Vaccine injury and compensation

The comment thread for my post last week about how philosophical vaccine exemptions in California are endangering herd immunity is rapidly approaching 500 comments as I write this and may well surpass that number by the time this post “goes live” in the morning. I mention this because buried in the comment thread are a number of comments by our old “friend,” that anti-vaccine-sympathetic pediatrician to the stars, Dr. Jay Gordon doing what Dr. Jay does best and basically making a fool of himself on matters of vaccine science through his preference for anecdote over sound epidemiology and clinical trials, his utter insistence that his 30 years of clinical experience trump the aforementioned sound epidemiology and clinical trials (hint to Dr. Jay: they don’t), and going about his usual job of insisting that vaccines cause autism and that, despite his extreme distrust of vaccines, his advocacy of not vaccinating for some common childhood diseases because he imagines the vaccines to be more dangerous than th disease, and his consorting with leaders of the anti-vaccine movement like Jenny McCarthy, he really and truly is “not anti-vaccine.”

His denials fool no one, least of all me.

The reason I bring up Dr. Jay is because, round about comment #389 in the seemingly endless thread, Dr. Jay wrote:

Just tweeted: AND today’s brand new judicial decision must not be exaggerated to the detriment of calm discussion either: http://bit.ly/9kZFhm

Correlation does not prove causation even if I agree with this individual MMR decision. I just think that side-effect-denialists need to calm down, too.

I’ll give Dr. Jay credit for “talking the talk” when it comes to giving lip service to the mantra of “correlation does not necessarily equal causation,” but unfortunately he never seems to be able to “walk the walk” and stop asserting baldly that “vaccines cause autism” or likening vaccine manufacturers to tobacco companies. Leaving aside for the moment my intense desire, barely held in check, to mock Dr. Jay for his transparent and laughably inappropriate attempt to hijack the term “denialist” for the side of pseudoscience, an attempt so hilariously inapt that I really did laugh when I read it, it turns out that over the last couple of days Dr. Jay is not alone in seemingly wanting to rub my nose in this particular decision, which was reported in the U.K.’s The Daily Mail over the weekend. Basically, it is the story of a young man named Robert Fletcher in the U.K. who is severely disabled and has been awarded £90,000 in compensation by the governement’s Vaccine Damage Payment Unit for having been injured by the MMR vaccine back in the early 1990s.

Before I discuss the case in more detail, I’m going to say something that may surprise some who read here. I don’t have much a problem with this ruling. Not really. In fact, the main problem I have with this ruling is not that it was made, but rather that it took so damned long to make it and the payout was paltry. You see, Dr. Jay is laying down what I like to refer to as a steamy, drippy turd of an argument when he claims that there is a such thing as a “vaccine injury denialist.” None of us who make it our business to refute the pseudoscience claiming that vaccines cause autism deny that vaccines can on occasion cause actual injury. Rather, what we argue, based on good science and strong clinical trials data, is that such injuries are rare and that they do not include among them autism, asthma, and the veritable panoply of various conditions that anti-vaccine zealots claim to be due to “vaccine injury.”

Not that science has any persuasive effect on anti-vaccine zealots and their fellow travellers (like Dr. Jay), who would have you believe that being vaccinated is extremely dangerous and that it causes all sorts of problems, the worst of which is autism. As I’ve discussed on this blog hundreds of times over the last five years, sometimes in utterly nauseating (to some) detail, neither vaccines nor their various components, have been linked to autism. They just haven’t, and it’s not as though a link hasn’t been sought by real scientists and physicians in multiple large epidemiological studies over the last dozen years. Researchers have looked for such a link and haven’t found it. More than a decade later, there is still no credible scientific or clinical evidence (and Wakefield’s or Hewitson’s execrable “science” doesn’t count) that vaccines cause or are correlated with autism and a lot of credible evidence that they are not, Dr. Jay’s confident pontifications notwithstanding.

However, there can be (and are) vaccine reactions. No one is denying that. And because vaccination is in essence a social pact, in which by vaccinating we all take an infinitesimally small risk for a very large benefit, when a child suffers an adverse reaction there should be compensation. Indeed, that’s just what we have here in the U.S. with the Vaccine Court, which I’ve written about many times before. As I’ve pointed out (for example, here), because of rising litigation that jeopardized the vaccine program and threatened to drive pharmaceutical companies out of the vaccine business, Congress passed the National Childhood Vaccine Injury Act of 1986 (Public Law 99-660), which created the National Vaccine Injury Compensation Program (VICP). The idea was to create an alternative to the tort system through which people injured by vaccines could be quickly compensated through what is in essence a no-fault system. True, litigants claiming vaccine injury, if denied compensation by the Vaccine Court, can still sue in conventional courts, but all claims for compensation for vaccine injury in the U.S. must first go through the VICP and the Vaccine Court. In addition, the standards of evidence in the Vaccine Court of the VICP are arguably lower than what would be required to obtain compensation through conventional federal courts. For example, in the Vaccine Court the Daubert rules for the admission of scientific testimony from expert witnesses do not apply. Virtually all scientific testimony is allowed, which is, by the way, how such awful testimony was allowed in the Autism Omnibus test cases on behalf of the complainants.

Further streamlining of the system occurred in 2005, when the United States Court of Appeals for the Federal Circuit ruled that an award should be granted if a petitioner either establishes that a “Table Injury” of injuries that are generally accepted as potentially being caused by vaccines) occurred or proves “causation in fact” by proving the following three prongs:

  • a medical hypothesis causally connecting the vaccination and the injury;
  • a logical sequence of cause and effect showing that the vaccination was the reason for the injury; and
  • a showing of a proximate temporal relationship between vaccination and injury.

Compensation is virtually automatic for so-called “table injuries” (i.e., known injuries that science attributed to vaccines listed on the Vaccine Injury Table) within the correct time frame. Also, compensation can be awarded if plaintiffs can meet a standard of evidence showing a 51% or greater chance that the plaintiff was injured by the vaccine in question. Indeed, as one lawyer who represents cases in front of the vaccine court put it:

“There is a difference between scientific proof and legal proof,” Conway said. “One is 95 percent certainty, and the other is . . . 50 percent and a feather.”

In other words, the award of compensation does not mean that a scientific link was found, only that a court of law thinks it more likely than not that a specific set of health problems is due to vaccine injury, no more, no less. A legal finding of causation does not necessarily imply a scientific finding of causation, no matter how much anti-vaccine activists trumpet rulings compensating children for vaccine injury as vindication of their pseudoscientific views that vaccines cause autism. Indeed, this ruling doesn’t even “prove” that MMR can cause brain damage, a contentious scientific question whose answer is not at all clear.

Finally, the VICP will reimburse plaintiffs for legal fees and court costs even if they lose in Vaccine Court. Indeed, certain unscrupulous lawyers (cough, cough, Clifford Shoemaker) have taken advantage of this feature of the Vaccine Court and racked up some very impressive billings representing complainants in front of the Vaccine Court. In other words, here in the U.S. at least, as little as the anti-vaccine movement believes it and would prefer to believe a conspiracy theorist view in which they are the downtrodden speakers of truth to power beaten down by The Man, the entire system bends over backwards to give complainants the benefit of the doubt. That the complainants for the test cases for the Autism Omnibus could not prevail, even in the relatively friendly venue of the Vaccine Court, should be evidence enough of just how weak their cases were, particularly given that the test cases were presumably the strongest cases the Omnibus lawyers could come up with. That point was driven home recently when the appeal for the first test case, that of a child named Michelle Cedillo, to the Federal Circuit Court, was denied, a ruling that was not unexpected and in which I take no pleasure but that was completely appropriate.

Now back to Robert Fletcher’s unfortunate case. As his mother told The Daily Mail:

Robert is nearly 19 but mentally he is like a 14-month-old toddler. He can’t stand unaided and he is doubly incontinent.

‘He can’t speak except to say “Hi, Mum” or “Hi, Daddy”.

‘We chop up his food and have to anticipate all his needs. He is prone to various illnesses and last week suffered around 40 severe epileptic seizures.

‘In April this year, we thought we’d lost him. He contracted a chest infection and had to go to hospital for several days.

‘He is such a lovely boy. When he’s not ill, he’s so cheerful and seems to take everything on the chin. In between seizures he says “Hi, Mum” and tries to kiss me.

My heart goes out to the Fletchers; it must be incredibly trying to have to deal with such a set of disabilities day in and day out. Moreover, I have no problem with the government finding legal causation. It’s almost irrelevant if on a strictly scientific basis the MMR vaccine caused Robert’s condition. There’s enough of an appearance that it did that, on a legal grounds and a societal basis, he should be given the benefit of the doubt and compensated. In fact, I agree with Mike Stanton that compensation took far too long and that the amount awarded was far too little. Mike makes a rather fascinating comparison between the U.K.’s vaccine compensation system and that of the U.S. The results are not favorable to the U.K.:

Again, the contrast with the USA could not be greater. Statistics about vaccine claims, verdicts and compensation paid are readily available on government websites. The UK government admitted to paying £3.5 million in compensation over the previous 8 years in 2005. The USA has paid out nearly $2 billion to 2,472 claimants over the past 21 years. They meet the legal costs of all claims whether upheld or not. The American Way seems to be to admit that vaccine injuries are a rare but unfortunate occurrence and to make the no fault compensation programme as transparent and user friendly as possible. By contrast the UK government is secretive, mean spirited and places obstacles in the path of potential claimants in a misguided attempt to bolster the vaccination programme. But insisting that vaccines are safe rather than being honest about the risks and benefits has not led to greater vaccine take up. On the contrary, whenever the government dismisses people’s fears instead of taking them seriously its “we know best” attitude merely reinforces people’s doubts.

Of course, the cost of the American system is widespread abuse by certain lawyers, who know they’ll be paid, win or lose. To me that is an acceptable price to pay to make the compensation system fair and relatively fast. True, some lawyers are not satistified because they can’t ever expect the truly large “lottery jackpot”-sort of pay-off from a Vaccine Court ruling. That’s the reason why some of them are arguing that the pre-emption of regular courts in vaccine cases by the Vaccine Court is unconstitutional.

Mike also makes a rather provocative observation that, had Jackie Fletcher been compensated in a timely fashion back in the 1990s, perhaps Andrew Wakefield would not have found such fertile ground for his anti-vaccine pseudoscience. Remember, Jackie Fletcher is the woman who formed JABS, which is in essence the British version of the NVIC or Generation Rescue. Whether this is true or not is, of course, impossible to say. Alternate history scenarios are fun to argue but impossible to prove one way or the other. It does, however, appear undeniable to me that the British system is neither fair nor transparent, and that can’t help but decrease confidence in the vaccination system, regardless of how safe vaccines are. After all, only 100% safety, which is unachievable for any intervention, would guarantee that there will not be the occasional child who suffers an injury due to vaccination. Like both Mike Stanton and Kev Leitch, I believe that such children deserve prompt, fair compensation.

Predictably, the anti-vaccine movement is crowing over this ruling, citing it as vindication. The anti-vaccine crank propaganda blog Age of Autism, for instance, has two stories up already, one entitled UK Vaccine Injury Win: MMR Caused Brain Damage and Vaccine Injury: The Fletchers and Cedillos – a Tale of Two Families. In one of these posts, Teresa Conrick struggles mightily to try to argue that, really and truly, the Fletcher decision means that vaccines cause autism after all:

Jacki and John Fletcher are warrior parents who have persevered in their care and legal case for Robert, now 18 years old. Jackie, in a recent email to Anne Dachel, here at Age of Autism, revealed that Robert suffers from a severe seizure disorder, with an inflamed oesophagus, brain damage and has some minor autistic traits. The award stressed epilepsy as the result of his injury. That is great news but for the thousands still waiting with children and teens also injured by the MMR, the lack of the word, “autism”, is baffling. Welcome UK parents, to our world, too. Here in the states, we also have heard those words, “but not autism.”

Whether it is severe autism or minor autism, isn’t “autism” a set of behaviors?

Uh, no. Nice try, though.

Of course, Autism is more than just a “set of behaviors,” but even if autism were nothing more than a set of behaviors I would retort that, for example, ADHD is a “set of behaviors” too, but that does not mean ADHD is the same thing as autism. Ditto any number of neurodevelopmental disorders. Claiming that the rare neurologic injuries that can be caused by vaccines are “the same thing” as autism based on such an argument is specious reasoning at best, disingenuous at worst. Still, such posts are revealing. Age of Autism claims that it is all about “autism advocacy,” but in the end its merry band of propagandists are all about the vaccines, and so are its readers. They are anti-vaccine to the core. To them, autism is “vaccine injury,” and that’s it. No amount of science will convince them otherwise.

Injuries and complications that can be scientifically shown to be due to vaccines deserve compensation that is prompt, fair, and not onerous to obtain, even at the cost of letting sleazy lawyers take advantage of the system. Meanwhile, scientists should (and, the pharma conspiracy mongering of the anti-vaccine movement notwithstanding, do) work to make vaccines as safe as possible, so that such injuries are as rare as possible. Unfortunately, there will likely never be such a thing as a vaccine that is 100% absolutely safe; all that can be reasonably requested are vaccines whose benefits and safety far exceed a tiny risk of complications and a system that compensates those injuries. Although the ethical issue of how much risk is acceptable and what frequency of vaccine injuries are tolerable in the vaccination program is complex and difficult, we should not lose site of the fact that vaccines do far more than good.

Comments

  1. #1 Dangerous Bacon
    September 3, 2010

    I think the problem with pD’s “voluminous” list of citations is that while they show varying evidence of a correlation between autoimmune dysfunction/disorders and autism, they are ineffectual in demonstrating that autoimmune problems cause autism, much less that vaccines interact with autoimmunity to do so.

    There’s nothing terribly wrong with Jay’s “math”; his odds numbers are carefully tailored to suggest that vaccines cause some or all of autism cases. Rather, the problem is that he pulled those numbers out of his nether region* without evidence to substantiate them.

    I’d also like to see Jay answer Todd W.’s questions, as well as tell us if his DTaP “series” follows the AAP/CDC guidelines for 5 doses, or whether (and why) he thinks fewer shots suffice for protection.

    *this is also the source of his recommended staggered/reduced/no vaccine schedule and many other pronouncements. It’s a prolific generator of Jay-wisdom.

  2. #2 augustine
    September 3, 2010

    [Pablo: For example, if the overall autism rate is 1 in 150, and vaccinated kids have a rate of 1 in 200, then that would require that vaccination actually prevents autism (because the majority of kids are vaccinated). ]

    Have you lost all sense of logic? That is how pharma scientist’s think though so I’m not surprised.

    Btw I would love to see that study on unvaccinated (zero vaccines) kids. Do you have a reference?

  3. #3 Kristen
    September 3, 2010

    I can’t help but comment on Dr. Jay’s behavior on this thread. In previous threads (I have been reading RI for about 15 months) he has seemed stuck in his beliefs, but at least somewhat respectful of most of the other commentators.

    Now he has reduced himself to insults and sarcasm. Accusations and veiled threats. If he were my children’s pediatrician I would be appalled. I can’t even imagine our (wonderful) pediatrician stooping to such levels.

    He has been in practice for almost as long as Dr. Jay but he is reasonable and takes time to keep educated, he noticed my son’s autism long before I did, but never tried to diagnose him. He gave me the name of a good (the only one in central Virginia at the time) developmental pediatrician and said I should set up an interview (they both wear cool bow-ties).

    He never once has given me advice on Gabriel’s autism, he has left that to the expert. Dr. Jay is arrogant, he is not qualified to do what he is doing. Being a pediatrician does not automatically make him an expert on neurodevelopmental disorders. He is also not an immunologist IIRC.

    It seems to me, a good doctor knows when he is outside his skill-set and will refer a patient to the proper expert.

    If I discovered my children’s doctor acting in such an asinine mannor, I would find another. Truthfully I would probably find another practice all together.

    BTW, why don’t the regular trolls learn HTML, it is easy and makes one so much easier to understand (at least learn to blockquote-follow the link). If you can copy-paste and use the shift key, you can do HTML tags.

  4. #4 K0ilar
    September 3, 2010

    well, I still see a problem with the math, but another question comes to my mind: What does he mean by 1:100-200?
    a) for every vaccination the probability for each kid to develop an ASD is that high?
    b) 1 in 100-200 kids is pre disposed to ASD if ever vaccinated?

    a) can obviously not be true, seeing how many vaccinations the average kid gets (after 5 vaccs you would get 5:100 or 1:25 kids with ASD), and if b) was true than you could give the non-predisposed kids any number of vaccs…

    Of course nothing is ever this simple, but still I’d like to see dr Jay pull another explanation out of his “nether region” (Dangerous Bacon is so much better at prose than me…).

  5. #5 passionlessDrone
    September 3, 2010

    Hi Dangerous Bacon –

    I think the problem with pD’s “voluminous” list of citations is that while they show varying evidence of a correlation between autoimmune dysfunction/disorders and autism, they are ineffectual in demonstrating that autoimmune problems cause autism, much less that vaccines interact with autoimmunity to do so.

    A statement was made that is in startling contrast to the literature:

    What’s your evidence for the proposition, or for that matter that there’s any link at all between autoimmunity and autism?

    This is a forum where statements so wildly at odds with the available evidence are usually shown to be fallacious with great glee and, indeed, insolence; at least when expedient to a particular point.

    The causal link between autism and observed autoimmune dysfunction is difficult to detangle, but that is no reason that we should let obviously unsupportable assertions to lay uncontested simply because they fit the over riding meme of the environment.

    – pD

  6. #6 Scott
    September 3, 2010

    pD,

    You need to learn some basic English. Asking for the evidence supporting a claim is a different thing from claiming that there IS no evidence. It cannot, in any way, be in ANY contrast to ANY body of literature or evidence. There is NO assertion there!

    In other words, you’re an idiot who can’t read. But we already knew that.

  7. #7 Calli Arcale
    September 3, 2010

    Dr Gordon:

    @Calli The diseases are very rare. New treatment modalities make discussions of mortality and morbidity rates from the thirties, forties, fifties pointless.

    It is true that the diseases are now rare, but you’ll note that I was not talking about mortality and morbidity rates from the thirties, forties, and fifties. I was talking about what they would be now if herd immunity declined. You seemed to be arguing that current technology for saving lives (and you specifically mentioned ventilators) meant that these diseases need not be feared. Perhaps a child would have died in the 1930s, but today, that same child might survive thanks to a ventilator.

    That’s what you were arguing. You were arguing that people who do contract measles etc. don’t die in such high percentages nowadays. And that’s true. Our ability to keep people alive at the brink of death is vastly greater today than it was then. But it is either callous or extremely ignorant of you to disregard the price that is paid, both the obvious financial cost and, more importantly, in the pain and suffering endured by the patient.

    A dear relative passed away a couple of years ago. She was on a ventilator for her last month. She stuck it out, but hated it; the tracheotomy they finally did came as a huge relief, because she loathed having that thing down her throat, but it rendered her mute, and she was always a talkative lady. Vivacious, loquacious, and an amazingly determined person. When all avenues had been exhausted and it became clear she’d live out her days, possibly for months or years, on a ventilator in a nursing home (as she had not regained the ability to breathe on her own), she made the decision to turn the ventilator off. She was willing to put up with it if it meant she could get better, but once she knew she wasn’t going to get any better, she preferred death.

    It’s great that kids with severe respiratory infections due to vaccine-preventable disease won’t necessarily die. But the price paid is very high, and you should not casually dismiss that.

    I hope you remember that the first time you have a patient hospitalized and put on a vent. I can only assume it has not happened to any of your patients yet. Note that it isn’t just vaccine-preventable diseases that can leave a child needing a vent. My brother’s condition was purely mechanical, and I have a friend whose daughter was comatose after a terrible injury due to severe weather; could have been any child, really. You take it too lightly, if you think being able to be saved by a vent is a reason to be more casual about vaccination. If you need a vent, you are in imminent danger of dying; this is not something to idly dismiss, as you have.

  8. #8 Science Mom
    September 3, 2010

    In other words, you’re an idiot who can’t read. But we already knew that.

  9. #9 Scott
    September 3, 2010

    Yes, it’s harsh. Deliberately so. Because that sort of deliberate gross misrepresentation is truly despicable and deserves nothing less.

  10. #10 Pablo
    September 3, 2010

    Yes, it’s harsh. Deliberately so. Because that sort of deliberate gross misrepresentation is truly despicable and deserves nothing less.

    Interesting. That’s how I feel about Jay Gordon…

  11. #11 passionlessDrone
    September 3, 2010

    Hi Mathew Cline –

    I don’t want to be seen as taking Dr. Gordon’s position(s) per se, but I had a few thoughts about your analysis that you might consider.

    If an attenuated virus vaccine posed a greater risk of causing autism than a innactivated virus vaccine, then wouldn’t the infection by the wild type virus pose an even greater risk? But if full blown infections could cause autism, wouldn’t reducing the rate of the full blown wild type diseases via vaccines have reduced autism rates? Unless there’s some weird thing about attenuated viruses that make them more likely to cause autism…

    I think a complete analysis would also need to take time dependent effects into consideration; i.e., having a robust immune response at two months of age may lead to different trajectories than a year, or four years of age. Obviously vaccination is given early in life for protective reasons, but in the past, lots of kids never got the measles, or any of our vaccine preventable diseases until they were much, much older. In complicated systems, we ignore factors such as time of insult and associated developmental status at great risk.

    The antigenic challenge from a vaccine isn’t going to be any larger than that from a baby catching a cold.

    I do not believe that you could validate this with any studies, though I would be genuinely interested in reading any links you could post to support this assertion.

    The bigger problem to my mind, is that the notion of simply counting antigens is a gross over simplification. I can think of four big reasons why our vaccine schedule does not lend itself well to a model of antigen counting.

    1) Antigens aren’t the only thing in vaccines; we also have aluminum salts designed to insure a robust immune response is generated. Because of this, simply counting the number of antigens in a vaccine may not necessarily be a meaningful metric for understanding the strength of the immune challenge. Again, I’d be happy to see a link, if possible, that details, for example, cytokine generation from a pediatric vaccine compared to a similar sickness. [tough one to do ethically]. For that matter, however, I’d love to see any study on a pediatric vaccine that detailed the level of the immune response in a metric other than antibody generation. Do you know of any?

