normal exposure to bacteria, molds and viruses that starts even before birth, as the fetus passed through the birth canal and all number of vaginal flora are ground into its skin. If the infant didn't mount an immune system response to those bacteria, it would be dead in a few days.

I am an attorney in the early stages of preparing a lawsuit on this issue.

I would like to speak with some of the people who posted in this thread. I am looking at toddlers who developed autism right after being given all three "stages" of vaccines at once because they were behind the usual vaccine "schedule".

Does anyone know of any studies that more directly speak to this situation?

Please contact me at