    2) Our vaccination schedule, as you are aware, confers protection from several different pathogen types during a single visit; i.e., you get vaccinated against many types of bacteria and viruses simultaneously. We have evidence that when your immune system detects multiple types of pathogens at the same time, the resultant immune response is synergistically increased.

    For examples of the synergistic response of the immune system to multiple pathogen types, you might evaluate,

    Toll-like receptor (TLR)2 and TLR3 synergy and cross-inhibition in murine myeloid dendritic cells [PMID: 18166232]

    Release of IL-12 by dendritic cells activated by TLR ligation is dependent on MyD88 signaling, whereas TRIF signaling is indispensable for TLR synergy [PMID: 20360404]

    Cooperation between MyD88 and TRIF pathways in TLR synergy via IRF5 activation [PMID: 17275788]

    For this reason, trying to compare the immune response between a common cold, and simultaneous vaccination for Hep-B, Hib, diptheria, tetanus, pertussis, rotavirus, and the flu may not necessarily be a useful model if our goal is to understand the relative immune impact.

    3) Some of our vaccines with the most antigens (varicella, with 75) cause relatively infrequent side effects when compared to our vaccines with very few antigens (DTP with 5). Clearly something is at work other than the number of antigens if we are to believe the CDCs values regarding antigen counts and adverse reactions (i.e., fever, fussiness).

    4) The time dependent problems I discussed above.

    Or are you concerned about the frequency of antigenic challenges, rather than the magnitude?

    The aggressive increase in our vaccine schedule at two, four, and six months represents something very different than what most infants encountered for most of human history. Of course, some were sick at two, four, and six months, but we’ve changed that to the point where nearly every infant is challenged during the first months of life.

    I’m not sure we are nearly clever enough to understand the implications of this, and as such, I guess I’d say I am worried about both. This belief, however, does not keep me from believing that vaccines work, that herd immunity is real, and that a large reduction in vaccinated children could lead to the return of very dreadful diseases.

    As for the rest, I think that Hib is still a big problem and I don’t think there are any medical advances in the past, besides vaccination which make it benign. Similarly, I have no idea how one would quantify a high risk infant. (?)

    – pD

  12. #12 Scott
    September 3, 2010

    Interesting. That’s how I feel about Jay Gordon…

    Well, I feel Jay deserves a lot more. Having his medical license taken away, being sued to within an inch of his life for malpractice, and then locked up for negligently endangering hundreds or thousands of children. For starters.

  13. #13 passionlessDrone
    September 3, 2010

    Hi Scott –

    Asking for the evidence supporting a claim is a different thing from claiming that there IS no evidence. It cannot, in any way, be in ANY contrast to ANY body of literature or evidence. There is NO assertion there!

    In other words, you’re an idiot who can’t read. But we already knew that.

    In this instance, I was simply trying to detail the a fraction of our existing evidence linking autism and autoimmune conditions. My assumption was that you did not believe there to be any such as evidence when you said:

    And if you have no evidence, why even bother talking about it?

    It would seem this was an inaccurate assumption on my part; though I will admit some confusion to the scenario where you thought there was such evidence, but felt someone else needed to present it in order for it to be relevant. In any situation, there is sufficient vitriol in this debate already, something I find very unfortunate. I should have worded my response to Dangerous Bacon more concisely.

    – pD

    @ScienceMom – Thank you.

  14. #14 Scott
    September 3, 2010

    pD,

    Such “assumptions” are grossly unjustifiable when used to justify terminology like “statement [] in startling contrast to the literature … statements so wildly at odds with the available evidence … obviously unsupportable assertions”. So I still consider the “vitriol” fully justified. If you’d simply presented evidence without falsely claiming that I had made a statement which I manifestly did NOT, and which you have now admitted you were simply assuming I meant, that would have been perfectly fine. For that matter, if I’d actually MADE such a statement I’d be more than willing to admit that it was mistaken.

    That said, the reason for presenting the question in that form was to challenge Jay to actually respond meaningfully. If he’d actually had the wit and knowledge to present such evidence from the literature, I would have altered the plan I mentioned to Todd and instead proceeded to the next question in line, which I now present to you:

    Now, show the evidence that such association is causal in a way that means vaccination is a risk factor.

  15. #15 Dangerous Bacon
    September 3, 2010

    pD is amped up about dreadful “aluminum salts” used as vaccine adjuvant (and which have an extensive record of safety in vaccination), while seemingly far less concerned about toxic products of bacterial and viral infection, whose deleterious effects are well-documented.

    While pD is going on about our “aggressive” vaccine schedule and busy “detangling the causal link between autism and observed autoimmune dysfunction” (i.e assuming there is one and making lists of studies that do not support the assumption), it’s notable that controlled studies continue to fail to demonstrate causative links between vaccination and known autoimmune diseases (such as type I diabetes) that antivaxers fulminate about. In fact, vaccination may one day hold the key to preventing such diseases (something that would undoubtedly drive antivaxers stark raving mad.*

    *assuming one could tell the difference between that consequence and their current condition.

  16. #16 Enkidu
    September 3, 2010

    Calli said: ” If you need a vent, you are in imminent danger of dying; this is not something to idly dismiss, as you [Dr. Jay] have.”

    Amen. My daughter spent 5 days on a vent. While I am thankful that it helped to save her life, I would much rather that she never had to go through that in the first place.

    I wonder if anti-vaxers think the same way about all preventative medicine. My daughter was 3 months premature. The docs told me that I should take progesterone shots if I ever get pregnant again to reduce the risk of premature delivery (even though my levels were okay, there is evidence that the shots still help). In Dr. Jay’s world, I guess he would rather take the 3 month preemie who spent 2 months in the NICU – firsy on a vent, then CPAP, then nasal cannula; 1 month in an incubator; two weeks on an IV; who was fed through a tube for 2 months; who needed blood tranfusions; who needed to have her eyes constantly monitored for ROP. Since everything “worked out” in the end, I guess this journey is acceptable over a series of shots during pregnancy.

    [feel free to find fault with my analogy, I’ll admit they are not my strong suit]

  17. #17 Jud
    September 3, 2010

    augustine writes:

    You believe someone can PREDICT who will or who won’t clear HPV and who will or won’t get CERVICAL CANCER? You sound silly.

    Sigh. augustine, there is a tremendous difference between what you are ranting about and known statistical efficacy of treatments or preventive measures, incidence and severity of side effects, etc., over large populations. In fact there is a quite profitable large industry built on the ability to reliably predict such statistics in large populations to within less than a percentage point. You may have heard of it, it’s called health insurance. People getting vaccines are relying on this same information (which works quite well – seen a lot of impoverished health insurance companies lately?) to become part of a vaccinated group that on a reliable basis has better disease outcomes among its members.

    Is it very, very likely that each member of the vaccinated group will have good outcomes re disease and side effects? Yep. Does this give us information regarding which particular individuals will be the rare ones to suffer from a disease or a specific side effect? Nope. It’s not necessary to have such predictive information about a specific individual to know that overall outcomes are far better, any more than it’s necessary for an insurance company to know exactly who’s going to get sick in order to set its health insurance premiums correctly.

    So you see, all that stuff about “prophetic medicine” and having to predict which particular individuals will or won’t get a disease just doesn’t hold water.

    Instead of coming up with scenarios that impress you as difficult (“Hah! Let’s see ’em claim they can predict who’ll get sick!”), but are really not serious contributions to a discussion of the pros and cons of vaccination, your time would be better spent learning about the subject you like to discuss so much. Once again I’d point to passionlessDrone as an example, who as ScienceMom mentioned upthread, deserves tremendous respect for marshalling actual studies and data to make us all think seriously about the potential health impacts of vaccines.

  18. #18 Captain Obvious
    September 3, 2010

    The aggressive increase in our vaccine schedule at two, four, and six months, near-eradication of nasty diseases like diptheria, pertussis, and polio in the U.S., a significant decline in infant mortality, and a sharp increase in life expectancy at birth, represent something very different than what most infants encountered for most of human history.

  19. #19 Jr
    September 3, 2010

    Some legal notes:

    First a minor correction: the Supreme Court will not decide whether the Vaccine Court is unconstitutional since no one has argued that it is.

    The question is only about the statue Congress passed. Specifically, whether it was intended to block all suits in state court. Specifically, whether Congress intended to block suits claiming that the manufacturer could have made a safer vaccine.

    Secondly, the fact that plaintiffs only need to have “50% plus a feather” of evidence is not unusual but the normal standard in tort cases.

  20. #20 passionlessDrone
    September 3, 2010

    Hi Dangerous Bacon –

    pD is amped up about dreadful “aluminum salts” used as vaccine adjuvant (and which have an extensive record of safety in vaccination), while seemingly far less concerned about toxic products of bacterial and viral infection, whose deleterious effects are well-documented.

    I’m not amped up about anything, I simply pointed out that a conversation about the strength of an immune response needs to include adjuvants, not just counting antigens. Again, this is (supposedly) a forum where arguments are formed on the basis of critical analysis and common sense conclusions must be reached with great caution. If our area of concern is the quantification of an immune response, adjuvants must be included in that discussion. Acknowledging the compexity of the situation doesn’t only apply if we are deconstructing a post from AOA.

    I have never said that I am unconcerned with the effects of actual infection, in fact, quite the opposite, though I don’t take the same umbrage with you that Scott seems to have taken with me.

    My primary concern with our relative lack of knowledge lies not with the toxic products of bacterial or viral infections, but rather, with potentially deliterious effects of the immune response itself, which I will attempt to detail in more depth in a response to Scott. My concerns are perfectly in line with the idea that an infection, any infection, during early life could cause developmental problems due to a vigorous immune response; something that happens regardless of the trigger, especially in a subset of indivduals shown to produce more inflammatory cytokines than their undiagnosed peers.

    While pD is going on about our “aggressive” vaccine schedule and busy “detangling the causal link between autism and observed autoimmune dysfunction” (i.e assuming there is one and making lists of studies that do not support the assumption), it’s notable that controlled studies continue to fail to demonstrate causative links between vaccination and known autoimmune diseases (such as type I diabetes) that antivaxers fulminate about.

    Perhaps a better wording would have been ‘detangling if there is a causal link. . . ‘. Is that better?

    In any situation, I will be quite clear in stating that a causal relationship between immune dysfuction and autism cannot be proven at this point; however, there are a great number of very well respected researchers who believe that an immune mediated cause is a biologically plausible possibiility requiring additional analysis. An intellectually honest reading of any of the articles I referenced above will support this statement. At this point, the only real question is if our only window of vulnerability is prenatal or not.

    – pD

  21. #21 Scott
    September 3, 2010

    At this point, the only real question is if our only window of vulnerability is prenatal or not.

    And even if it’s postnatal, what risk is posed by vaccines.

  22. #22 Chris
    September 3, 2010

    pD, since my son’s seizures were caused before he had a vaccine, I am not convinced that every seizure is associated with a vaccine. Especially since he another very major seizure while suffering from a real disease.

    Young Robert Fletcher has a seizure disorder, not autism.

    So I am going to ask you again: Why do vaccines have to be the only possible cause?

    Also, Jr, the government and courts in the UK is not covered by the American Constitution. Robert Fletcher is not American.

  23. #23 augustine
    September 3, 2010

    [Sigh Jud: In fact there is a quite profitable large industry built on the ability to reliably predict such statistics in large populations to within less than a percentage point.]

    That’s great. That industry should cooperate and communicate with the medical industry to vastly improve health care outcomes and drastically reduce the number of poor treatments that cause harm and do no good. They could also tell who needs a vaccine who doesn’t.

    [You may have heard of it, it’s called health insurance.]

    Doh! Really?

    [ People getting vaccines are relying on this same information (which works quite well – seen a lot of impoverished health insurance companies lately?) to become part of a vaccinated group that on a reliable basis has better disease outcomes among its members.]

    You mean vaccine manufacturers in collaboration with insurance companies are doing quite well. So all of this detailed elaborate information about risks and the end result is f*%k it? Everybody get’s all of the vaccines. Paul Offit could have told you that. Hell, Brian Deer could have told you that. Even Chris could have told you that. There’s no need for a fancy calculator. Just use mass vaccine ideology. You get the same conclusion. Who needs science when ideology can get the job done.

    [Is it very, very likely that each member of the vaccinated group will have good outcomes re disease and side effects? ]

    So all I have to do is listen to my insurance company to be the healthiest that I can be? Then I’ll thrive. My insurance company has MY best interest as their main priority. Their profit really is secondary to me having the best health. Gee, I never though of that way before. I take back everything I’ve said. I’m going to call my insurance auditor and apologize for not appreciating him/her as I should have. Then I’m going to spread the good word about how insurance is going to save this country if we all just do what they say.

    Thanks, JUD. You’re swell guy.

  24. #24 augustine
    September 3, 2010

    Every seizure is not associated vaccines. But vaccines are associated with seizures.

    I don’t know why you would be hung up on that. It’s pretty straight forward.

  25. #25 Bronze Dog
    September 3, 2010

    Sneaking in a peek, and I’m facepalming over augie going on about “prophetic medicine.” How can this guy function in the real world?

    When he goes to buy a car, will he try to buy one without seatbelts, airbags, or crumple zones because he can’t predict whether or not he’ll be in an accident? Or does he make a case-by-case decision to not buckle every time he gets in a car?

    We’re in favor of playing the best odds and minimizing the risks while augie seems to live his life by blindly rolling the dice and hoping (without bothering to look at or understand probability) that the universe is feeling generous.

  26. #26 Sid Offit
    September 3, 2010

    @Pablo

    If vaccinated kids have an autism rate of 1 in 100-200, and unvaccinated kids have an autism rate of 1 in 100-200, then there is no indication that vaccination causes autism.

    And that is what is found.
    —————-
    Found where?

  27. #27 augustine
    September 3, 2010

    [Doggy Dog: When he goes to buy a car, will he try to buy one without seatbelts, airbags, or crumple zones because he can’t predict whether or not he’ll be in an accident? Or does he make a case-by-case decision to not buckle every time he gets in a car?]

    293 posts without a seatbelt gambit analogy. I knew it. Can’t have an good Sceptic based medicine post on vaccines without one.

    What I usually ask the car salesman is “how many of your customers have sat in one of your cars, put the seatbelt on and had a seizure BEFORE they got into a wreck or without ever having a wreck?”

    I also ask “how many customers have contracted a severe permanent neurological disease in the same scenario? How many have died by just putting on the seatbelt.”

    He says “NONE!” and I believe him. If the doctor says “NONE” I don’t believe him.

    [We’re in favor of playing the best odds and minimizing the risks]

    That’s what he said too
    “Stock Market and Securities Fraud”
    http://www.greekshares.com/fraud.php

    http://www.investorhome.com/scam.htm

    “The Stock-Market Scam is a classic numbers game illustrating how investors can be fooled into believing someone possesses predictive ability.”

  28. #28 passionlessDrone
    September 3, 2010

    Hi Scott –

    Now, show the evidence that such association is causal in a way that means vaccination is a risk factor.

    As I tried to mention to Dangerous Bacon previously, my concern is primarily in the relative dearth of our knowledge of vaccination. We know it works at preventing disease. And that’s good, but I’m not sure we understand if it may be doing something else. Furthermore, at this point, a causal relationship between autism and immune dysfunction cannot be proven. However, there is, as I tried to display, an abundance of evidence of a linkage, and many researchers believe that the possibility is biologically plausible from several different avenues.

    So why am I such a skeptic on our existing research set concerning vaccination? Because it fails to take into consideration a commonality between all vaccines; the generation of an immune response, and the intersection with our observations within autism, particularly a dysregulated immune response with much evidence of a propensity towards an exaggerated inflammatory response in the innate arm of the immune system (see PMIDs: 20705131, 20302902, 18676531, 19666104 for supporting references on this claim). But even that isn’t much without our existing animal studies that tell us that even a faux infection may not necessarily be harmless if it occurs within critical developmental windows.

    By way of example, check out these two studies:

    Viral-like brain inflammation during development causes increased seizure susceptibility in adult rats [PMID: 19660546]

    Postnatal inflammation increases seizure susceptibility in adult rats [PMID: 18596165]

    Here researchers report that a single bout of inflammation during development (post natal day 14 in rodents) induced by either bacterial mimics (LPS/TLR4 agonist), or viral mimics (Poly:IC / TLR3) was sufficient to permenantly alter the suceptibility to seizures in treatment animals. Remember, these animals were not getting sick, a pathogen attack was simulated. Of particular salience is that the researchers found that different anti-inflammatory agents were capable of attenuating the effect; this tells us that it was the immune response was responsible for changing the underlying neurological function.

    Besides the fact that we know that seizures, epilepsy, and abnormal eegs are highly associated with autism (voluiminous references provided upon request); we also know that when challenged, children with autism respond with more pro-inflammatory cytokines than their undiagnosed peers. If a similar mechanism of early life vulnerability to immune challenge exists in human infants, the autism population is a subgroup of individuals predisposed to be more at risk of developing reactions of this type.

    Similar findings involving immune response and persistent effects are available in the animal relam involving alterations to the HPA-Axis [PMID: 20534845, 19524372], neuroimmune functions [PMID: 19782746, 19738918], among others. (References for altered HPA-Axis function in autism provided upon request).

    I cannot make the claim to prove that immune dysfunction in autism is causal. Similarly, I cannot prove that vaccination can cause autism. I am not advocating stopping vaccination.

    That being said, I can make the claim that the overwhelming majority of our existing research is completely blind to the possibility of innate immune responses altering development in a meaningful way. Here is a completely genuine request that you might find enlightening, try to find a single study on the pediatric vaccine schedule that measures innate immune system components. They aren’t there. The notion that immune response, sans actual pathogenic effects from microbial invaders could cause persistent changes is a relatively new idea, one that significantly postdates the additions to our vaccine schedule; and indeed, proclomations that the science has spoken.

    It looks as if some people are catching on that this might be something worth evaluating, at least in the sense of gathering general information. On August 11 of this year the NIH announced an initiative to gain more understanding of the effects of infection and vaccination on immune profiles (google if you want, not linking to avoid the filter). A great step, in my opinion; but one that ought to tell you something about how good our research actually is regarding the effects of vaccination in areas other than their designed use, antigen presentation.

    I don’t have to claim that all autism, or even a tiny fraction of it is caused by vaccination to make our lack of research coupled with our recent findings in the animal realm any less alarming.

    – pD

  29. #29 Sid Offit
    September 3, 2010

    @pD.

    Great post. Very though provoking. It is however amusing to see how hard this group tries not to be provoked into thinking.

    Vaccines good. Don’t hurt vaccine. Anti vaccine bad.

  30. #30 passionlessDrone
    September 3, 2010

    Hi Chris –

    So I am going to ask you again: Why do vaccines have to be the only possible cause?

    I have given you the same answer many, many times and it hasn’t changed. They do not have to be. I don’t know how else to tell you that. (?)

    I have absolutely no problem with a bazillion other mechanism of action; pure genetics, the environmental ubiquity of endorcrine disruptors, pesticides, and other chemicals, the fattening of the populace, actually getting a viral or bacterial infection, difficulties in birthing and/or gestation, epigenetic alterations from any combination of the above, whatever. My worldview is far, far away from a place where vaccines are the only potential problem.

    What you are seeing is a reflection of the fact that most of the discussion about autism seems to center on vaccines; the intellectual disingenuousness that seems part and parcel of these discussion does get me fiesty from time to time.

    Jesus Christ, if Orac or someone else would start a discussion about the potential for things like PDBEs potentially contributing to our observations of apparent increase in autism, I would be all over it. That never happens though; it’s always about bashing Wakefield, cheerleading the goalpost shifting of expanded criteria, or deconstructing something written by AOA. Frankly, I think that’s a shame and a waste.

    I wish I had a way to rephrase this in a way that would convince you. I don’t seem to have that ability, unfortunately. (?)

    – pD

  31. #31 augustine
    September 3, 2010

    ditto Sid

  32. #32 Todd W.
    September 3, 2010

    @pD

    Interesting post, regarding the role of innate immune responses. Certainly there are interesting questions to be asked and investigated, particularly in light of what we know about infectious agents and autism, namely, that congenital rubella syndrome is one known cause of autism, though by no means the only one.

    We also know that individuals who do not receive any vaccinations or whose mothers did not contract rubella while pregnant can still be autistic (see Kim Stagliano’s daughter as a well-known example, as well as a number of studies). Whether other infections or immune responses in these children played a role, who knows.

    The question then, is, are the immune dysfunctions noted in the studies you cited causal of autism, a result of whatever is causing the autism, or just coincidental due to some unrelated factor.

  33. #33 Science Mom
    September 3, 2010

    Great post. Very though provoking. It is however amusing to see how hard this group tries not to be provoked into thinking.

    Vaccines good. Don’t hurt vaccine. Anti vaccine bad.

    Careful with that broad brush-stroke Sid, you will invariably be wrong. But you’re used to that.

  34. #34 Chris
    September 3, 2010

    pD:

    I wish I had a way to rephrase this in a way that would convince you. I don’t seem to have that ability, unfortunately. (?)

    You would be more convincing if you did not try to find the most oblique (though thought provoking) connections to just vaccines. Or if you actually answered the question. You make it like the other factors are possible, but you don’t seem to follow through. And there seems to be a missing bit about relative risks.

    It is more probable that Mr. Fletcher would have had a seizure disorder even without the vaccine. The fact that it happened at a time shortly after his vaccine may have been pure coincidence. My son’s later seizures were also shortly after his MMR vaccine (in 1989), it just happened that he caught another disease a week later (I actually did a double take when I looked at his shot record after the Wakefield press conference when he was between eight and ten years old and noticed the dates).

  35. #35 Dangerous Bacon
    September 3, 2010

    pD: “I have absolutely no problem with a bazillion other mechanism of action (causing autism…My worldview is far, far away from a place where vaccines are the only potential problem.

    What you are seeing is a reflection of the fact that most of the discussion about autism seems to center on vaccines; the intellectual disingenuousness that seems part and parcel of these discussion does get me fiesty from time to time.”

    So your response is to “just ask questions” about…vaccines. I’d find it more intellectually ingenuous if your posts were directing us towards non-blame-the-vaccine causes of autism.

    pD:“:Here is a completely genuine request that you might find enlightening, try to find a single study on the pediatric vaccine schedule that measures innate immune system components. They aren’t there.”

    I don’t find this to be the case, depending on just what you mean by “innate immune system components”. I easily can locate studies in PubMed that study pediatric vaccines’ effect on human humoral and cell-mediated immune response components. It’s a routine part of effectiveness and safety testing for vaccines. The NIH study you referred to will provide welcome information to help us improve vaccines and make them more effective in protecting us against disease, notably in subsets of people (i.e. elderly, immunocompromised) that may not derive optimal benefit from today’s vaccines.

    One other thing that may help increase your understanding of immunization is if you stop seeing it as inducing “disease”. Getting vaccinated is not the equivalent of contracting a disease, or even a “faux” disease (as you put it). The potential for harm from a high antigenic load and dealing with toxigenic effects are claims that antivaxers (and the “just asking questions” folks) use to damn vaccines, but they seem oblivious to the fact that these concerns are vastly more applicable to the diseases vaccines prevent.

  36. #36 dt
    September 3, 2010

    @pD
    Your point that vaccines may provoke an autoimmune response is not really something up for debate – they might indeed do this. But natural infection with pathogens is a recognised cause of autoimmunity. Indeed, many of the complications/problems following infection are precisely due to this phenomenon, be they GBS after influenza or campylobacter, or ADEM after measles virus infection to take but 2 examples.

    Now you may talk about artificially induced immunity causing these problems (and they can do) but you seem to imagine that because vaccines contain substances that help boost the predicted immune response (adjuvants) they are somehow “more” likely to provoke auto-immunity than natural infection. I assume you think this – if you do please provide evidence for it, if you don’t, then stop implying it.

    You see, it is a well-known fact (and a mantra oft repeated by antivaxers) that even with the assistance of adjuvants, artificial vaccination-induced immunity is less robust and less durable than natural immunity.

    Now if you can somehow shoe-horn this fact into your theory that vaccine-induced auto-immunity is a significant problem (and more so that with natural infection) then I’d be pleased to see you do so. This is the elephant in the room, and you are ignoring it.

  37. #37 passionlessDrone
    September 3, 2010

    Hi Dangerous Bacon

    So your response is to “just ask questions” about…vaccines. I’d find it more intellectually ingenuous if your posts were directing us towards non-blame-the-vaccine causes of autism.

    Well, my blog is slightly less visited than Oracs, but if you were to visit it, you would find entries epigenetics, genetic expression studies, environmental pollutants, and others. I genuinely welcome skeptical viewpoints.

    I don’t have many other options to convince you; my post in this thread started as I tried to illustrate the amount of data that clearly links autism to autoimmnity. I was subsequently challenged to provide a link to vaccination. (?)

    I don’t find this to be the case, depending on just what you mean by “innate immune system components”. I easily can locate studies in PubMed that study pediatric vaccines’ effect on human humoral and cell-mediated immune response components. It’s a routine part of effectiveness and safety testing for vaccines.

    OK. This was a problem on my part, what if I said, ‘proinflammatory cytokine generation’? What then? Can you point me to a pre / post vaccination study with pediatric vaccines that measures those? Some of the studies I referenced above found specific inflammatory cytokines, such as tnf-alpha alone was capable of causing persistent effects [18596165]. Considering I specifically mentioned that several studies showed attenuation of effects based on administration of anti-inflammatory agents, could you should me any studies on innate immune functioning that would be affected by similar agents with vaccination?

    One other thing that may help increase your understanding of immunization is if you stop seeing it as inducing “disease”. Getting vaccinated is not the equivalent of contracting a disease, or even a “faux” disease (as you put it).

    I called it a faux infection, and our functional end point, generation of an inflammatory response, is the same from vaccination or wild infection. Generating an immune response is part and parcel to the process of vaccination, you don’t get one without the other. Despite my repeated requests that someone, anyone show me a link that can actually demonstrates the robustness of an inflammatory response between vaccination and illness, no one has seen fit to do so. Can you?

    – pD

  38. #38 Antiquated Tory
    September 3, 2010

    I’m just about to go to bed, but it seems to me that pD is talking about two separate issues, and they would have to be addressed in this order:
    1) What is the causal connection, if any, between autoimmune responses and autism?
    2) What contributing factors are there to this connection, provided one is established in sufficient detail? (Vaccines might be a contributing factor, but this appears to be contrary to the mass of epidemiological research on vaccines and autism.)
    Also note that even if it turned out that despite the epidemiological evidence, vaccines were established as a contributing factor to immune responses that increased the risk of autism, the increased risk of autism would have to be compared against the risk of vaccine preventable disease.
    All in all, I don’t see why pD’s concerns should focus on vaccines at all at this point.

  39. #39 passionlessDrone
    September 3, 2010

    Hi dt –

    Now you may talk about artificially induced immunity causing these problems (and they can do) but you seem to imagine that because vaccines contain substances that help boost the predicted immune response (adjuvants) they are somehow “more” likely to provoke auto-immunity than natural infection.

    I have made no such assertion or imagination; please re-read my post @221. The only reason adjuvants were discussed was because they are a necessary parameter to any discussion that involves drawing equivalencies between natural infection and vaccines regarding the strength of the immune response; a discussion that frequently focuses on counting antigens, which, as I tried to explain, is a gross over simplification. I don’t know if they are more likely to promote auto-immunity or not, but I do know that reducing interactions as complex as the immune response to addition is poor methodology and ignores the messy reality of trying to understand biological systems. That isn’t supposed to happen here.

    Now if you can somehow shoe-horn this fact into your theory that vaccine-induced auto-immunity is a significant problem (and more so that with natural infection) then I’d be pleased to see you do so. This is the elephant in the room, and you are ignoring it.

    Your analysis still fails to take into consideration time dependent effects. Why? Do you believe it might be possible that the effects of an immune challenge at two months of age might be different than one at a year, or at five years, or twenty? Seriously, please consider this.

    How many infants were naturally infected with Hep-b, influenza, rotavirus, diptheria, pertussis, tetanus, and hib on their sixtieth day from the womb? Do you think it was a large percentage? Even getting infected by a single one of those diseases at that age was very rare, pre vaccination; it happened, but no where close to the 90%+ range we currently have for vaccinations. You are trying to take massively important variables, time and associated developmental status, and color all things equal with infections that children were getting years into childhood. Talk about shoe horning!

    This is particularly salient because several of the papers in the animal realm show very clear time specific time periods during which an effect was observed. PMID 18596165 is a particularly good example of this; also 16395304.

    – pD

  40. #40 Matthew Cline
    September 3, 2010

    In my opinion you all should lay off pD:

    1) Talk about autoimmune disease, vaccination and autism is a lot more on topic than, for example, jen’s claim about Tylenol causing autism.

    2) pD doesn’t seem to be saying that autoimmune disease does cause autism, but that it might, and that there should be research into it.

    3) pD doesn’t ignore questions like Dr Jay is doing.

  41. #41 dedicated lurker
    September 3, 2010

    Jen brings up the tylenol thing in vaccine threads because tylenol is sometimes given before a vaccine in case of fever. She’s arguing that there might be a correlation with vaccines and autism onset, but it is caused by another factor instead of the vaccine itself.

    I’m not sure how convincing that argument is, but it’s partially on topic.

  42. #42 ERV
    September 3, 2010

    … Um, do you all want me to do more immunology posts? Cause we actually learn about this stuff (when to vaccinate and why, vaccines and autoimmunity, how adjuvants work, etc) in school and seminars… I just prefer to write about viruses :-/

    Theres nothing wrong with pDs questions– the answers require advanced/modern immunology. I mean its not like a Creationist bringing up the second law of thermodynamics or anything. I just hope pD isnt confusing their ignorance with ‘problems for the field’.

  43. #43 Drivebyposter
    September 3, 2010

    Jen brings up the tylenol thing in vaccine threads because tylenol is sometimes given before a vaccine in case of fever. She’s arguing that there might be a correlation with vaccines and autism onset, but it is caused by another factor instead of the vaccine itself.

    Holy crap. I read her posts mentioning it a time or two and thought she was being sarcastic.
    I’m making a prediction that eventually someone will claim the active ingredients in placebos can cause infertility. If I’m right I get to ride Orac’s pony.

  44. #44 augustine
    September 3, 2010

    [grad student:.. Um, do you all want me to do more immunology posts? Cause we actually learn about this stuff (when to vaccinate and why, vaccines and autoimmunity, how adjuvants work, etc) in school and seminars… I just prefer to write about viruses :-/]

    Um, no. It would be better if your professors chimed in instead of you. You’re just a student.Shouldn’t you be registering for class or something? Don’t you need some more college cash? You should be working on better topics for your own blogs instead of XMRVs ad nauseum. Don’t you bloggers get paid for traffic? Looks like you need to drum up more traffic.

    BTW, How big are you?

  45. #45 Jay Gordon
    September 4, 2010

    passionlessDrone has written some words worth considering:

    “I cannot make the claim to prove that immune dysfunction in autism is causal. Similarly, I cannot prove that vaccination can cause autism. I am not advocating stopping vaccination.”

    [So I am going to ask you again:
    Why do vaccines have to be the only possible cause?]

    “I have given you the same answer many, many times and it hasn’t changed. They do not have to be. I don’t know how else to tell you that.”

    I support the above statements completely. I’m sorry that you’re tarring a well-informed, well read fellow poster like pD with the same brush you use for me. As you persistently know (and vilify) my posts here are, for the most part, to mention that my experience is at odds with your version of science. (“Science: The Monolithic Idea”) pD, on the other hand, supports his ideas with peer-reviewed research and a questioning point of view. He is correct: Most people here want fuss and fight rather than being provoked into thinking. Vaccines are obviously not the only cause of autism and may not even be a cause of autism at all! I think they are one of the environmental triggers to genetic predisposition but I have insufficient proof right now.

    “Jesus Christ, if Orac or someone else would start a discussion about the potential for things like PDBEs potentially contributing to our observations of apparent increase in autism, I would be all over it.”

    Again, great thought. Please understand that neither Orac nor most of the other “scientists” here are interested in thoughtful discussion. Just speculative and vituperative narrative about possible toxins (vaccines, aluminum) rather than a reasoned debate about known toxins like PDBEs. The goal is getting others angry and generating traffic.

    Jay

  46. #46 Sid Offit
    September 4, 2010

    @ERV
    Um, do you all want me to do more immunology posts? Cause we actually learn about this stuff (when to vaccinate and why, vaccines and autoimmunity, how adjuvants work, etc) in school and seminars…
    —————————-

    I’m glad you have it all figured out. I hope you’ll share more with those of us not having access to the “seminars” in which the mysteries of the immune system have been revealed to you

    P.S.
    ————————-
    Discov Med. 2010 Feb;9(45):90-7.
    Vaccines and autoimmune diseases of the adult.
    it is feasible that vaccinations may also contribute to the mosaic of autoimmunity
    ————————-
    How Do Adjuvants Work? Important
    Considerations for New Generation Adjuvants

    Despite its long use, we still do not know exactly how alum mediates its adjuvant effects.
    ————————-
    Littman says he continues to be fascinated by the immune system. “While we know far more about the immune system than any other complex system in the body, I am astounded by how limited our knowledge really is,”
    Dr. Littman is also Professor of Pathology and Microbiology at the Skirball Institute of Biomolecular Medicine of New York University School of Medicine

  47. #47 Dangerous Bacon
    September 4, 2010

    pD: “…what if I said, ‘proinflammatory cytokine generation’? What then? Can you point me to a pre / post vaccination study with pediatric vaccines that measures those?”

    Here’s one that deals with measles vaccination in infants. A quick search on PubMed turns up several others, dealing with cytokine generation following measles, mumps and rubella vaccine. I only used one set of search terms and looked at the first page and a half of results, so there should be quite a few more papers out there.
    I expect the NIH study previously referenced to build on this research to develop even more effective and safe vaccines in the future.

    “I called it a faux infection, and our functional end point, generation of an inflammatory response, is the same from vaccination or wild infection.”

    I hope you’re not equating the “inflammatory response” from immunization with the body’s reaction to developing a full-blown infection. I suggest you spend some time studying the pathology of infectious diseases and the medical struggle to contain and eradicate them.

    You might develop a newfound appreciation for our “aggressive” vaccine schedule. This would be a worthwhile endeavor after you “detangle” the difference between correlation and causation as it applies to immune parameters in autistic children.

    I would also welcome your discussion here of the potential etiologies of autism that you say you’d love to get into, but have unaccountably gotten sidetracked into pointing a finger at vaccines.

  48. #48 Gonzo
    September 4, 2010

    From Dr. Jay Gordon’s comment all the way back at 101:
    —————————

    I don’t support blanket exclusion of unvaccinated children [from public schools] any more than I support exclusion of HIV positive children from schools.

    —————————

    How is it possible to conflate the presence of children that have a higher likelihood to have (and spread) very contagious diseases with children that have a disease transmitted sexually/by direct fluids exchange? Did a medical doctor actually write that? Holy mackerel, that’s just unbelievable.

  49. #49 adelady
    September 4, 2010

    “…known toxins like PDBEs…”

    Now you’re talking. If you’re seriously considering environmental or dietary toxins, I doubt you’ll get very far with parents who have convinced themselves that an *external* agent has invaded their child’s body to cause autism.

    The driving force underlying many parents’ anguish over this is not just the disability, it’s the fear that it might be something they did or failed to do to cause it themselves. I’m not involved with health but with learning difficulties.

    The number of parents who refuse point blank to believe that there’s anything amiss with little Johnny is extraordinary. Let alone that little Johnny would do better with a caffeine free diet and a good night’s sleep. “Nothing wrong with my boy,” says dad who’s just been (politely) told that the child is as blind as a bat, and will not, under any circumstances, take him to an optometrist. He’s not doing well at school because he has a personality clash with the teacher – therefore the teacher’s fault.

    Someone might come up with an explanation for autism that tells parents that the mother’s pregnancy diet and home environment with the usual load of chemicals could be responsible if she herself absorbs them in a particular way. These might possibly be absorbed into her body and then through the placenta to affect the foetus.

    Too confronting.

    It’s much, much more reassuring to believe that malign outside forces caused such problems. If there’s trouble believing it’s just the luck of the draw, there’ll be worse in store if someone tries to say that eating your favourite food or buying the furniture you fell in love with could be as damaging as boozing throughout pregnancy.

  50. #50 passionlessDrone
    September 4, 2010

    Hi Dangerous Bacon –

    Here’s one that deals with measles vaccination in infants. A quick search on PubMed turns up several others, dealing with cytokine generation following measles, mumps and rubella vaccine. I only used one set of search terms and looked at the first page and a half of results, so there should be quite a few more papers out there.
    I expect the NIH study previously referenced to build on this research to develop even more effective and safe vaccines in the future.

    Thanks for the link. It isn’t quite what I’m looking for; but I think that I am starting to understand why we aren’t seeing the same thing. I’m much more interested in the immediate, pro-inflammatory release of things like tnf-alpha, IL-6 or IL-1B following vaccination.

    Something along the lines of this study: Effect of influenza vaccine on markers of inflammation and lipid profile [PMID: 15976761]

    Check out the first sentence from their abstract:

    Despite wide use of the influenza vaccine, relatively little is known about its effect on the measurement of inflammatory markers.

    No kidding. The study you linked to is primarily concerned with T and B cells, not the initial inflammatory response. I think I needed to bee even more concise with my thoughts. Sorry.

    I hope you’re not equating the “inflammatory response” from immunization with the body’s reaction to developing a full-blown infection. I suggest you spend some time studying the pathology of infectious diseases and the medical struggle to contain and eradicate them.

    OK. I think this is where a disconnect might lie; it probably seems to you as if I’m narrowing down on something seemingly innocous, (and goal shifty). But I’m not. A lot of our newer research in the animal realm suggests that an inflammatory response during development need not be robust nor pro-longed in order to have persistent effects, if the challenge occurs during critical timeframes.

    We know that vaccines often times cause mild reactions; i.e., fevers, and this is likely due to induction of the immune response and associated creation of inflammatory and pyrogenic cytokines. This would seem to be straightforward with how we think vaccines are actually marshalling an immune response. Can we agree on that?

    So what? Well, I’m going to dare the spam filter gods here with this paper, Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats

    From the discussion section:

    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.

    I’d say that is a surprising finding. To my google educated mind, that tells me that may not necessarily have to encounter an immune response as the result of a ‘full blown infection’ in order to have long term effects. Shoot, all you really needed was a boost of tnf-alpha. And remembe, this is a cytokine shown again and again to be created at exaggerated levels in vitro by children with autism.

    When I look for something that tells me about our pediatric shots; especially the ones given at the earliest ages, and measures creation of things like tnf-alpha, I come up bare. It isn’t for lack of looking, but it could be for lack of skill. [I have found some other papers that measure this type of thing, one on HPV for example, but always on adults, and they have tended to show an increase in pro-inflammatory cytokines, as expected.] I do know that while I appreciate the paper you sent me above, it by no means provides the type of data that would speaks towards this study.

    While the paper I listed above is the most elegant in demonstrating the possibility of time dependent, inflammatory cytokine driven effects that has me (unnecessarily?) worried, you’ll find that there are about twenty papers with similar findings; i.e., an immune challenge during development can reprogram the immune system or HPA-axis in ways that we are only beginning to understand.

    This would be a worthwhile endeavor after you “detangle” the difference between correlation and causation as it applies to immune parameters in autistic children.

    I’ll let you know how it turns out!

    I would also welcome your discussion here of the potential etiologies of autism that you say you’d love to get into, but have unaccountably gotten sidetracked into pointing a finger at vaccines.

    OK!

    – pD

  51. #51 passionlessDrone
    September 4, 2010

    Hi ERV –

    … Um, do you all want me to do more immunology posts? Cause we actually learn about this stuff (when to vaccinate and why, vaccines and autoimmunity, how adjuvants work, etc) in school and seminars… I just prefer to write about viruses

    Those seminars sound pretty impressive. For example, I was looking at this paper: Early life activation of toll-like receptor 4 reprograms neural anti-inflammatory pathways that was published a few moonths ago and thought the findings were pretty neat:

    A single postnatal exposure to the bacterial endotoxin, lipopolysaccharide (LPS), reduces the neuroimmune response to a subsequent LPS exposure in the adult rat. The attenuated fever and proinflammatory response is caused by a paradoxical, amplified, early corticosterone response to LPS. Here we identify the mechanisms underlying the heightened corticosterone response to LPS in adults after early life exposure to LPS. In postnatal LPS-treated rats, hypothalamic corticotrophin-releasing hormone mRNA, pituitary proopiomelanocortin mRNA, and circulating adrenocorticotrophic hormone were all increased after adult exposure to LPS without significant modification to hippocampal or hypothalamic glucocorticoid receptor mRNA or protein or vagally mediated afferent signaling to the brain. Postnatal LPS administration did cause a persistent upregulation of the LPS Toll-like receptor-4 (TLR4) mRNA in liver and spleen, but not in brain, pituitary, or adrenal gland. In addition, cyclooxygenase-2 (COX-2), which is a prostaglandin biosynthetic enzyme and is normally undetectable in most peripheral tissue, was constitutively expressed in the liver. Adult immune activation of the upregulated TLR4 and COX-2 caused a rapid, amplified rise in circulating, but not brain, prostaglandin E(2) that induced an early, enhanced activation of the hypothalamic-pituitary-adrenal (HPA) axis. Thus, postnatal LPS reprograms the neuroimmune axis by priming peripheral tissues to create a novel, prostaglandin-mediated activation of the HPA axis brought about by increased constitutive expression of TLR4 and COX-2.

    Do you think it would be OK for you to post your lecture notes on the mechanisms of action of TLR mediated reprogramming of neural anti-inflammatory pathways as a result of early life challenge and how that intersects with our existing understanding of how adjuvants work, when and why we vaccinate, ect?

    I just hope pD isnt confusing their ignorance with ‘problems for the field’.

    I think my new signature might be, “less ignorant than a Creationist”.

    – pD

  52. #52 LW
    September 4, 2010

    “How many infants were naturally infected with Hep-b, influenza, rotavirus, diptheria, pertussis, tetanus, and hib on their sixtieth day from the womb?”

    This argument doesn’t make sense to me. Of that list of diseases, only influenza and rotavirus are available as live virus vaccines (as best I can tell from googling), and the influenza live virus vaccine is recommended ages two years and up, so it shouldn’t be given to a two-month-old. Hence, the only disease an infant might be infected with via vaccination is attenuated rotavirus, and apparently wild rotavirus is not uncommon in that age group, and is quite harmful. So the hand-wringing about infecting infants with numerous viruses by the sixtieth day of life is unjustified.

    As to confronting a child with the various antigens in the other viruses — I believe the point Dr. Offit was making in his frequently abused comment was that infants have historically been, and even now are, daily confronted with a huge array of antigens in the environment, all of which their immune systems will attack as best they can. The immune system does not and cannot know that this little molecule is part of a pertussis virus which might be deadly if the whole virus were present, which it isn’t, and the that little molecule is part of a dust mite, which is harmless. It just recognizes them all as not-self. The antigens themselves are not the diseases.

  53. #53 colmcq
    September 4, 2010

    hi Pd

    I’ve really admired your posts; very thoughtful and considerate.

    Q: if there was a predisposition towards certain kinds of adverse reactions following vaccination as you suggest, would this have been established via the epidemiological studies that have been carried out to date (fombonne madsen etc)?

    regards

    Col

  54. #54 Composer99
    September 4, 2010

    Nitpick, LW: pertussis bacterium.

    passionlessDrone: If memory serves, you can get up to two links. After that it has to get by the filter.

    ugh troll: ‘Critical thinking’. You keep using that phrase. You consistently demonstrate an inability to understand what critical thinking is all about, even as you cut and paste definitions of it from online dictionaries and/or Wikipedia. So I’m sure you’ll forgive me for taking your claims not at all seriously.

  55. #55 passionlessDrone
    September 4, 2010

    Hi lw –

    This argument doesn’t make sense to me. Of that list of diseases, only influenza and rotavirus are available as live virus vaccines (as best I can tell from googling), and the influenza live virus vaccine is recommended ages two years and up, so it shouldn’t be given to a two-month-old. Hence, the only disease an infant might be infected with via vaccination is attenuated rotavirus, and apparently wild rotavirus is not uncommon in that age group, and is quite harmful. So the hand-wringing about infecting infants with numerous viruses by the sixtieth day of life is unjustified.

    I must have done a poor job of explaining my position. The argument was made to me that wild type infection produces a longer lasting immunity than vaccine type. (I agree)

    You see, it is a well-known fact (and a mantra oft repeated by antivaxers) that even with the assistance of adjuvants, artificial vaccination-induced immunity is less robust and less durable than natural immunity.

    I believe the underlying argument here is that if my suggested mechanism of action is correct, a robust immune response (specifically, the initial inflammatory response), that therefore, regular infections would be much more problematic than vaccines. (Please forgive me, dt, if I have misunderstood your argument.)

    BUT. This analysis fails to take into consideration the possibility of a time dependent effects; i.e., can we or should we safely equate an infection (and associated inflammatory response) a child gets when they are four years old with an inflammatory response an infant gets when they are two months old?

    The official schedule for two month vaccinatiosn includes Hep-B, Hib, DTaP, Polio, rotavirus, and pneumococcal are included. My initial list, including influenza was wrong, but I had left out pneumococcal.

    I’m not “hand-wringing about infecting infants with numerous viruses by the sixtieth day of life “, I am merely making the point that from a developmental standpoint, we have precious little evidence to say that the response and corresponding effects of an infection at three, five, or ten years can safely be equated with one at two months. Infection with one of these diseases was very rare at this age; no doubt the repercussions were very dire, but on a percentage basis, very, very few infants actually got these diseases by sixty days. If our focus is not on pathogenic capacity of the microbes, but rather, potential effects of the corresponding immune response, our effort to bring vaccination rates up to 90%+ is a big, big change. The animal studies I have tried to present in posts 246 & 247 are examples of early life immune system activation, and nothing more, having long term, persistent effects.

    As to confronting a child with the various antigens in the other viruses — I believe the point Dr. Offit was making in his frequently abused comment was that infants have historically been, and even now are, daily confronted with a huge array of antigens in the environment, all of which their immune systems will attack as best they can.

    Technically true, but misses the point. You are confusing baseline exposure with exposre designed and delivered to initiate an immune response. For a common sense example of this, have you considered that fever is a known side effect about 1/4 of the time you get the DTAP, but your child fails to get a fever one in four days he is ‘confronted with a huge array of antiens’ on an everyday basis?

    From a clinical standpoint, look at this study:

    HPV-16 L1 VLP vaccine elicits a broad-spectrum of cytokine responses in whole blood.

    Here, we evaluated innate and adaptive immune system cytokine responses induced by HPV-16 L1 VLP in whole blood (WB) cultures from individuals receiving the vaccine (n=20) or placebo (n=4) before and after vaccination. 11 cytokines were measured: IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IFN-gamma, TNF-alpha, and GM-CSF using multiplex bead arrays. Cytokine profiles from WB samples clearly discriminated between vaccine and placebo recipients and between pre and post-vaccination responses. Significant increases in Th1, Th2 and inflammatory cytokines were observed in WB assays following vaccination. Results from WB assays were compared against parallel PBMC-based assays in a subset of patients. Differences between whole blood assay and PBMC were observed, with the highest levels of induction found for WB for several cytokines. Our results indicate that multiplex assays for cytokine profiling in WB are an efficient tool for assessing broad spectrum, innate and adaptive immune responses to vaccines and identifying immunologic correlates of protection in efficacy studies.

    I would be curious in how you would reconcile this finding, significant increases in pro-inflammatory cytokines post vaccination in the non placebo group only? Both groups were exposed to the same bewildering array of antigens during daily exposure, yet only one group showed an increase in inflammatory cytokines. Mr. Offits back of the napkin calculations regarding T and B cell capacity are a nice way of destroying the over used canard of an ‘overwhelmed’ immune system, but in no way address the possibility of a persistently modified immune system. Once again, I would direct you to the studies I referenced in post 246 and 247 for examples of this.

    The immune system does not and cannot know that this little molecule is part of a pertussis virus which might be deadly if the whole virus were present, which it isn’t, and the that little molecule is part of a dust mite, which is harmless. It just recognizes them all as not-self. The antigens themselves are not the diseases.

    But I am not worried about the disease. I am worried about the resultant immune response, and you get one of those if the disease is real or not.

    – pD

  56. #56 Kristen
    September 4, 2010

    adelady,

    Someone might come up with an explanation for autism that tells parents that the mother’s pregnancy diet and home environment with the usual load of chemicals could be responsible if she herself absorbs them in a particular way. These might possibly be absorbed into her body and then through the placenta to affect the foetus.

    Too confronting.

    It’s much, much more reassuring to believe that malign outside forces caused such problems.

    I know I am not a “typical” autism mom, but I feel knowing would be more important than my guilt. I think most parents of autistic children already feel incredible guilt. Some deal with it by believing some evil entity (big pharma™, government, CDC, FDA etc…) intentionally caused their children to become autistic. It would be very hard for most of us to face facts if this conjectural “cause” were found, but if it would help to prevent problems in the future it would be worth it.

    I think many parents with autistic children have gotten over-zealous (stating the obvious, I know) but I can’t say I blame them for getting angry, just for staying ignorant. One year ago, when I found RI I was very angry and had wrong ideas, probably still do (look in the archives for my comments in 2009, not pretty). It is very difficult to refine ones understanding, but the facts are more important to furthering our understanding.

    That said, I don’t think there will ever be found a “cause” of autism, just risk factors (Genetic, perhaps. Environmental, perhaps. Both?) and possible preventative measures for those at risk.

    The biggest issue has to be caring for our children now, and developing the resources they need to meet their potential. The majority of autistics can learn to live in society and be happy and successful. Finding out how to teach them effectively and putting services in place to support them as adults. These are the things our children need. I think parents need to stop getting distracted looking for a “cure”, accept their children’s extraordinary needs and move foreword.

    PD does make well thought out comments. I think he should be treated with respect FWIW. I can’t say I agree with the direction of his argument, but he is being reasonable and deserves the same courtesy.

  57. #57 LW
    September 4, 2010

    passionlessDrone, I have no experience with children. My impression from reading, and from people around me who do have children, is that infants do occasionally have fevers. I find it difficult to believe (but I’m willing to be educated) that for all of human history, the average child never had a single episode of fever prior to the age of sixty days. I frankly find it difficult to believe that that is even true now in twenty-first century America, but again I am willing to be educated.

    My objection is to the term “infection” when speaking of vaccines that do not include live diseases. An infection gives rise to a race between the infecting organism, trying to be fruitful and multiply, and the defending immune system, trying to kill it off before it is well-established. If the immune system is slow off the mark, the patient may become very ill or even die. A vaccine that includes only antigens or deactivated viruses is simply there, giving the immune system a good look at the enemy. If the immune system doesn’t respond at all, the patient just goes on about his or her life but doesn’t have the desired immunity.

    Your argument is that immune system activation, not infection, is the issue, so I don’t think you should be asking “How many infants were naturally infected with Hep-b, influenza, rotavirus, diptheria, pertussis, tetanus, and hib on their sixtieth day from the womb?” since that isn’t anything like what is happening now. Using the word “infection” in this case strikes me as unnecessarily inflammatory, and it is a strawman.

    You continue to use it in your follow-up comment: “we have precious little evidence to say that the response and corresponding effects of an infection at three, five, or ten years can safely be equated with one at two months.” Since we’re still not talking about infection at two months, this is still inflammatory and a strawman.

  58. #58 Orac
    September 4, 2010

    Again, great thought. Please understand that neither Orac nor most of the other “scientists” here are interested in thoughtful discussion. Just speculative and vituperative narrative about possible toxins (vaccines, aluminum) rather than a reasoned debate about known toxins like PDBEs. The goal is getting others angry and generating traffic.

    Confirmation bias, Dr. Jay. You only seem ever to show up at my more “flame-throwing” posts. I can’t recall ever seeing you show up at my more thoughtful posts, like this:

    http://scienceblogs.com/insolence/2010/09/the_saga_of_avastin_and_breast_cancer.php

    Or this post, where I took Nancy Snyderman to task for going too far:

    http://scienceblogs.com/insolence/2010/07/dr_snyderman_please_be_more_careful.php

    Come to think of it, why are you making such a comment on this post, which basically agrees that the Fletchers should have been given the benefit of the doubt and compensated a lot sooner?

    I sense a new meme that Dr. Jay will be beating into the ground. It’s basically a variant of the “pharma shill” gambit. Unable, however, to connect me in any way with a pharmaceutical company, Dr. Jay has decided that I’m some sort of blog traffic whore who only does what he does for the money and fame that comes with more traffic and repeats that lie over and over again.

    Of course, Dr. Jay is well aware that I have another blog under my real name and that I receive zero compensation for doing that. I do it because I’m passionate about science-based medicine.. He is well aware that sometimes I even crosspost the very same post (with minor modifications) about vaccines over there. He is also aware that I have written posts very critical of him–yes, him–over at that other blog without crossposting that criticism here. Yet, oddly enough, Dr. Jay has never, ever shown up at that other blog to complain or criticize what I wrote over there. He would rather show up here, because here he can whine about how mean and nasty I supposedly am, what a self-indulgent traffic whore he seems to think me to be.

    Sorry, Dr. Jay. If you want to show me up, show up at my other blog in the posts about vaccines and I might start to take your whines a little more seriously. In the meantime, since you can’t answer the criticisms here, you’ve simply jumped onto the convenient (and false) claim that I’m in it for the money and notoriety.

  59. #59 passionlessDrone
    September 4, 2010

    Hi colmcg –

    Thank you for the kind words.

    Q: if there was a predisposition towards certain kinds of adverse reactions following vaccination as you suggest, would this have been established via the epidemiological studies that have been carried out to date (fombonne madsen etc)?

    Maybe. Unfortunately, the studies you refer to were all about the MMR, which generally is not given until at least a year of age, and up to eighteen months. These studies have no way to track the effect, if any, of shots given shortly after birth, or at two, four, and six months. Similarly, the thimerosal related studies, provides us information regarding the presence or absence of thimerosal, not the act of invoking an immune response. The animal studies I have been reading tend to be focussed on what would seemingly be an earlier stage of life, if applicable to humans; though the jump from rodent to human is fraught with unknowns.

    While the people who claim to have witnessed dramatic regressions in their child following MMR vaccination are definitely vocal; my concerns are more along the lines of subtle changes. The more we learn about things like exposures during development, it seems that our conclusions towards no effect are forced downwards as we learn apply finer filters.

    One recent study, Smith (2010) did perform an analysis of children from a thimerosal study and used thimerosal values as proxies for vaccine reception. I’m not convinced it was comprehensive enough to spot a subpopulation, and it was comprised of a selective population, but none the less, I must admit its findings do argue against my ideas.

    – pD

  60. #60 LW
    September 4, 2010

    Quoth Dr. Gordon,

    @LW I wonder just how much experience Dr. Gordon really has with vaccines. I know, I know, 31 years practicing, but I’ve been reading Respectful Insolence for years, and he’s always said that he vaccinates only rarely.

    I have a huge amount of experience with vaccines. I have been in private practice for only 31 years but involved in medicine and medical research since 1967.

    On the other hand::

    My vaccine schedule? Either none or just a DPT in the first 24 months of life. I think that there’s a greater risk vaccinating males under 24 months and would prefer not to unless there are special circumstances. I use very few other shots except the Varivax as a child approaches ten years because teen and adult pox are nasty and even a little dangerous especially during pregnancy. I give Hep B vaccines to nursing student/moms and dads, other medical moms and dads and higher risk teens and college kids.

    I know several doctors who have been in private practice since the mid-60s. All of them have more clinical experience than Dr. Gordon, and much more than Orac. All of them have a bit of experience with cancer (I expect any doctor sees cancer patients once in a while), but if I had a question about cancer, I’d rather ask Orac than one of them. His clinical experience is directly in oncology and theirs, while much more extensive, isn’t in oncology and isn’t worth much in this context.

    So Dr. Gordon has 31 years of clinical experience, and involvement of some kind with medicine and medical research for 43 years. That does not alter the fact that he gives minimal vaccines in his practice. He vaccinates none of his patients against rubella, not even young women who are not immune and may get pregnant, unless they have “very unusual travel plans”. He states that he does not regularly vaccinate against Hep-B (only in certain cases not including young children), and apparently he does not regularly vaccinate against influenza, Hib, polio, rotavirus, or pneumococcal disease, since he didn’t feel the need to mention any of them.

    I see no reason to believe that Dr. Gordon has much relevant and recent experience with vaccines.

  61. #61 colmcq
    September 4, 2010

    Thanks PD. A nice, reasoned response 😉

  62. #62 Dangerous Bacon
    September 4, 2010

    pD:“The study you linked to is primarily concerned with T and B cells, not the initial inflammatory response. I think I needed to bee even more concise with my thoughts. Sorry.”

    The study I linked to (as well as numerous others readily found with a simple PubMed search) measured cytokine response, the very aspect you complained was totally absent from research into pediatric vaccines. Your attempted shifting of the goalposts here does not even make sense.

    I do applaud your posting a detailed passage from another linked paper and attempting to explain why its findings concern you regarding vaccines (though you still seem to have the idea that infants exist in a pristine environment without any immune challenge unless someone vaccinates them, which is ridiculous). I hope you will continue to be specific in this manner instead of just posting long lists of papers which could be interpreted as a form of “Gish gallop”. This as you may know is a classic altie tactic of tossing out an extensive array of quotes and links meant to overwhelm opposition, but which on closer examination show minimal to no relevance to the subject, are taken out of context or represent outmoded and debunked views.

    I would also like to know which of your sources have equated immunization with infection in terms of potential negative effects on development, or claimed that infants would exist in a safe bubble without any form of antigenic challenge were it not for vaccination.

  63. #63 passionlessDrone
    September 4, 2010

    Hi Dangerous Bacon –

    The study I linked to (as well as numerous others readily found with a simple PubMed search) measured cytokine response, the very aspect you complained was totally absent from research into pediatric vaccines.

    The study measured cytokine response to subsequent challenge with measles, not whether or not the children experienced increases in inflammatory cytokines in vivo systemically as a result of the vaccination. Look at the HPV vaccination I posted above in 256 for an example; that’s a lot different than the study you posted. The adults in both groups in the study in 256 weren’t in a bubble, but only one group experienced an increase in pro-inflammatory cytokines. Why?

    I hope you will continue to be specific in this manner instead of just posting long lists of papers which could be interpreted as a form of “Gish gallop”.

    Very well. My style is already lengthy, and I was trying to keep from writing a manifesto.

    I would also like to know which of your sources have equated immunization with infection in terms of potential negative effects on development, or claimed that infants would exist in a safe bubble without any form of antigenic challenge were it not for vaccination.

    None of them. But again, evaluate the HPV vaccine study I referenced in 256; it isn’t about baseline exposure, it is about robust respose. An increase in pro-inflammatory cytokines is an increase in pro-inflammatory cytokines, there isn’t any escaping that. The mechanism of action, initiation of an immune response, is something that happens during vaccination.

    You aren’t going to argue that vaccination doesn’t result in a rise pro-inflammatory cytokines are you?

    – pD

  64. #64 Todd W.
    September 4, 2010

    @pD

    One thing that occurs to me regarding the study you posted at #256 (besides the rather small control group) is that they are looking at what happens after the introduction of non-self particles that have not already been recognized by the body vs. particles that most likely have (the placebo). How is this different than any other first-time exposure to a non-self particle, whether it be a vaccine or a bit of something that gets into a cut, is inhaled or is swallowed?

    Unfortunately, I don’t have access to the full text of that article to see what they actually did (or how they managed to get significant results with so few subjects in the control group). It just seems to me that it doesn’t exactly show what you seem to think it shows. Or at the very least, that the significance of what it shows doesn’t necessarily support the idea that vaccination at a specific point is either better or worse than exposure to some other intruding particles at the same point.

  65. #65 Jay Gordon
    September 4, 2010

    Orac, my apologies for taking the conversation in a completely unnecessary direction. Your post #259 is correct. In the heat of this discussion I believe I was rude and I am sorry. I am in the midst of reading your excellent post about our mutual hero Dr. Folkman.

    Have a nice weekend.

    Jay

  66. #66 Todd W.
    September 4, 2010

    @Dr. Jay

    I’m sorry that you’re tarring a well-informed, well read fellow poster like pD with the same brush you use for me.

    First off, Dr. Jay, pD is not being tarred with the same brush as you. Notice how people are actually giving his statements some serious thought and asking respectful, intelligent questions. They may not necessarily agree with him, but they aren’t scoffing at him.

    pD, on the other hand, supports his ideas with peer-reviewed research and a questioning point of view.

    And therein lies the reason pD is treated with far more respect than you, Dr. Jay. Notice how pD supports his assertions with evidence and science. Very unlike you. Notice, also, how pD actually answers the substantive questions posed to him, and quite promptly, I might add. Another trait that is quite at odds with your own behavior.

    For instance, we are now going on day 6 since these questions were first asked of you. Still, no answer:

    * You say that vaccine side-effect denialists (VSEDs) exist here at RI. Please provide a concrete example of VSED behavior, which you have defined as saying that there are no or virtually are no side effects.
    * What is your definition of “those at highest risk” (in the original context of the question – HiB)?
    * Am I correct that your recommendation is that except for people who meet that definition, everyone else should not bother with the [HiB] vaccine?

    It is for those reasons, Dr. Jay, that pD is treated tolerably well, while you, with all due respect, are seen as something of a joke. That may hurt your feelings, but really, you should know better by now, since you have been through the ringer so much here. You ought to know what kind of things you should be doing, such as actually answering questions and supporting your claims with something other than mere personal stories and tales.

  67. #67 Jay Gordon
    September 4, 2010

    Todd, I apologized to David for my rudeness and I’m also sorry I’ve offended you to the point that you relentlessly ask the same questions over and over. I’ll respect your questions as best I can by answering one more time:

    I am not willing to spend the time searching the archives to find a post denying all vaccine side effects. If you say there are none, I’ll accept the possibility that you have done that archive search and merely say that I must then accept that my only problem will be when and if VSEDs attribute most major vaccine side effects to coincidence. I take issue with that attribution. I will no longer dispute your claim that there has never been a single person here claiming that vaccines have no side effects.

    I cannot define the type of high risk patient who would benefit sufficiently from the HIB vaccine for me to recommend it with enthusiasm. Perhaps a family traveling to countries where there is still a large number of HIB cases would be one example. In most of the developed world herd immunity protects children and has nearly eradicated the invasive form of HIB. I am not recommending that we stop giving the vaccine. I do tell parents that the choice is theirs and that, because of the vaccine and herd immunity, their informed choice may be to decline the vaccine.

    No, I don’t recommend that “everyone else should not bother with the [HIB] vaccine. I recommend that parents inform themselves, trust their doctors’ opinions and make their decision based on the facts available.

    Those answers will have to suffice. I have no others.

    Have a nice holiday weekend, Todd.

    Jay

  68. #68 Dangerous Bacon
    September 5, 2010

    pD: “I’d love to see any study on a pediatric vaccine that detailed the level of the immune response in a metric other than antibody generation. Do you know of any?”

    (pD is informed that numerous vaccine studies look at both cell-mediated and humoral responses to immunity. The goal posts shift.)

    pD: “pD: “…what if I said, ‘proinflammatory cytokine generation’? What then? Can you point me to a pre / post vaccination study with pediatric vaccines that measures those?”

    (pD is given a link to a pediatric vaccine study that measures proinflammatory cytokine response following immunization and given directions to finding other similar papers. pD responds that, well, the linked study isn’t quite cytokine-y enough for him/her.)

    pD: “pD:”The study you linked to is primarily concerned with T and B cells, not the initial inflammatory response. I think I needed to bee even more concise with my thoughts. Sorry.””

    (pD is reminded that the study in question does in fact deal with this inflammatory response, the very issue of cytokine generation which pD implied had never been studied in vaccinated children. The goal posts are shifted again.)

    pD: “The study measured cytokine response to subsequent challenge with measles, not whether or not the children experienced increases in inflammatory cytokines in vivo systemically as a result of the vaccination.”

    This appears to be not just another goalpost shift but incorrect as well, as the linked study (as well as another in measles-immunized infants with a link on the same page as the study abstract) measured cytokine response in children (i.e., from baseline levels following immunization).

    No doubt pD will have another goalpost shift to present in response (pD is sort of the human equivalent of influenza, which drifts and shifts its genome frequently to complicate immunization efforts). These examples, however are sufficient to show the game being played.

    I agree with some other posters that pD is an improvement on other posters here – certainly a lot better than the antivax trolls and pseudomedical “authorities” that engage in denial about the seriousness of once-common infectious diseases and the success of immunization in vastly reducing or eliminating them, and personal nastiness (interspersed with complaints about how others are mean to them). Given pD‘s tactics of goalpost-shifting, his/her equating of vaccination with inducing “disease”, Gish galloping and assurance of being open to many theories of autism etiology while in actuality singlemindedly focusing on vaccines, I fear that we are seeing a person who, while less obvious and not as vituperative as his/her peers, is still deeply into antivax ideology.

    For the benefit of any who see vaccination as a hazardous interruption into the lives of infants and children who otherwise would be unexposed to DISEASE ORGANISMS and TOXINS, here’s an excerpt from an interesting paper about cytokines. It explains that such immune modulators are constantly acting even in the absence of overt disease:

    “Defining the role of cytokines in nonpathological states requires careful definition of what constitutes the pathological state. Bacteremia (i.e., viable bacteria in the bloodstream) is clearly an example of an extreme pathological condition. There is no question that cytokines are produced, circulate, and have profound influences on physiological function in sepsis. One might propose that the other extreme, namely absolutely no bacterial burden, would represent a purely physiological condition. But such a condition does not exist in nature. A small but steady influx of microorganisms and their toxins through the gastrointestinal mucosa and other epithelial barriers is constantly and effectively handled by resident macrophages and local lymphoid tissues. Therefore, we always exist in some relative state of infection.”

  69. #69 titmouse
    September 5, 2010

    One of the reasons Respectful Insolence rocks is because of people like Dangerous Bacon, who take the time to cite references and describe the points made within them. That’s a lot of work.

  70. #70 titmouse
    September 5, 2010

    Dr. Jay,

    As far as I can tell, your argument against the current recommended vaccine schedule boils down to, “Listen to me; I know what I’m talking about.”

    What happens if you are hit by a bus today? Won’t mankind suffer the loss of your evidence –something apparently so convincing that it trumps all the data aggregated by the CDC over several decades?

    Thankfully, humans invented something called “science,” which is a method of examining claims using tests of corroboration, falsification, logic, and parsimony. The corroboration bit frees us from the tyranny of people citing themselves as their own authority.

  71. #71 passionlessDrone
    September 5, 2010

    Hi Todd W –

    One thing that occurs to me regarding the study you posted at #256 (besides the rather small control group) is that they are looking at what happens after the introduction of non-self particles that have not already been recognized by the body vs. particles that most likely have (the placebo). How is this different than any other first-time exposure to a non-self particle, whether it be a vaccine or a bit of something that gets into a cut, is inhaled or is swallowed?

    Vaccines are achieving their end point, immunological memory of a pathogen in two primary ways; introduction of the bacterial or viral structures that our bodies have developed mechanisms to identify (i.e., via toll like receptors), and inclusion of adjuvants that insure an immune response is generated considering the relatively small amount of pathogen material included in the vaccine. The vaccine is designed to invoke an immune response; without one, you don’t get your desired endpoint, eventual presentation of the molecular structure of the pathogen to memory retaining cells of the immune system. A vaccine that doesn’t invoke an immune response is just a shot in the arm.

    Again, consider the frequency of minor adverse events as reported from the CDC, available here. Check out the DTAP, which causes a fever in about 25% of the cases. Do you think you’ve goten a fever 25% of the time after you ever got a cut?

    Similarly, the kernel of truth to the ‘bubble boy’ theory as presented to me here in several situations, is that our bodies are engulfed with antigens millions of times a day; every time you breath, drink from a glass, or eat a bite of food you ingest bacteria, yeast and other microbes. Also, don’t forget that the lungs, mucous, skin, and gastric acid are well developed systems for helping to insure that lots of these things are kept external to the body. Things that come out of needles bypass all of those. We must strive not to over simplify.

    A baby infant is exposed to ‘new’ things through many of the methods you describe from the second they are delivered. Do you think they suffer from adverse reactions such as fever at the rate of vaccination? When would it stop?

    It just seems to me that it doesn’t exactly show what you seem to think it shows.

    It shows exactly what I think it shows if the argument to be defeated is the notion that there is no difference immunologically between getting a shot and the multitudle of things we encounter on a daily basis.

    I’m going to attempt a rather lengthy response to Dangerous Bacon that hopefully will go into further detail towards why I think this study shows precisely what I think it does, and why the study he provided is a poor equivalent.

    – pD

  72. #72 sesli sohbet
    September 5, 2010

    Jay’s assumption that he is so much smarter than the Scientific Consensus is exactly like the climate change denialists. He is of course oblivious to the irony of calling us denialists.

  73. #73 dt
    September 5, 2010

    pD, I think you are in danger of generalising here.
    Fever correlates with certain immune responses, but is not invariable with infection, not specific for infection and is not a good surrogate for either the nature of the immunopathogenic reaction to infection or the aetiological trigger organism.

    Effective vaccination will usually reliably produce a specific immune response, yet despite effective vaccination, only a small minority of recipients will also get a febrile response. You quote a high 25% incidence with DTaP (which I assume is a correct quote, I haven’t had a chance to check your citation, but this is in excess of the usual incidence of fever following even pentavalent or hexavalent combination vaccines). If only a small fraction of vaccinees get fever, one should not presume fever and vaccination have immunopathological equivalence.

    It shows exactly what I think it shows if the argument to be defeated is the notion that there is no difference immunologically between getting a shot and the multitudle of things we encounter on a daily basis.

    No, I don’t recall anyone here impliing or stating that the multitude of antigenic challenges we encounter every day are directly equivalent to vaccination – that is a straw man.

    It has been proposed that the human infant’s immune system is potentially capable of responding to thousands of contemporaneous antigenic challenges – something I have no problem accepting. And I accept some challenges are different to others. However you seem to be saying that fever (which is a very common problem in infancy, and which does not even need to arise from invasive infection) is the key to the problems that concern you and that this is not something that will affect an infant until they are vaxed. That notion (if it is indeed what you are saying) is plainly wrong.

    The other thing you seem to forget is that fever may be beneficial, and not necessarily detrimental.

  74. #74 passionlessDrone
    September 5, 2010

    Hi Dangrous Bacon –

    You seem quite hung up on the idea that the study you provided somehow illustrates that I am changing my position; it would seem I need to provide additional detail on my thoughts, and as usual, this has been a useful learning experience for me regarding the need for clarity when defining my position. The balance between length of response that is overly technical is a difficult one, but I have apparently done a poor job deliniating where I think there might be a potential for problems from vaccination, and which types of studies I think would shed light on this problem. So more clarity it is.

    While Effects of Interleukin-12 and Interleukin-15 on Measles-Specific T-Cell Responses in Vaccinated Infants does technically measure one inflammatory cytokine as a result of vaccination, it only does so several months after the fact. This study, at the end of the day is about developing better ways for enhancing immunological memory, in stark contrast to attempting to evaluate the immediate pro-inflammatory response, which as I will attempt to detail below, is my focus.

    The animal studies I used to form my opinions, including the ones referenced above have all utilized a single exposure of an agent to invoke or mimic an inflammatory cytokine response, and in some instances, great care has been taken to insure that the inflammatory cytokine release was responsible for persistent resullts in the treatment group.

    So lets take a look at the methods section from, Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats, a link to the full paper which I published above. For space considerations I am only posting parts of the methods, but the entire paper is freely available.

    Step 1: Animals were injected wiith LPS to ‘determine whether a single inflammatory event during development can influenze seizure susceptibility in later life’.

    Lipopolysaccharide injections. To determine whether a single inflammatory event during development can influence seizure susceptibility in later life, male rats were injected intraperitoneally on P14 with LPS (Escherichia coli, serotype O26:B6; 25, 100, or 250 µg/kg) or pyrogen-free saline. We previously established that 100 µg/kg LPS generates a mild inflammatory response in the host that lasts for 6–8 h (Heida et al., 2004; Ellis et al., 2006). Additional groups of rats were also injected on P14 with saline or LPS (100 µg/kg) to evaluate both the acute and chronic effects of LPS on cytokine and glial cell activity in the hippocampus (a seizure-vulnerable region). P14 is considered by some to be developmentally equivalent to a human infant of 1–2 years of age (Gottlieb et al., 1977; Avishai-Eliner et al., 2002). To determine whether there was a critical age at which LPS could cause long-term changes to seizure susceptibility, rats were also treated with saline or LPS (100 µg/kg) at P1, P7, or P20.

    Step 2: Several hours after infjection, brain tissue was evaluated for cytokine expression. This is an absolutely critical difference between what I am proposing and the study you provided. I’ll provide the pertinent snipets to make this point shortly.

    Cytokine assay and glial cell immunohistochemistry. To assess the acute effects of LPS on P14 rat microglia and cytokine (IL-1β and TNF) levels, we collected blood plasma at 2 h after injection, as well as hippocampal tissue 3 and 6 h after LPS (100 µg/kg) or saline injection (n = 4–6/group). Previous reports show that cytokine expression is increased within the adult hippocampus 6 h after peripheral LPS (Nguyen et al., 1998; Turrin et al., 2001; Oprica et al., 2006).

    Step 3: To validate that the changes being observed were, indeed, the result of an inflammatory response, the authors also performed direct injections of an inflammatory cytokine, TNF-alpha, as well as TNF-Alpha antibodies to discern if effects similar to LPS could be achieved.

    Intracerebroventricular injections. Cytokines are synthesized and released in the brain after a peripheral injection of LPS (Nguyen et al., 1998; Turrin et al., 2001). To evaluate the contribution of the central cytokine responses to peripheral LPS on the programming of the long-term effect on seizure susceptibility after peripheral LPS administration, P14 rats were given intracerebroventricular injections of the natural antagonist for IL-1, IL-1ra (Anakinra; 10 or 50 µg/5 µl), or the TNF neutralizing antibody (Infliximab; 50 µg/5 µl), concurrently with LPS (100 µg/kg, i.p.) or saline. We chose these dosages of IL-1ra because previous reports indicate that 4 µg intracerebroventricularly effectively antagonizes effects of peripheral pyrogens on rat behavior (Kent et al., 1992) and that 10 µg intracerebroventricularly significantly reduces the incidence of febrile seizures in rat pups (Heida and Pittman, 2005). In other P14 rats, rrTNF was administered intracerebroventricularly (bilaterally) at 1 µg/2.5 µl per side to determine the role of this cytokine in promoting long-term seizure susceptibility (n = 5–7/group). Dosages of TNF similar to this have been shown to influence neuronal transmission in the absence of negative side effects (Ignatowski et al., 1999; Reynolds et al., 2004). The surgical procedure, described in detail previously (Heida and Pittman, 2005), was performed under halothane anesthesia and required 10 min to conduct. Animals were returned to their dams, and seizure thresholds were examined 6–8 weeks later using the PTZ paradigm described above.

    To recap, some animals were injected with LPS, a known immune stimulant that triggers an inflammatory response via TLR4, some subjects were euthanized and assayed for brain cytokine expression within a few hours, and another set of animals were given injections of either tnf-alpha antibodies alongside LPS, or straight tnf-alpha in the absence of LPS. This is a study about the effect of the result of the immune response.

    Note:For space considerations, I am leaving out some of of the methods regarding the mechanisms by which the researchers went on to discern seizure susceptibility in the adult rats. I do not believe that they are necessarily salient for a discussion that involves the potential for an inflammatory cytokine response to have very difficult to predict consequences if present during critical developmental windows. But the entire paper is quite interesting.

    Now, lets compare this set of methods with the paper that you provided, Effects of Interleukin-12 and Interleukin-15 on Measles-Specific T-Cell Responses in Vaccinated Infants

    Subjects included 115 infants receiving well child care in Palo Alto, California, who received their primary measles vaccination at 6 (n = 33), 9 (n = 35), or 12 (n = 47) mo of age. Blood samples were taken before, 12 wk after monovalent measles vaccine given at 6 or 9 months of age, or 24 weeks after MMR administered to the 12-month-old infants.

    Ten children (aged 5-11 y) and 15 adults (aged 20-49 y) who had received two doses of MMR (the children according to the routine schedule of 12 mo and 5 y, and adults in childhood) were also evaluated with one blood sample. Not all assays were performed on all samples.

    Again, my presentation hasn’t been sufficiently clear to detail that my concerns involve the immediate rise in inflammatory cytokines following immune challenge, as was measured in Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats, but I think that any intellectually honest reading of these methods will, at the very least, be forced to admit that there is a significant difference between evaluated for cytokine expression several hours after challenge, and measurements that were taken either twelve or twenty four weeks after challenge. Do you agree?

    More from your paper:

    Supernatants from PBMCs stimulated with measles antigen or uninfected cell control in the presence or absence of rhIL-12 (final concentration 5 U/mL) or rhIL-15 (final concentration 0.25 ng/mL and 2.5 ng/mL) each alone or in combination were collected from wells on days 5 and 7, and stored at -70°C. Preliminary studies showed peak production of IFN-γ between days 5 and 7 post-stimulation

    Here we can see that while an inflammatory cytokine, INF–γ was measured, it was only done as a result of subsequent stimulation with measles antigen. This is qualitatively different than the methods described in the study I linked to; and in fact, speaks very directly to the question I asked of you in post 238, but you neglected to to answer, nor include in your blockquote fest attempt to paint me as a goalpost shifter, namely:

    Considering I specifically mentioned that several studies showed attenuation of effects based on administration of anti-inflammatory agents, could you should me any studies on innate immune functioning that would be affected by similar agents with vaccination?

    Regarding Effects of Interleukin-12 and Interleukin-15 on Measles-Specific T-Cell Responses in Vaccinated Infants, the answer to this question is quite resoundingly, no.

    From a technical standpoint, I will admit, this study does evaluate for a pro-inflammatory cytokine following vaccination. Unfortunately, from a meaningful standpoint, it tells us nothing about the immediate inflammatory response following vaccination that is at the heart of my concerns.

    This appears to be not just another goalpost shift but incorrect as well, as the linked study (as well as another in measles-immunized infants with a link on the same page as the study abstract) measured cytokine response in children (i.e., from baseline levels following immunization).

    Would you be willing to post a PMID, title, or link to these studies?

    No doubt pD will have another goalpost shift to present in response (pD is sort of the human equivalent of influenza, which drifts and shifts its genome frequently to complicate immunization efforts). These examples, however are sufficient to show the game being played.

    If I wasn’t sure that I’d failed at properly defining my position, I would be a little offended at this point.

    I agree with some other posters that pD is an improvement on other posters here – certainly a lot better than the antivax trolls and pseudomedical “authorities” that engage in denial about the seriousness of once-common infectious diseases and the success of immunization in vastly reducing or eliminating them, and personal nastiness (interspersed with complaints about how others are mean to them). Given pD’s tactics of goalpost-shifting, his/her equating of vaccination with inducing “disease”, Gish galloping and assurance of being open to many theories of autism etiology while in actuality singlemindedly focusing on vaccines, I fear that we are seeing a person who, while less obvious and not as vituperative as his/her peers, is still deeply into antivax ideology.

    My posting history here is relatively sparse, though verbose when present. Anyone interested (I doubt that is few and far between), could see that my discussion at places like LBRB, or on my own blog are not confined to the vaccine space. Further insistence on this particular point seems to be less than useful. Google searches can provide anyone actually curious with the answer.

    At risk of being accused of a spammer as opposed to a “gish gallloper”, I’d like to specifically address the issue of ‘equating vaccniation with inducing “disease”‘ with more detail. The study I posted above shows with great elegance that tnf-alpha during development can permenantly modify susceptibility to seizures through several possible mechanisms. Here is a snipet from the discussion section of those papers.

    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.

    We showed that the LPS-precipitated changes to adult seizure susceptibility are linked to a critical developmental period (P7 and P14). This time window is similar to the period we previously observed for other physiological changes caused by postnatal LPS (Spencer et al., 2006b). Interestingly, this is also the time when long-term potentiation-induced plasticity first becomes apparent (e.g., P7) and shows maximum responsivity (e.g., P15) (Harris and Teyler, 1984). Thus, we may suspect that some permanent change has taken place during this relatively sensitive period of development in which the effects of LPS (and TNF) can modify synapses. Alternatively, TNF is known to be essential in the normal development of the hippocampus through regulation of neurotrophic factors such as nerve growth factor and brain-derived neurotrophic factor (Golan et al., 2004). The possibility exists that “optimal” levels of TNF may be perturbed after LPS-induced inflammation, even at potentially low doses (Fig. 2A). Future studies will be needed to address the potential mechanisms through which postnatal TNF permanently alters neuronal function to enhance excitability and seizure propensity.

    Clinically, CNS infections occur with some frequency in young children and may be associated with an increased risk for late unprovoked seizures (Rantakallio et al., 1986; Herman, 2002). In those patients surviving CNS infections, the risk for epilepsy was highest during the first 5 years after infection and remained elevated for the next 15 years (Annegers et al., 1988). Currently, there is limited clinical evidence to suggest that peripheral childhood infection contributes to the etiology of adult epilepsies. However, based on the novel data presented here, relatively mild early-life inflammation may be associated with permanent modifications in seizure susceptibility that persist well into adulthood. This may warrant additional patient history review to ascertain whether such a relationship exists. Our data raise the possibility that the known differences in adult seizure susceptibility to very similar insults may have their etiology in a common postnatal infection.

    There seems to be a lot of concern about my supposed confusing vaccination with disease state; but lets be clear about the mechanics of this study. None of the treatment aniimals were infected with any actual pathogen. None of them actually got sick. None of them had a disease or an infection. Even given that, the authors equating the immune challenge resulting from either LPS, or direct tnf-alpha injection, with ‘a common postnatal infection’.

    What should we make of this? Is it possible that the authors of this paper, the peer review staff at the journal that published it, and the people who funded the study, all are unable to discern that there is a difference between having a disease and having an immune challenge? Does this scenario really make sense to anyone?

    The reason is that that the actionable effect, the immune response, and in this case, specifically tnf-alpha, is created as a result of immune stimulation; and that pro-inflammatory cytokine response is absolutely the same if it is triggered by an actual pathogen, LPS, direct tnf-alpha injection, or dare I say, vaccination. If anyone has any doubt about this, again refer to the study on the HPV vaccine I posted in 256; one group and one group only developed a significant increase in pro-inflammatory cytokines, including tnf-alpha. We only have one innate immune system to trigger and vaccines trigger it. There isn’t any bypassing this simple fact.

    A common theme on this thread and in many others here seems to be asking someone a question, and then bashing them if they refuse to answer. So lets try. Dangerous Bacon:

    Does a vaccine initiate an immune response? Does this immune response include the creation of pro-inflammatory cytokines, such as tnf-alpha, IL-6 or Il-1beta? And finally, if the answer to those questions is yes, what is the functional difference between an pro-inflammatory cytokine release when the trigger is vaccination, versus infection with an actual pathogen?

    I have provided direct, clinical evidence in post #256 to answer the first two questions, but it is still possible, though unlikely, that Dangerous Bacon would like to dispute them.

    There are unknowns about the robustness of an LPS induced reaction as compared to a vaccine, but at the end of the day, LPS and the vaccines are recognized by toll like receptors and initiate the innate immune response. In other words, perhaps an actual infection creates a more vigorous immune response than a vaccination; I’d say this is certainly possible, but barring any studies, we cannot know for sure. The studies I mentioned regarding synergistic effects of stimulating multiple toll like receptors simultaneously makes this a difficult problem.

    But, that is why our studies on particular immunological functions within the autism realm can help us. Earlier I referenced, ,Differential monocyte responses to TLR ligands in children with autism spectrum disorders . Here is the abstract:

    Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. Recent evidence has suggested that impairments of innate immunity may play an important role in ASD. To test this hypothesis, we isolated peripheral blood monocytes from 17 children with ASD and 16 age-matched typically developing (TD) controls and stimulated these cell cultures in vitro with distinct toll-like receptors (TLR) ligands: TLR 2 (lipoteichoic acid; LTA), TLR 3 (poly I:C), TLR 4 (lipopolysaccharide; LPS), TLR 5 (flagellin), and TLR 9 (CpG-B). Supernatants were harvested from the cell cultures and pro-inflammatory cytokine responses for IL-1beta, IL-6, IL-8, TNFalpha, MCP-1, and GM-CSF were determined by multiplex Luminex analysis. After in vitro challenge with TLR ligands, differential cytokine responses were observed in monocyte cultures from children with ASD compared with TD control children. In particular, there was a marked increase in pro-inflammatory IL-1beta, IL-6, and TNFalpha responses following TLR 2, and IL-1beta response following TLR 4 stimulation in monocyte cultures from children with ASD (p<0.04). Conversely, following TLR 9 stimulation there was a decrease in IL-1beta, IL-6, GM-CSF, and TNFalpha responses in monocyte cell cultures from children with ASD compared with controls (p<0.05). These data indicate that, monocyte cultures from children with ASD are more responsive to signaling via select TLRs. As monocytes are key regulators of the immune response, dysfunction in the response of these cells could result in long-term immune alterations in children with ASD that may lead to the development of adverse neuroimmune interactions and could play a role in the pathophysiology observed in ASD.

    Given the same trigger, the immune response from children with autism included a marked increase in pro-inflammatory IL-1beta, IL-6 and TNFAlpha. Similar studies that have shown an exaggerated production of inflammatory cytokines in the autism realm would include Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder, or Preliminary evidence of the in vitro effects of BDE-47 on innate immune responses in children with autism spectrum disorders.

    Even if for most infants the immune response from a vaccination would be relatively weak, we cannot say the same thing for an infant who will go on to develop autism; they may be genetically, epigenetically, environmentally, or otherwise predisposed to react more vigorously to the same challenge. And the way they react, with increased levels of inflammatory cytokines, are the very same chemical messengers identified in the animal study above.

    Finally, I thought I’d spend my last hotlink to Macrophage Migration Inhibitory Factor and Autism Spectrum Disorders. On several occassions on this thread the problem with correlation and causation was brought up regarding immune abnormalities in autism; this is a problem, and we don’t have answers currently. That being said, I think that it is time to dispell the notion that the only people who believe such a relationship could be causal are internet cranks.

    Here is the abstract:

    Macrophage migration inhibitory factor (MIF) is an upstream regulator of innate immunity that promotes monocyte/macrophage-activation responses by increasing the expression of Toll-like receptors and inhibiting activation-induced apoptosis. On the basis of results of previous genetic linkage studies and reported altered innate immune response in autism spectrum disorder, we hypothesized that MIF could represent a candidate gene for autism spectrum disorder or its diagnostic components.

    Look at how gracefully this fits with the Enstrom study above; one finds genetic linkages and associated increased levels of a messenger known to promote monocyte/macrophage activation responses; and the other finds that when monocytes are stimulated, those from children with autism respond more vigorously. It is completely unsurprising.

    Despite the problems in understanding causation, one thing is certain, having autism isn’t causing children to be born with the MIF promoter allele.

    The following is from the Introduction:

    Given a complex model of the inheritance of ASD, possible etiopathic mechanism might involve an immunologic insult to the central nervous system (CNS) in individuals with a susceptible genetic background. We evaluated the genetic association between the innate mediator, macrophage migration inhibitory factor (MIF), and different behavioral components of ASD. MIF is encoded in a functionally polymorphic locus on chromosome 22q11.2 (Online Mendelian Inheritance in Man No. 153620, GenBank accession No. NM 002415) that has been associated with the incidence or severity of different autoimmune inflammatory conditions. Given its location in a previously identified locus of interest and its upstream action in immunity, MIF may represent acandidate gene for ASD or its components. Thus, the central hypothesis underlying this research was that a genetic predisposition to a particular level of MIF production may lead to a proinflammatory profile of cell activation that, if present during a neurodevelopmentally sensitive period, might contribute to the etiopathogenesis of autism.

    This was an expensive, and time consuming study to
    perform. It involved genotyping of hundreds of individuals, autism diagnosis on all children with autism, and measurement of blood levels of MIF for several hundred inviduals. The researchers involved with the study were from four continents, and it was partially funded by the National Institute of Health. It was published in Pediatrics. This is a real paper, and the underlying hypothesis was that a particular level of MIF production may lead to a proinflammatory profile of cell activation that, if present during a neurodevelopmentally sensitive period, might contribute to the etiopathogenesis of autism. The researchers undertaking this research were not doing so on a whim, but rather, on the basis of a wealth of underlying data implicating immunological dysfunction in autism.

    What were the findings of this paper?

    Collectively, these data identify MIF as a potential ASD susceptibility gene and support earlier suggestions of a role for innate immunity in the etiopathogenesis of this disease.

    Overall, the polymorphisms and plasma results provide suggestive evidence for neuroglial and innate immune activation in brain tissue and cerebrospinal fluid and increased expression of proinflammatory cytokines in the CNS or blood of patients with ASD. Persistent elevation of cytokines in the CNS may reflect an ongoing inflammatory process, microglial activation, or developmental arrest, because some cytokine levels increase during phases of neurodevelopment. Because MIF regulates the expression of innate cytokines, we hypothesize that a genetic predisposition at the MIF locus may lead to an inappropriate level of MIF production during a neurodevelopmentally sensitive period, contributing to the pathogenesis of ASD. Our data add to the evidence that some innate immunity genes may play an important role in the development of ASD.

    Does anyone reading this think that the authors of this study, the peer reviewers in Pediatrics, and the people who funded the study are confused by the concept of correlation versus causation? We do not know what causes the vast majority of autism. Very real and substantial attempts are being made to detagle if autism is immunologically mediated; to suggest otherwise is either intellectually dishonest, or alternatively, born out of a lack of understanding of a large body of evidence.

    With that, I will leave it to the individual reader to determine if this post is “gish gallosh” by someone “deeply into antivax ideology”, or the refinement of a ideas that have theoretical defense within the published literature.

    – pD

  75. #75 skeptiquette
    September 6, 2010

    One of the reasons Respectful Insolence rocks is because of people like Dangerous Bacon, who take the time to cite references and describe the points made within them. That’s a lot of work.

    Seriously?

    Let’s take a look at Dangerous Bacon’s post and cited references to see if his conclusions are accurate.

    pD: “I’d love to see any study on a pediatric vaccine that detailed the level of the immune response in a metric other than antibody generation. Do you know of any?”

    (pD is informed that numerous vaccine studies look at both cell-mediated and humoral responses to immunity. The goal posts shift.)

    The goal posts did not shift. Cell mediated and humoral refer to T-cells and B-cells, respectively, which make up the adaptive arm of the human immune system. pD is referring to the innate arm of the human immune system, which, when encountered by a pathogen, reacts immediately initiating a cascade of pro-inflammatory cytokines. These cytokines have many actions on our bodies other than just directing the adaptive immune response. One of these actions is to adjust behaviour patterns to better suit the host for the ensuing battle with the pathogen, generally referred to as “sickness behavior.” This phenomenon is largely modulated by pro-inflammatory cytokines (IL-1B, IL-6, TNF alpha).

    Cytokines are not considered humoral or cell mediated immune responses. Although cytokines can act on both of these types of immune responses they would be considered part of the innate immune response.

    pD: “pD: “…what if I said, ‘proinflammatory cytokine generation’? What then? Can you point me to a pre / post vaccination study with pediatric vaccines that measures those?”

    (pD is given a link to a pediatric vaccine study that measures proinflammatory cytokine response following immunization and given directions to finding other similar papers. pD responds that, well, the linked study isn’t quite cytokine-y enough for him/her.)

    Are you talking about the link in post 248 that you said you found on the first page of results in a pubmed search??

    I just perused it. The study was not designed to measure any sort of comprehensive pro-inflammatory response in the infants who were taking part.

    In a nutshell, the study was undertaken to evaluate the difference in T-cell and antibody (cell mediated and humoral) responses between adults and infants after measles vaccination, with the intent on trying to figure out why the adult response is more robust than that of an infant. Building on their previous work the authors (scientists) also wanted to look at the adaptive immune response in association with two cytokines, IL-12 and IL-15. Lastly, they wanted to evaluate the status of CD40L, a protein which stimulates B-cell proliferation. The primary goal of the study was not to comprehensively evaluate the innate immune response to measles vaccination. The goal was to gain an understanding into the differences in how and why the T-cell and B-Cell responses are diminished in infants under one year old; with the eventual goal of moving closer to a more effective pediatric vaccine in a more vulnerable cohort of infants (those under one year).

    The problem isn’t that the study is not cytokine-y enough (whatever that means, IMO just a good example of rhetoric), but more so that you either:

    a. Did not read the paper you cited.
    b. Did not understand what you read.
    c. Wanted so badly to refute one single point of pD’s argument you just tried to ram a square through a circle (figuratively)

    pD: “pD:”The study you linked to is primarily concerned with T and B cells, not the initial inflammatory response. I think I needed to bee even more concise with my thoughts. Sorry.””

    (pD is reminded that the study in question does in fact deal with this inflammatory response, the very issue of cytokine generation which pD implied had never been studied in vaccinated children. The goal posts are shifted again.)

    Nope, pD is spot on. You, on the other hand, are dead wrong. (for reasons discussed above)

    pD: “The study measured cytokine response to subsequent challenge with measles, not whether or not the children experienced increases in inflammatory cytokines in vivo systemically as a result of the vaccination.”

    This appears to be not just another goalpost shift but incorrect as well, as the linked study (as well as another in measles-immunized infants with a link on the same page as the study abstract) measured cytokine response in children (i.e., from baseline levels following immunization).

    Nope again.

    Once again, the scientists collected samples of whole blood from the subjects. Next, the removed the PBMC’s (peripheral blood mononuclear cells, basically, white blood cells) from the whole blood so that they could run tests on these cells. They put these cells in to 96 well microtiter plates so that they could add other components to the cells, run further tests on the supernatants from these wells and record the results.

    The first order of business was to challenge the subject cells with measles vaccine antigen. Next they added recombinant IL-12 and IL-15 both individually and together to the stimulated PBMCs. They looked at what happened to T-cell proliferation and Interferon gamma production in the presence and absence of these two cytokines.

    Dangerous Bacon, can you explain, using actual references to the study design, how this study measured the pro-inflammatory response of a pediatric population to the measles vaccine?

  76. #76 Jay Gordon
    September 6, 2010

    “No, I don’t recall anyone here impliing or stating that the multitude of antigenic challenges we encounter every day are directly equivalent to vaccination – that is a straw man.

    I love that one.

    In fact, that argument can be found scattered all throughout the past days, weeks, months, years. Here and elsewhere. And, no Todd, I won’t go through the archives to cite chapter and verse.

    Dave, nice “Adams” post at SBM. I’ve never heard of Mike Adams but I share your ambivalence about Dr. Oz.

    Best,

    Jay

  77. #77 dt
    September 6, 2010

    Dr Jay, I see you are indulging in your usual MO of drive-by sniping at cherry-picked, out of context quotes from people, while all the time ignoring the primary discussion that is going on and ignoring any meaningful response to the issues or the questions that have been asked of you. And you wonder why we laugh at you?

    I, and not Todd, said the bit about antigenic challenge. Let’s put it into context, shall we?
    Antivaxers claim the immune system is overwhelmed by the challenge of a few dozen antigens given during the recommended infant vax schedule. This claim is countered by pointing out that:
    (a) The immune system is perfectly capable of responding to numerous simultaneous challenges, and that this is quite fortunate, because
    (b) We are all exposed to numerous antigenic challenges from the moment of birth.

    The straw man, which you have grasped so firmly that your little fists are full of splinters, is to claim that we regard every antigenic challenge as equivalent to a vaccine antigen challenge. Patently they are not, and I would not equate the encountering of say ingested dog salivary proteins as tantamount to an MMR shot. But we do still get numerous challenges that are equivalent- exposures to certain infections for example, which may be frequent throughout childhood, and which can all induce significant systemic immunological host responses.

    There is nothing to see here Jay, move along now. You can leave the discussion to people who know what they are talking about and who engage in proper debate.

  78. #78 passionessDrone
    September 6, 2010

    Hi Dangerous Bacon –

    [Note: The original version of this response landed in the spam filter, so I have removed one of the links, and resubmitted. Orac: Feel free to terminate / ignore the entry in the spam filter. Thanks]

    You seem quite hung up on the idea that the study you provided somehow illustrates that I am changing my position; it would seem I need to provide additional detail on my thoughts, and as usual, this has been a useful learning experience for me regarding the need for clarity when defining my position. The balance between length of response that is overly technical is a difficult one, but I have apparently done a poor job deliniating where I think there might be a potential for problems from vaccination, and which types of studies I think would shed light on this problem. So more clarity it is.

    While Effects of Interleukin-12 and Interleukin-15 on Measles-Specific T-Cell Responses in Vaccinated Infants does technically measure one inflammatory cytokine as a result of vaccination, it only does so several months after the fact. This study, at the end of the day is about developing better ways for enhancing immunological memory, in stark contrast to attempting to evaluate the immediate pro-inflammatory response, which as I will attempt to detail below, is my focus.

    The animal studies I used to form my opinions, including the ones referenced above have all utilized a single exposure of an agent to invoke or mimic an inflammatory cytokine response, and in some instances, great care has been taken to insure that the inflammatory cytokine release was responsible for persistent resullts in the treatment group.

    So lets take a look at the methods section from, Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats, a link to the full paper which I published above. For space considerations I am only posting parts of the methods, but the entire paper is freely available.

    Step 1: Animals were injected wiith LPS to ‘determine whether a single inflammatory event during development can influenze seizure susceptibility in later life’.

    Lipopolysaccharide injections. To determine whether a single inflammatory event during development can influence seizure susceptibility in later life, male rats were injected intraperitoneally on P14 with LPS (Escherichia coli, serotype O26:B6; 25, 100, or 250 µg/kg) or pyrogen-free saline. We previously established that 100 µg/kg LPS generates a mild inflammatory response in the host that lasts for 6–8 h (Heida et al., 2004; Ellis et al., 2006). Additional groups of rats were also injected on P14 with saline or LPS (100 µg/kg) to evaluate both the acute and chronic effects of LPS on cytokine and glial cell activity in the hippocampus (a seizure-vulnerable region). P14 is considered by some to be developmentally equivalent to a human infant of 1–2 years of age (Gottlieb et al., 1977; Avishai-Eliner et al., 2002). To determine whether there was a critical age at which LPS could cause long-term changes to seizure susceptibility, rats were also treated with saline or LPS (100 µg/kg) at P1, P7, or P20.

    Step 2: Several hours after infjection, brain tissue was evaluated for cytokine expression. This is an absolutely critical difference between what I am proposing and the study you provided. I’ll provide the pertinent snipets to make this point shortly.

    Cytokine assay and glial cell immunohistochemistry. To assess the acute effects of LPS on P14 rat microglia and cytokine (IL-1β and TNF) levels, we collected blood plasma at 2 h after injection, as well as hippocampal tissue 3 and 6 h after LPS (100 µg/kg) or saline injection (n = 4–6/group). Previous reports show that cytokine expression is increased within the adult hippocampus 6 h after peripheral LPS (Nguyen et al., 1998; Turrin et al., 2001; Oprica et al., 2006).

    Step 3: To validate that the changes being observed were, indeed, the result of an inflammatory response, the authors also performed direct injections of an inflammatory cytokine, TNF-alpha, as well as TNF-Alpha antibodies to discern if effects similar to LPS could be achieved.

    Intracerebroventricular injections. Cytokines are synthesized and released in the brain after a peripheral injection of LPS (Nguyen et al., 1998; Turrin et al., 2001). To evaluate the contribution of the central cytokine responses to peripheral LPS on the programming of the long-term effect on seizure susceptibility after peripheral LPS administration, P14 rats were given intracerebroventricular injections of the natural antagonist for IL-1, IL-1ra (Anakinra; 10 or 50 µg/5 µl), or the TNF neutralizing antibody (Infliximab; 50 µg/5 µl), concurrently with LPS (100 µg/kg, i.p.) or saline. We chose these dosages of IL-1ra because previous reports indicate that 4 µg intracerebroventricularly effectively antagonizes effects of peripheral pyrogens on rat behavior (Kent et al., 1992) and that 10 µg intracerebroventricularly significantly reduces the incidence of febrile seizures in rat pups (Heida and Pittman, 2005). In other P14 rats, rrTNF was administered intracerebroventricularly (bilaterally) at 1 µg/2.5 µl per side to determine the role of this cytokine in promoting long-term seizure susceptibility (n = 5–7/group). Dosages of TNF similar to this have been shown to influence neuronal transmission in the absence of negative side effects (Ignatowski et al., 1999; Reynolds et al., 2004). The surgical procedure, described in detail previously (Heida and Pittman, 2005), was performed under halothane anesthesia and required 10 min to conduct. Animals were returned to their dams, and seizure thresholds were examined 6–8 weeks later using the PTZ paradigm described above.

    To recap, some animals were injected with LPS, a known immune stimulant that triggers an inflammatory response via TLR4, some subjects were euthanized and assayed for brain cytokine expression within a few hours, and another set of animals were given injections of either tnf-alpha antibodies alongside LPS, or straight tnf-alpha in the absence of LPS. This is a study about the effect of the result of the immune response.

    Note:For space considerations, I am leaving out some of of the methods regarding the mechanisms by which the researchers went on to discern seizure susceptibility in the adult rats. I do not believe that they are necessarily salient for a discussion that involves the potential for an inflammatory cytokine response to have very difficult to predict consequences if present during critical developmental windows. But the entire paper is quite interesting.

    Now, lets compare this set of methods with the paper that you provided, Effects of Interleukin-12 and Interleukin-15 on Measles-Specific T-Cell Responses in Vaccinated Infants

    Subjects included 115 infants receiving well child care in Palo Alto, California, who received their primary measles vaccination at 6 (n = 33), 9 (n = 35), or 12 (n = 47) mo of age. Blood samples were taken before, 12 wk after monovalent measles vaccine given at 6 or 9 months of age, or 24 weeks after MMR administered to the 12-month-old infants.

    Ten children (aged 5-11 y) and 15 adults (aged 20-49 y) who had received two doses of MMR (the children according to the routine schedule of 12 mo and 5 y, and adults in childhood) were also evaluated with one blood sample. Not all assays were performed on all samples.

    Again, my presentation hasn’t been sufficiently clear to detail that my concerns involve the immediate rise in inflammatory cytokines following immune challenge, as was measured in Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats, but I think that any intellectually honest reading of these methods will, at the very least, be forced to admit that there is a significant difference between evaluated for cytokine expression several hours after challenge, and measurements that were taken either twelve or twenty four weeks after challenge. Do you agree?

    More from your paper:

    Supernatants from PBMCs stimulated with measles antigen or uninfected cell control in the presence or absence of rhIL-12 (final concentration 5 U/mL) or rhIL-15 (final concentration 0.25 ng/mL and 2.5 ng/mL) each alone or in combination were collected from wells on days 5 and 7, and stored at -70°C. Preliminary studies showed peak production of IFN-γ between days 5 and 7 post-stimulation

    Here we can see that while an inflammatory cytokine, INF–γ was measured, it was only done as a result of subsequent stimulation with measles antigen. This is qualitatively different than the methods described in the study I linked to; and in fact, speaks very directly to the question I asked of you in post 238, but you neglected to to answer, nor include in your blockquote fest attempt to paint me as a goalpost shifter, namely:

    Considering I specifically mentioned that several studies showed attenuation of effects based on administration of anti-inflammatory agents, could you should me any studies on innate immune functioning that would be affected by similar agents with vaccination?

    Regarding Effects of Interleukin-12 and Interleukin-15 on Measles-Specific T-Cell Responses in Vaccinated Infants, the answer to this question is quite resoundingly, no.

    From a technical standpoint, I will admit, this study does evaluate for a pro-inflammatory cytokine following vaccination. Unfortunately, from a meaningful standpoint, it tells us nothing about the immediate inflammatory response following vaccination that is at the heart of my concerns.

    This appears to be not just another goalpost shift but incorrect as well, as the linked study (as well as another in measles-immunized infants with a link on the same page as the study abstract) measured cytokine response in children (i.e., from baseline levels following immunization).

    Would you be willing to post a PMID, title, or link to these studies?

    No doubt pD will have another goalpost shift to present in response (pD is sort of the human equivalent of influenza, which drifts and shifts its genome frequently to complicate immunization efforts). These examples, however are sufficient to show the game being played.

    If I wasn’t sure that I’d failed at properly defining my position, I would be a little offended at this point.

    I agree with some other posters that pD is an improvement on other posters here – certainly a lot better than the antivax trolls and pseudomedical “authorities” that engage in denial about the seriousness of once-common infectious diseases and the success of immunization in vastly reducing or eliminating them, and personal nastiness (interspersed with complaints about how others are mean to them). Given pD’s tactics of goalpost-shifting, his/her equating of vaccination with inducing “disease”, Gish galloping and assurance of being open to many theories of autism etiology while in actuality singlemindedly focusing on vaccines, I fear that we are seeing a person who, while less obvious and not as vituperative as his/her peers, is still deeply into antivax ideology.

    My posting history here is relatively sparse, though verbose when present. Anyone interested (I doubt that is few and far between), could see that my discussion at places like LBRB, or on my own blog are not confined to the vaccine space. Further insistence on this particular point seems to be less than useful. Google searches can provide anyone actually curious with the answer.

    At risk of being accused of a spammer as opposed to a “gish gallloper”, I’d like to specifically address the issue of ‘equating vaccniation with inducing “disease”‘ with more detail. The study I posted above shows with great elegance that tnf-alpha during development can permenantly modify susceptibility to seizures through several possible mechanisms. Here is a snipet from the discussion section of those papers.

    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.

    We showed that the LPS-precipitated changes to adult seizure susceptibility are linked to a critical developmental period (P7 and P14). This time window is similar to the period we previously observed for other physiological changes caused by postnatal LPS (Spencer et al., 2006b). Interestingly, this is also the time when long-term potentiation-induced plasticity first becomes apparent (e.g., P7) and shows maximum responsivity (e.g., P15) (Harris and Teyler, 1984). Thus, we may suspect that some permanent change has taken place during this relatively sensitive period of development in which the effects of LPS (and TNF) can modify synapses. Alternatively, TNF is known to be essential in the normal development of the hippocampus through regulation of neurotrophic factors such as nerve growth factor and brain-derived neurotrophic factor (Golan et al., 2004). The possibility exists that “optimal” levels of TNF may be perturbed after LPS-induced inflammation, even at potentially low doses (Fig. 2A). Future studies will be needed to address the potential mechanisms through which postnatal TNF permanently alters neuronal function to enhance excitability and seizure propensity.

    Clinically, CNS infections occur with some frequency in young children and may be associated with an increased risk for late unprovoked seizures (Rantakallio et al., 1986; Herman, 2002). In those patients surviving CNS infections, the risk for epilepsy was highest during the first 5 years after infection and remained elevated for the next 15 years (Annegers et al., 1988). Currently, there is limited clinical evidence to suggest that peripheral childhood infection contributes to the etiology of adult epilepsies. However, based on the novel data presented here, relatively mild early-life inflammation may be associated with permanent modifications in seizure susceptibility that persist well into adulthood. This may warrant additional patient history review to ascertain whether such a relationship exists. Our data raise the possibility that the known differences in adult seizure susceptibility to very similar insults may have their etiology in a common postnatal infection.

    There seems to be a lot of concern about my supposed confusing vaccination with disease state; but lets be clear about the mechanics of this study. None of the treatment aniimals were infected with any actual pathogen. None of them actually got sick. None of them had a disease or an infection. Even given that, the authors equating the immune challenge resulting from either LPS, or direct tnf-alpha injection, with ‘a common postnatal infection’.

    What should we make of this? Is it possible that the authors of this paper, the peer review staff at the journal that published it, and the people who funded the study, all are unable to discern that there is a difference between having a disease and having an immune challenge? Does this scenario really make sense to anyone?

    The reason is that that the actionable effect, the immune response, and in this case, specifically tnf-alpha, is created as a result of immune stimulation; and that pro-inflammatory cytokine response is absolutely the same if it is triggered by an actual pathogen, LPS, direct tnf-alpha injection, or dare I say, vaccination. If anyone has any doubt about this, again refer to the study on the HPV vaccine I posted in 256; one group and one group only developed a significant increase in pro-inflammatory cytokines, including tnf-alpha. We only have one innate immune system to trigger and vaccines trigger it. There isn’t any bypassing this simple fact.

    A common theme on this thread and in many others here seems to be asking someone a question, and then bashing them if they refuse to answer. So lets try. Dangerous Bacon:

    Does a vaccine initiate an immune response? Does this immune response include the creation of pro-inflammatory cytokines, such as tnf-alpha, IL-6 or Il-1beta? And finally, if the answer to those questions is yes, what is the functional difference between an pro-inflammatory cytokine release when the trigger is vaccination, versus infection with an actual pathogen?

    I have provided direct, clinical evidence in post #256 to answer the first two questions, but it is still possible, though unlikely, that Dangerous Bacon would like to dispute them.

    There are unknowns about the robustness of an LPS induced reaction as compared to a vaccine, but at the end of the day, LPS and the vaccines are recognized by toll like receptors and initiate the innate immune response. In other words, perhaps an actual infection creates a more vigorous immune response than a vaccination; I’d say this is certainly possible, but barring any studies, we cannot know for sure. The studies I mentioned regarding synergistic effects of stimulating multiple toll like receptors simultaneously makes this a difficult problem.

    But, that is why our studies on particular immunological functions within the autism realm can help us. Earlier I referenced, Differential monocyte responses to TLR ligands in children with autism spectrum disorders . Here is the abstract:

    Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. Recent evidence has suggested that impairments of innate immunity may play an important role in ASD. To test this hypothesis, we isolated peripheral blood monocytes from 17 children with ASD and 16 age-matched typically developing (TD) controls and stimulated these cell cultures in vitro with distinct toll-like receptors (TLR) ligands: TLR 2 (lipoteichoic acid; LTA), TLR 3 (poly I:C), TLR 4 (lipopolysaccharide; LPS), TLR 5 (flagellin), and TLR 9 (CpG-B). Supernatants were harvested from the cell cultures and pro-inflammatory cytokine responses for IL-1beta, IL-6, IL-8, TNFalpha, MCP-1, and GM-CSF were determined by multiplex Luminex analysis. After in vitro challenge with TLR ligands, differential cytokine responses were observed in monocyte cultures from children with ASD compared with TD control children. In particular, there was a marked increase in pro-inflammatory IL-1beta, IL-6, and TNFalpha responses following TLR 2, and IL-1beta response following TLR 4 stimulation in monocyte cultures from children with ASD (p<0.04). Conversely, following TLR 9 stimulation there was a decrease in IL-1beta, IL-6, GM-CSF, and TNFalpha responses in monocyte cell cultures from children with ASD compared with controls (p<0.05). These data indicate that, monocyte cultures from children with ASD are more responsive to signaling via select TLRs. As monocytes are key regulators of the immune response, dysfunction in the response of these cells could result in long-term immune alterations in children with ASD that may lead to the development of adverse neuroimmune interactions and could play a role in the pathophysiology observed in ASD.

    Given the same trigger, the immune response from children with autism included a marked increase in pro-inflammatory IL-1beta, IL-6 and TNFAlpha. Similar studies that have shown an exaggerated production of inflammatory cytokines in the autism realm would include Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder, or Preliminary evidence of the in vitro effects of BDE-47 on innate immune responses in children with autism spectrum disorders.

    Even if for most infants the immune response from a vaccination would be relatively weak, we cannot say the same thing for an infant who will go on to develop autism; they may be genetically, epigenetically, environmentally, or otherwise predisposed to react more vigorously to the same challenge. And the way they react, with increased levels of inflammatory cytokines, are the very same chemical messengers identified in the animal study above.

    Finally, I thought I’d spend my last hotlink to Macrophage Migration Inhibitory Factor and Autism Spectrum Disorders. On several occassions on this thread the problem with correlation and causation was brought up regarding immune abnormalities in autism; this is a problem, and we don’t have answers currently. That being said, I think that it is time to dispell the notion that the only people who believe such a relationship could be causal are internet cranks.

    Here is the abstract:

    Macrophage migration inhibitory factor (MIF) is an upstream regulator of innate immunity that promotes monocyte/macrophage-activation responses by increasing the expression of Toll-like receptors and inhibiting activation-induced apoptosis. On the basis of results of previous genetic linkage studies and reported altered innate immune response in autism spectrum disorder, we hypothesized that MIF could represent a candidate gene for autism spectrum disorder or its diagnostic components.

    Look at how gracefully this fits with the Enstrom study above; one finds genetic linkages and associated increased levels of a messenger known to promote monocyte/macrophage activation responses; and the other finds that when monocytes are stimulated, those from children with autism respond more vigorously. It is completely unsurprising.

    Despite the problems in understanding causation, one thing is certain, having autism isn’t causing children to be born with the MIF promoter allele.

    The following is from the Introduction:

    Given a complex model of the inheritance of ASD, possible etiopathic mechanism might involve an immunologic insult to the central nervous system (CNS) in individuals with a susceptible genetic background. We evaluated the genetic association between the innate mediator, macrophage migration inhibitory factor (MIF), and different behavioral components of ASD. MIF is encoded in a functionally polymorphic locus on chromosome 22q11.2 (Online Mendelian Inheritance in Man No. 153620, GenBank accession No. NM 002415) that has been associated with the incidence or severity of different autoimmune inflammatory conditions. Given its location in a previously identified locus of interest and its upstream action in immunity, MIF may represent acandidate gene for ASD or its components. Thus, the central hypothesis underlying this research was that a genetic predisposition to a particular level of MIF production may lead to a proinflammatory profile of cell activation that, if present during a neurodevelopmentally sensitive period, might contribute to the etiopathogenesis of autism.

    This was an expensive, and time consuming study to
    perform. It involved genotyping of hundreds of individuals, autism diagnosis on all children with autism, and measurement of blood levels of MIF for several hundred inviduals. The researchers involved with the study were from four continents, and it was partially funded by the National Institute of Health. It was published in Pediatrics. This is a real paper, and the underlying hypothesis was that a particular level of MIF production may lead to a proinflammatory profile of cell activation that, if present during a neurodevelopmentally sensitive period, might contribute to the etiopathogenesis of autism. The researchers undertaking this research were not doing so on a whim, but rather, on the basis of a wealth of underlying data implicating immunological dysfunction in autism.

    What were the findings of this paper?

    Collectively, these data identify MIF as a potential ASD susceptibility gene and support earlier suggestions of a role for innate immunity in the etiopathogenesis of this disease.

    Overall, the polymorphisms and plasma results provide suggestive evidence for neuroglial and innate immune activation in brain tissue and cerebrospinal fluid and increased expression of proinflammatory cytokines in the CNS or blood of patients with ASD. Persistent elevation of cytokines in the CNS may reflect an ongoing inflammatory process, microglial activation, or developmental arrest, because some cytokine levels increase during phases of neurodevelopment. Because MIF regulates the expression of innate cytokines, we hypothesize that a genetic predisposition at the MIF locus may lead to an inappropriate level of MIF production during a neurodevelopmentally sensitive period, contributing to the pathogenesis of ASD. Our data add to the evidence that some innate immunity genes may play an important role in the development of ASD.

    Does anyone reading this think that the authors of this study, the peer reviewers in Pediatrics, and the people who funded the study are confused by the concept of correlation versus causation? We do not know what causes the vast majority of autism. Very real and substantial attempts are being made to detagle if autism is immunologically mediated; to suggest otherwise is either intellectually dishonest, or alternatively, born out of a lack of understanding of a large body of evidence.

    With that, I will leave it to the individual reader to determine if this post is “gish gallosh” by someone “deeply into antivax ideology”, or the refinement of a ideas that have theoretical defense within the published literature.

    – pD

  79. #79 passionlessDrone
    September 6, 2010

    Hi dt –

    Effective vaccination will usually reliably produce a specific immune response, yet despite effective vaccination, only a small minority of recipients will also get a febrile response. You quote a high 25% incidence with DTaP (which I assume is a correct quote, I haven’t had a chance to check your citation, but this is in excess of the usual incidence of fever following even pentavalent or hexavalent combination vaccines). If only a small fraction of vaccinees get fever, one should not presume fever and vaccination have immunopathological equivalence.

    I asked Bacon this question, which he neglected to address. Maybe you will respond:

    We know that vaccines often times cause mild reactions; i.e., fevers, and this is likely due to induction of the immune response and associated creation of inflammatory and pyrogenic cytokines. This would seem to be straightforward with how we think vaccines are actually marshalling an immune response. Can we agree on that?

    My concern is with the immediate, inflamatory cytokine response. I am asserting that vaccination causes a rise in pro-inflammatory cytokines that is significant over everyday exposure. It may, or may not, be equivalent when compared to actual infection, but that is lagely besides the point. Why do you believe the mechanism of action was in the study I posted in 256, if not the designed intention of vaccines, the generation of an immune response? You just don’t get from point A to point B without toggling the innate immune response. You don’t. The frequency with which this results in fever is only applicable if you can describe a mechanism by which vaccines can achieve their result without initiating an innate immune response. Can you do this?

    Antivaxers claim the immune system is overwhelmed by the challenge of a few dozen antigens given during the recommended infant vax schedule. This claim is countered by pointing out that:
    (a) The immune system is perfectly capable of responding to numerous simultaneous challenges, and that this is quite fortunate, because
    (b) We are all exposed to numerous antigenic challenges from the moment of birth.

    Unfortunately, this is a common cannard proposed by “anti-vaxxers”. It is an easy target to dismantle. It is also a gross over simpliciation. What we really need to be discussing is the ability for vaccines to persistently modify the immune system in ways we may not understand.

    This isn’t controversial, after all, the immunological memory created is such an example; we are not immune to a pathogen, and then we are immune. So clearly, at the adaptive level, immunization can modify the immune system.

    But what about the innate immune arm of the immune system? Can that be modified by vaccination? I’d recommend you give some good thought towards this question. What reasons would you give if you had to defend the notion that only the adaptive arm of the immune system is modified through vaccination?

    As evidence that such changes are possible, why not take a look at this study, which I referenced above: Early life activation of toll-like receptor 4 reprograms neural anti-inflammatory pathways

    Here is the abstract:

    A single postnatal exposure to the bacterial endotoxin, lipopolysaccharide (LPS), reduces the neuroimmune response to a subsequent LPS exposure in the adult rat. The attenuated fever and proinflammatory response is caused by a paradoxical, amplified, early corticosterone response to LPS. Here we identify the mechanisms underlying the heightened corticosterone response to LPS in adults after early life exposure to LPS. In postnatal LPS-treated rats, hypothalamic corticotrophin-releasing hormone mRNA, pituitary proopiomelanocortin mRNA, and circulating adrenocorticotrophic hormone were all increased after adult exposure to LPS without significant modification to hippocampal or hypothalamic glucocorticoid receptor mRNA or protein or vagally mediated afferent signaling to the brain. Postnatal LPS administration did cause a persistent upregulation of the LPS Toll-like receptor-4 (TLR4) mRNA in liver and spleen, but not in brain, pituitary, or adrenal gland. In addition, cyclooxygenase-2 (COX-2), which is a prostaglandin biosynthetic enzyme and is normally undetectable in most peripheral tissue, was constitutively expressed in the liver. Adult immune activation of the upregulated TLR4 and COX-2 caused a rapid, amplified rise in circulating, but not brain, prostaglandin E(2) that induced an early, enhanced activation of the hypothalamic-pituitary-adrenal (HPA) axis. Thus, postnatal LPS reprograms the neuroimmune axis by priming peripheral tissues to create a novel, prostaglandin-mediated activation of the HPA axis brought about by increased constitutive expression of TLR4 and COX-2.

    Permenant changes to the HPA axis and neuro-immune responses to subsequent challenges as a result of a single activation of TLR4 in early life. We can quibble about the lack of data one way or another regarding the robustness of an inflammatory response from vaccination, but make no mistake, TLR4 does get activated at the two, four, and six month visits.

    But we do still get numerous challenges that are equivalent- exposures to certain infections for example, which may be frequent throughout childhood, and which can all induce significant systemic immunological host responses.

    Yes but are the frequent throughout infancy? That is where we must focus our attention, the very first few months of life. The vaccine schedule, for good reason, is top heavy at the earliest ages of life; two, four, and six month appointments in the US. Do you honestly think that pre-vaccination 90%+ of infants experienced one of the equivalent events you describe at two, four, and six months of age? Again, developmental status is critical, we cannot allow ourselves to confuse infancy with ‘childhood’; broad assumptions that ignore the complexity of development are the kiss of death for reaching sound conclusions.

    – pD

  80. #80 dt
    September 6, 2010

    @ pD
    I admit I haven’t been able to give the LPS study a thorough reading as yet. But why do you think LPS exposure in postnatal rats provides an equivalent example of human vaccination with quite different antigens, such as DTaP?

    1. I know of no human vaccine that uses LPS as an antigen.
    2. Endotoxin provokes a fairly unique immune response, involving cytokines more often linked into the severe sepsis cytokine cascade.
    3. LPS responses markedly differ between rodents and humans (who are interestingly enough much more sensiive and responsive to it’s stimulus)
    4. Human infants get exposed to endotoxin too, and quite naturally. So one would expect your extrapolations to apply to all these human infants. In fact, seeing as how humans are exquisitely sensitive to endotoxin, if your rat study holds any weight at all, then just about ALL human infants would be having epileptic seizures.

    I really don’t see where you are trying to go with all of this.

  81. #81 Enkidu
    September 6, 2010

    Dr Jay says: ” In most of the developed world herd immunity protects children and has nearly eradicated the invasive form of HIB. I am not recommending that we stop giving the vaccine. I do tell parents that the choice is theirs and that, because of the vaccine and herd immunity, their informed choice may be to decline the vaccine.”

    Dr. Jay as the voice of “informed choice.” I love how you use herd immunity as a reason not to vaccinate, thereby setting up to destroy herd immunity in the future.

  82. #82 Militant Agnostic
    September 6, 2010

    Dr Jay says: ” In most of the developed world herd immunity protects children and has nearly eradicated the invasive form of HIB. I am not recommending that we stop giving the vaccine. I do tell parents that the choice is theirs and that, because of the vaccine and herd immunity, their informed choice may be to decline the vaccine.”

    In other words, Dr. “I’m not anti-vaccine but” Jay encourages parents to be sociopathic parasites.

  83. #83 passionlessDrone
    September 6, 2010

    Hi dt –

    But why do you think LPS exposure in postnatal rats provides an equivalent example of human vaccination with quite different antigens, such as DTaP?

    You need to move up one level, to understanding the Toll Like Receptors; very specialized sensing mechanisms of our immune system that detect foreign particles as the first step of an immune response. We’ve got a lot of different types of them, and they are designed to understand different classifications of pathogens as a result of some very fine level molecular structure that pathogens share as broad classes.

    So, for example, TLR4 has evolved to detect molecular patterns that are common to gram negative bacteria. LPS is a major component of the cell wall for gram negative bacteria, which is why it is so useful as to simulate a pathogen invasion. This is also why, for example, the authors are using LPS and consequent TLR4 activation as a mechanism for learning about common infections. TLR2 detects a variety of pathogen types, including gram positive bacteria. TLR3 is a viral detector. There are many more, and very likely some overlap and crosstalk between them.

    We have different adaptive memories for specific antigens, i.e., diptheria, pertussis, or measles; but the first line of defense, the innate immune response, understands invaders at a far, far more generalized level.

    But the classification system of TLRs is very important if you want to understand why our shot schedule that combines viruses and a variety of bacterial pathogens at the same time. Why? Because of the articles I posted in #211 tell us that in some instances, if you stimulate several different TLRs simultaenously, the resultant inflammatory cytokine response is syngeristic.

    In other words, if you body detects that it is under attach from a gram positive bacteria, a gram negative bacteria, and a virus all at the same time, the response is not additive. From a survival standpoint, this makes sense; better to risk an increased inflammatory response with the benifit of surviving a multipronged attack. However, it significantly complicates matters if our goal is to try to understand the inflammatory response from getting vaccinated against nine or ten pathogens simulatenously; especially barring any clinical evidence.

    Regarding the DTaP, for example, the pertussis bacteria is gram negative; it is detected by TLR4, the same gatekeeper that detects LPS. From that point on, the resultant chemical messages, inflammatory cytokines, are no different in function between LPS and pertussis. Tnf-alpha is tnf-alpha, regardless of the triggering agent.

    . I know of no human vaccine that uses LPS as an antigen.

    But do you know of any vaccines that use gram negative bacteria as an antigen?

    2. Endotoxin provokes a fairly unique immune response, involving cytokines more often linked into the severe sepsis cytokine cascade.

    3. LPS responses markedly differ between rodents and humans (who are interestingly enough much more sensiive and responsive to it’s stimulus)

    While cross species problems are present, they are still triggering the same top level system, the TLR. Use of LPS to initiate an immune response is an exceedingly common tool; it isn’t because we want to learn more about rats. Do you believe that the authors, peer reviewers, and funders from the LPS / seizure study I referenced all fail to understand this problem?

    4. Human infants get exposed to endotoxin too, and quite naturally. So one would expect your extrapolations to apply to all these human infants. In fact, seeing as how humans are exquisitely sensitive to endotoxin, if your rat study holds any weight at all, then just about ALL human infants would be having epileptic seizures.

    You seem to be crossing your own wires here; does this natural exposure to endotoxin lead to sepsis and cytokine cascade all the time? Following your logic, ‘just about ALL human infants’ would have had a bout with sepsis. It is more complicated than that.

    And again, please take a look at how common it is to use LPS to induce an immune response; it happens all the time; you can’t color my study as not having any weight without also painting thousands, or tens of thousands of other studies with the same brush.

    And remember, we have plenty of experimental evidence that the same trigger will result in different inflammatory cytokine production in the autism pouplation. Take a look at the study I published above, Differential monocyte responses to TLR ligands in children with autism spectrum disorders which describes a highly exaggerated inflammatory response after stimulation of TLR2 and TLR4. For some reasons why this might be the case, read the Macrophage Migration Inhibitory Factor and Autism Spectrum Disorders study I also referenced, which found increased levels of a known TLR upregulator in the autism cohort.

    – pD

  84. #84 dt
    September 6, 2010

    “It is more complicated than that”

    Quite. Picking and choosing the bits you think support your hypothesis is disingenuous, to say the least.

    You quite erroneously assume that a vaccine prepared from a GNB (like pertussis) must contain LPS/endotoxin.

    For example, acellular pertussis vaccines consist of 5 antigenic components. None of them is LPS.
    (but whole cell pertussis on the other hand……?)

    The acellular pertussis vaccine component of Daptacel® contains 5 acellular pertussis antigens isolated from B. pertussis grown in modified Stainer-Scholte liquid media. The fimbriae types 2 and 3 are extracted from the bacterial cells and the pertussis toxin (PT), filamentous hemagglutinin (FHA), and pertactin (PRN) are prepared from the supernatant. The pertussis antigens are then purified using sequential filtration, salt-precipitation, ultrafiltration and chromatography. Pertussis toxin is detoxified with glutaraldehyde and FHA is treated with formaldehyde.

    http://www.medscape.com/druginfo/monograph?cid=med&drugid=149818&drugname=Diph%2CPertus(Acel)%2CTet+Ped+(PF)+IM&monotype=monograph&secid=7

    Pertussis toxin is a 105 kDa protein composed of six subunits: S1, S2, S3, (2)S4, and S5. The toxin is both secreted into the extracellular fluid and cell bound. Some components of the cell-bound toxin (S2 and S3) function as adhesins, and appear to bind the bacteria to host cells. S2 and S3 utilize different receptors on host cells. S2 binds specifically to a glycolipid called lactosylceramide, which is found primarily on the ciliated epithelial cells. S3 binds to a glycoprotein found mainly on phagocytic cells.

    The S1 subunit of pertussis toxin is the A component with ADP ribosylating activity, and the function of S2 and S3 is presumed to be involved in binding the intact (extracellular) toxin to its target cell surface. Antibodies against PTx components prevent colonization of ciliated cells by the bacteria and provide effective protection against infection.

    http://www.textbookofbacteriology.net/pertussis.html

    The clue to “LPS” is in the name – lipo-polysaccharide. It contains a portion of Lipid-A joined to a core oligosaccharide and a polysaccharide O antigen. Previous attempts to vaccinate with LPS to protect mammals against endotoxic shock have ended in failure.

    No current vaccines of GNB use LPS as an antigen.

    You talk a good talk pD, but there are gaping holes in your concept. I am reminded of the attempts by Mohamed Al Bayati to demonstrate that Eliza-Jane Scovill died of an allergic reaction to amoxicillin rather than PCP/AIDS. He quoted extensive literature demonstrating the feasibility of the sequence of events as he wished to presume. A clinician would take one look and cry “utter crap!” but to a semi-informed audience who were not well versed in clinical medicine it all sounds so plausible and sciency, with apparently valid scientific references to boot.

    I fear your immunological treatise here, with its talk of pyrogenic cytokines, TLRs and signalling pathways, may be in the same vein. An immunologist (and I am not one) would likely see the glaring errors and logical disconnects sticking out like sore thumbs, seeing how even someone like me can see obvious problems.

  85. #85 dt
    September 6, 2010

    ETA I see pD that you (cleverly?) don’t specifically say vaccines like pertussis contain LPS, you just strongly imply it (eg. “they are gram negative bacilli”) and state that any vaccine based on a GNB will signal through TLR4.

    But the ligand for TL4 is lipopolysaccharide. (Other suspected ligands include some heatshock proteins from C. pneumoniae, some RSV components and extracellular matrix components)

  86. #86 sid offit
    September 6, 2010

    pD vs dt = chess vs. checkers

  87. #87 sid offit
    September 6, 2010

    pD vs dt = Brock Lesner vs. Barney Fife

  88. #88 sid offit
    September 6, 2010

    pD vs dt = Godzilla vs. Bambi

  89. #89 augustine
    September 7, 2010

    Pd really is taking it to you guys. But it doesn’t really matter. In the end ideology rules the day in this blog. There is a new king in town. The neo-atheists. “We are science. And there’s nothing you can do about it.”

  90. #90 augustine
    September 7, 2010

    For those of you, who last time, confused neo-atheism with paleo-atheism, here is an excerpt from the internet encyclopedia of philosophy:

    http://www.iep.utm.edu/n-atheis/

    “A standard observation is that New Atheist authors exhibit an unusually high level of confidence in their views. Reviewers have noted that these authors tend to be motivated by a sense of moral concern and even outrage about the effects of religious beliefs on the global scene.”

    “Regarding the metaphysical component, the New Atheist authors share the central belief that there is no supernatural or divine reality of any kind. The epistemological component is their common claim that religious belief is irrational. The moral component is the assumption that there is a universal and objective secular moral standard.”

    “The New Atheists make substantial use of the natural sciences in both their criticisms of theistic belief and in their proposed explanations of its origin and evolution. They draw on science for recommended alternatives to religion. They believe empirical science is the only (or at least the best) basis for genuine knowledge of the world, and they insist that a belief can be epistemically justified only if it is based on adequate evidence. Their conclusion is that science fails to show that there is a God and even supports the claim that such a being probably does not exist.”

    The new atheist = critical thinking, skepticism, with a “mixture” of science.

  91. #91 Chris
    September 7, 2010

    dt is winning.

  92. #92 colmcq
    September 7, 2010

    fascinating. Do continue.

  93. #93 titmouse
    September 7, 2010

    Hey hey hey, people. Polarized debates are like drinking a six-pack. The buzz can be satisfying and a little addictive. But “my team gud! ur team bad!” is as embarassing to watch as the lampshade-on-head dance.

    Everyone wins when the truth wins. Including the bad people too stupid to realize this.

    I like pD, but I’m not following his major point. Is he/she worried that vaccination correlates with autism incidence? Cuz that horse has ceased-to-be.

    At best, one might argue that an association exists but is too subtle for our epidemiologists to detect currently.

    When you have a broad hypothesis, it’s not too difficult to weave an appearance of support from details in the scientific literature. That’s why we want more than, “Hey look at this biochemistry which might result in symptoms X,Y, and Z.”

    It’s possible to write computer code using genetic algorithms involving random mutation and natural selection. However, such code is impossible for programmers to later debug. Random shit in the code that seems to do nothing actually makes a difference in how the code runs on a particular machine. Remember that as we struggle to decode human physiology.

    Regarding the autism-vaccine hypothesis, the first evidential hurdle is a real correlation between vaccination and autism. Until that’s present, the biochemical details are pretty moot.

  94. #94 Todd W.
    September 7, 2010

    @Dr. Jay

    Todd, I apologized to David for my rudeness and I’m also sorry I’ve offended you to the point that you relentlessly ask the same questions over and over.

    I’m not offended at all. The reason that I asked my questions over and over is because you have this tendency to make claims and then completely ignore requests for clarification or substantiation. The only way, it seems, to get even a vague answer from you is to hector you until you finally respond. It’s like pulling teeth.

    I am not willing to spend the time searching the archives to find a post denying all vaccine side effects. If you say there are none, I’ll accept the possibility that you have done that archive search and merely say that I must then accept that my only problem will be when and if VSEDs attribute most major vaccine side effects to coincidence. I take issue with that attribution. I will no longer dispute your claim that there has never been a single person here claiming that vaccines have no side effects.

    I made no claim, Dr. Jay, though nice try to turn that around. I merely asked for you to back up your claim with evidence. But, you can’t be bothered to do so. Got it. You’ll simply argue by assertion and leave it at that.

    I cannot define the type of high risk patient who would benefit sufficiently from the HIB vaccine for me to recommend it with enthusiasm.

    I didn’t ask what the definition would be to recommend it “with enthusiasm”, but rather what exactly your definition of “highest risk” was, since you pretty clearly stated that such individuals would be the only ones to whom you would give the HiB vaccine.

    Also, if you cannot define who you would consider at “highest risk”, then how do you decide who to give it to?

    I am not recommending that we stop giving the vaccine…No, I don’t recommend that “everyone else should not bother with the [HIB] vaccine. I recommend that parents inform themselves, trust their doctors’ opinions and make their decision based on the facts available.

    First off, I didn’t ask if your recommendation was to stop using the HiB vaccine altogether, so I’m not sure why you’re stating that you wouldn’t recommend stopping it.

    Your reply to my final question doesn’t really make much sense, in light of your opinion of the HiB vaccine. Do you just not make any recommendations at all? Do you lack conviction in your beliefs? If you think that the HiB is only useful in those at “highest risk”, then why avoid making the recommendation that anyone who is not at high risk needn’t bother with the vaccine? Seems pretty simple to me: If you are in the high risk group (whatever that is), then get the vaccine. If you are not in the high risk group, you can get it if you want, but you don’t need it.

    Let’s recap:

    * What is your definition of a “vaccine side effect denialist” (VSED)?

    Dr. Jay: VSED is saying that there are no side effects or virtually are no side effects from vaccines.

    * You say that VSEDs exist here at RI. Please provide a concrete example of VSED behavior.

    Dr. Jay: I cannot or am unwilling to offer any concrete examples.

    * What is your definition of “those at highest risk” [for HiB]?

    Dr. Jay: I have no definition by which I operate. The closest I can come is to suggest that those traveling to regions with high rates of HiB are at “high risk”.

    * Am I correct that your recommendation is that except for people who meet that definition [of high risk for HiB], everyone else should not bother with the [HiB] vaccine?

    Dr. Jay: I will make no solid recommendation one way or the other, even though I believe that only those at high risk for HiB would benefit from the vaccine. Patients should listen to their doctors [how does one listen to their doctor if their doctor won’t make a recommendation, one wonders] and inform themselves.

    Do those summaries sound about right, Dr. Jay? I do not want to misconstrue your words.

    Man. It took about one and a half week just to get those vague, noncommittal answers?

  95. #95 Todd W.
    September 7, 2010

    @pD

    [The study linked to in post #256] shows exactly what I think it shows if the argument to be defeated is the notion that there is no difference immunologically between getting a shot and the multitudle of things we encounter on a daily basis.

    But that’s not the question that the study is addressing. It is looking at the effect of a novel non-self assault. You had said in post 256:

    I would be curious in how you would reconcile this finding, significant increases in pro-inflammatory cytokines post vaccination in the non placebo group only? Both groups were exposed to the same bewildering array of antigens during daily exposure, yet only one group showed an increase in inflammatory cytokines.

    This study, since it was examining HPV vaccine, presumably used adults (or, at the very youngest, teens). One can fairly safely assume that by that age, all of the “bewildering array of antigens during daily exposure” is old hat to the immune system. It already recognizes all that stuff. So, the study is not comparing the vaccine vs. other novel non-self particles. It is comparing novel non-self particles to absence of non-self particles.

    Therefore, the study cannot be used to show that there is a difference between getting a vaccine and being exposed to the variety of new particles (bacterial, viral, chemical) one encounters in the first hours, days, months or years of life. The best we can conclude from the study at 256 is that the HPV vaccine triggers “increases in Th1, Th2 and inflammatory cytokines”. It says nothing about what a non-vaccine novel invading non-self particle would do. Also, due to the probably ages of the subjects, it says nothing about how an infant immune system would respond.

    So I stand by my original thought, that the study at 256 does not say what you think it says.

  96. #96 Antaeus Feldspar
    September 7, 2010

    Augie:(or should I say Auger, since you’re so good at boring)

    Oh, I like this one. I almost never bother responding to Augie except when exposing his Goofus moves, but when I do, it’ll be Auger from now on.

  97. #97 whiplash injury
    September 8, 2010

    A recent study published in PLoS One, the online journal of the Public Library of Science concluded that there is no link between MMR and autism. The study tested the proposition that the vaccine’s weakened muscle virus somehow lodged in and inflamed intestines, allowing wasted products to escape and reach the central nervous system. The research team had two questions: Does measles virus really persist in children with both disorders (autism and gastrointestinal complaints), and did vaccination precede the GI complaints which in turn preceded autism? Studying 25 children with both autism and GI disorders, the researchers found no relationship with vaccine timing as 5 of the children had MMR vaccines preceeding GI complaints which in turn preceeded autism symptoms, and only one child had traces of measles genetic material in his bowels.

  98. #98 passionlessDrone
    September 8, 2010

    Hi dt –

    Do you have some reason to believe that the inflammatory cytokine tnf-alpha is functionally different when LPS is the triggering agent? I only ask because you seem extremely caught up with this particular facet of the study design, for reasons I’m not really clear on.

    First and foremost, don’t forget that the animals in Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats also found the following:

    1) Direct injection of tnf-alpha resulted in synaptic excitability differences.
    2) Administration of LPS concurrently with tnf-alpha blockers had the same effect as saline.

    Alternatively, we could look to a very similar study by the same group of researchers, Viral-like brain inflammation during development causes increased seizure susceptibility in adult rats

    Here is the abstract:

    Viral infections of the CNS and their accompanying inflammation can cause long-term neurological effects, including increased risk for seizures. To examine the effects of CNS inflammation, we infused polyinosinic:polycytidylic acid, intracerebroventricularly to mimic a viral CNS infection in 14 day-old rats. This caused fever and an increase in the pro-inflammatory cytokine, interleukin (IL)-1β in the brain. As young adults, these animals were more susceptible to lithium-pilocarpine and pentylenetetrazol-induced seizures and showed memory deficits in fear conditioning. Whereas there was no alteration in adult hippocampal cytokine levels, we found a marked increase in NMDA (NR2A and C) and AMPA (GluR1) glutamate receptor subunit mRNA expression. The increase in seizure susceptibility, glutamate receptor subunits, and hippocampal IL-1β levels were suppressed by neonatal systemic minocycline. Thus, a novel model of viral CNS inflammation reveals pathophysiological relationships between brain cytokines, glutamate receptors, behaviour and seizures, which can be attenuated by anti-inflammatory agents like minocycline .

    Please note the similarities with our previous study; an inflammatory response during development leads to increased seizure susceptibility. But more importantly for your fascination with LPS, notice also that the triggering agent, Poly:IC is different than LPS, and that a different anti-inflammatory agent, minocycline, was able to suppress the effect.

    The mechanism of action isn’t about LPS or Poly:IC; it is about whether there is an inflammatory response, or there isn’t an inflammatory response. I don’t know how to be more clear on this, unfortnately.

    Regarding the meaningfullness of whether or not the DTaP actually triggers TLR4 for creation of inflammatory cytokines, we could look to Developmental biology of the innate immune response: implications for neonatal and infant vaccine development. [PMID: 19918215], published in May of 2009, which states in part:

    It is increasingly appreciated that an important determinant of vaccine efficacy is the ability of a given vaccine to activate the innate immune system to enhance APC function and Th1-polarizing adaptive responses (52). Currently, the two vaccines that are regularly given at birth in humans are the bacillus Calmette-Guerin (BCG) vaccine and the hepatitis B (HepB) vaccine (Table 1). BCG is capable of inducing a strong Th1-type immune responses in human neonatal cells in vitro (53) and in vivo (54), which is in part due its ability to activate multiple TLRs expressed by APCs (55).

    Haemophilus influenzae type b (Hib) conjugate vaccines are initially administered at 6 to 8 weeks of age. Hib activates transfected HEK293 cells in a TLR2- and TLR4-dependent manner, likely reflecting expression of bacterial lipopeptides (TLR2) and lipopolysaccharide (TLR4) (63) (64) (Table 1). Indeed, the outer membrane protein complex (OMPC) found within the Hib-OMPC glycoconjugate vaccine is TLR2 and MyD88-dependant, and in the absence of TLR2, the immunogenicity of the Hib-OMPC vaccine is significantly reduced (64).

    I suppose, the informed reader could argue that we have evidence that some pediatric vaccines might achieve the entirity of their immunostimulatory effects through interferrence with processes downstream of the TLRs (though we still really do not understand how alm adjuvants work), and because we also do not understand precisely how or where an exaggerated immune response is being generated by TLR stimulation in the autism subgroup, it is possible that the mechanisms of action are separate and distinct. It is an example of logical acrobatics that hinges on our lack of knowledge, which has always been my largest concern, but it is an argument my ideas are potentially susceptible to.

    At the end of the day, unfortunately, what we have is a lack of evidence. No studies on autism that study the effect of early life immune stimulation unless they involve the presence or absence of thimerosal. No studies on the release of pro-inflammatory cytokines as a result of vaccination in the pediatric shot schedule. No clear understanding of how alum actually achieves its immunostimulatory effects and a nascent understanding of the neonatal immune response. This is in stark contrast to the over riding narrative of this site, and indeed, the media hype.

    – pD

  99. #99 titmouse
    September 8, 2010

    This is just a test to see if I’m still in the spam trap.

  100. #100 titmouse
    September 8, 2010

    The tufted titmouse is now free of the filter!

    Woohoo!

    If anyone can explain to me why I’ve been filtered out of ScienceBlogs for nearly a year, I would be most appreciative.

  101. #101 passionlessDrone
    September 8, 2010

    Hi Todd W –

    It is looking at the effect of a novel non-self assault.

    You keep on dancing around the elephant in the room, vaccines are designed to invoke an immune response. If we were talking about something whose intention was other than to insure an immune response was generated you might have a point.

    This study, since it was examining HPV vaccine, presumably used adults (or, at the very youngest, teens). One can fairly safely assume that by that age, all of the “bewildering array of antigens during daily exposure” is old hat to the immune system. It already recognizes all that stuff. So, the study is not comparing the vaccine vs. other novel non-self particles. It is comparing novel non-self particles to absence of non-self particles.

    Please forgive me if I misunderstand your underlying argument, but doesn’t your logic follow that we ought to see an increasing trend in inflammatory cytokines, baseline, as a child is younger? In other words, the day a child is born, he is exposed to a million antigens (or whatever), an immunolgoical response is created, the next day, he is exposed to a million, but he already encountered a hundred of them, and they are considered ‘non novel’ at this point; consequently leading to a less robust immunological response. As age increases, the number of new novel non self particle dwindles. Is that correct?

    I found this, which somewhat speaks towards this line of thought Age-specific analysis of normal cytokine levels in healthy infants [PMID:14580162]

    While pathophysiology of elevated cytokines is well delineated, reference values for children are unknown, although they may vary physiologically with age and differ from those of adults. Between June and November 2001, interleukin (IL)-6, IL-10 and tumor necrosis factor-α (TNF-α) concentrations from blood samples of 79 healthy children in six different age groups (group I: 03 months; group II: 4-12 months; group III: 13-24 months; group IV: 25-36 months; group V: 37-48 months; group VI: 49-60 months) were measured with ELISA. TNF-α was within 2.2-3.5 pg/ml in all groups with a trend toward higher values in groups II and III (p = ns). IL-6 was significantly lower in group III than in groups IV (p = 0.0165) and VI (p = 0.0147). IL-10 was within 3.35.5 pg/ml in all groups (p = ns). In regression analysis no correlation between age and cytokine concentrations was found. Although not statistically significant, IL-6 was lower and TNF-α higher than the adult reference values provided by the kit manufacturer. Although reference cytokine levels seem not agerelated during early infancy, IL-6 is significantly lower during the second year of life than later. In infants aged 5 years or younger, reference levels of IL-6 should be chosen lower, and those of TNF-α higher, than the adult reference values.

    So between the age of zero months and five years, the authors could detect no change in baseline cytokine values; though paradoxical trending of inflammatory cytokines were observed. Presumably a child of five has encountered significantly more antigens than a child of three months, at yet baseline values do not seem to be different. Despite all those environmental antigens, baseline values of cytokines did not fluctuate. Does this have any impact on your thoughts regarding novel non self particle exposures?

    Therefore, the study cannot be used to show that there is a difference between getting a vaccine and being exposed to the variety of new particles (bacterial, viral, chemical) one encounters in the first hours, days, months or years of life.

    But what if we goto basic research on vaccines? For example, what if we look at this paper, Alum induces innate immune responses through macrophage and mast cell sensors, but these are not required for alum to act as an adjuvant for specific immunity [PMID: 2912728]

    Here is the most pertinent snipet in regards to our discussion:

    Our results show that many proinflammatory cytokines and chemokines are rapidly produced in vivo after exposure to alum.

    Or, we could look here at Mechanism of action of licensed vaccine adjuvants, also published in 2009 that states in part:

    However, recent work on alum and on the squalene-based emulsion MF59, has demonstrated that besides antigen delivery functions, these classes of adjuvants can also activate innate immunity pathways in vivo, generating an immunocompetent environment at injection site. Interestingly, it has been demonstrated that alum adjuvanticity depends on the activation of a protein complex called NLPR3/inflammasome, which is required for the correct processing of a number of pro-inflammatory cytokines, including IL1β.

    This is a forum where you expected to do more than shoot holes in studies, but instead, to provide evidence to support claims; especially if those claims run counter to a variety of evidence.

    If you would like to claim that vaccines do not invoke an inflammatory immune response, or perhaps do not do so in infants, you need to bring more to the table than the utter lack of studies in the infant population and claim maybe it is the case. You don’t like the fact that I used an HPV study and adults, fine. Find a study that discerns the inflammatory response in infants; especially one that shows a lack of inflammatory cytokines. This task should be exceedingly simple if the studies are actually available.

    Also, due to the probably ages of the subjects, it says nothing about how an infant immune system would respond.

    We do have some evidence that at the neonatal stage, right after birth, there are significant differences in the immune response; which is one reason we generally wait until a few months to start it up (except Hep-B or some others in other countries, I believe). [See Developmental biology of the innate immune response: implications for neonatal and infant vaccine development which I referenced above for some of what is known in this regard.]

    During the course of looking at this it occurred to me that this is a very curious evolutionary development, when the infant is absolutely at its most vulnerable, it has different immune response profile. We might consider that opposed to being a problem to overcome in order to vaccinate neonates even earlier, it might be a sign of evoluationarily selection; maybe nature is trying to tell us something.

    – pD

  102. #102 Todd W.
    September 8, 2010

    @pD

    I’m not making any claims, one way or the other. I am merely addressing one particular point you made and the evidence you presented in support of that claim.

    Your claim (paraphrased): Vaccines induce production of inflammatory cytokines, but the normal background exposure to antigens and other agents do not (or do, but at significantly lower levels).

    Your supporting evidence: A study in, presumably, adults examining administration of HPV VLPs vs. placebo and the resulting immune response.

    The study you presented does not support your argument. It shows that vaccines lead to increased production of inflammatory cytokines in adults vs. placebo. It does not show that vaccines lead to increased production of inflammatory cytokines in individuals (specifically, children) vs. background antigen exposure.

    That is all that I am saying. My reasoning is that, probably, by the time individuals reach the age of the subjects in the HPV study, they have been exposed to and their immune systems react differently to the everyday background antigens they encounter as compared to children.

    Your follow-up citation, “Age-specific analysis of normal cytokine levels in healthy infants” [PMID:14580162] suggests that the immune response in adults vs. children may not differ that greatly, at least in regard to IL-6, IL-10 and TNF-α. However, that still says nothing about the immune response to daily antigen exposures vs. vaccine exposure.

    Your citation on alum is not really surprising, in that we know alum incites a stronger immune response, but it only has significance if we are discussing vaccines that use alum as an adjuvant. Yes, we know that alum induces an immune response. That says nothing about the immune response to other antigenic exposure from daily life in infancy. And I got the impression that you were speaking of the immune response to vaccines in general, not specifically those containing an adjuvant.

    This is a forum where you expected to do more than shoot holes in studies, but instead, to provide evidence to support claims; especially if those claims run counter to a variety of evidence.

    The only claim I am making is that the study you provided does not appear to support your claim.

    If you would like to claim that vaccines do not invoke an inflammatory immune response, or perhaps do not do so in infants, you need to bring more to the table than the utter lack of studies in the infant population and claim maybe it is the case.

    Again, I am not making any such claim. Since I am not making a claim, other than what I’ve already stated just above, the onus is not on me to produce supporting evidence for a straw man you’ve created.

    You don’t like the fact that I used an HPV study and adults, fine. Find a study that discerns the inflammatory response in infants; especially one that shows a lack of inflammatory cytokines.

    You were the one trying to show that the immune response to vaccines is significantly different than the immune response to daily antigen exposure (in childhood). It is therefore your responsibility to produce the evidence to support that assertion.

    To recap, I do not deny that there is an inflammatory response to vaccines. You have provided ample evidence that that can and does occur in a variety of different manners and degrees. What you have not done, however, is support the rest of your argument: that daily antigen exposure in infancy produces marked differences in immune response vs. vaccines (e.g., that daily novel antigen exposure does not result in production of proinflammatory cytokines).

  103. #103 dt
    September 8, 2010

    So, in essence this is pD’s argument…….

    Vaccines induce immune responses, acting to produce specific protective immune responses against specific antigens, but also via a common final pathway they generate proinflammatory cytokines, which may have adverse consequenses. (So far, so “good”:- there is reasonable evidence to suggest this may happen).

    pD’s extrapolation: Vaccines induce these responses whereas other antigenic exposures do not. His evidence for this? ……..Nothing.

    It is dependent upon you pD to show that the human infant does not respond in this fashion to antigenic challenges. Many of the thousands of challenges infants face may be minor, true, and provoke muted responses which are not typically associated with significant proinflammatory cytokine production, but quite clearly many other challenges are not minor. They provoke significant systemic responses on exposure to numerous posssible pathogens (the list of candidates that infants are exposed to is considerable). The added challenge of vaccines would appear to be pretty insignificant in the grand scheme of things.

  104. #104 passionlessDrone
    September 8, 2010

    Hi dt –

    You are close to my argument, but for some reason you left out the part about our evidence that children with autism seem to create more pro-inflamatory cytokines than their undiagnosed peers, however. And while I haven’t detailed it on this thread, for the sake of brevity, we also have several studies that tell us that as the proposensity for an inflammatory state increases, so too, does the severity of the autistic behaviors.

    For example, in Macrophage migration inhibitory factor and autism spectrum disorders

    There were genetic associations between known functional polymorphisms in the promoter for MIF and autism spectrum disorder-related behaviors. Also, probands with autism spectrum disorder exhibited higher circulating MIF levels than did their unaffected siblings, and plasma MIF concentrations correlated with the severity of multiple autism spectrum disorder symptoms

    Or, we could look at Increased serum levels of high mobility group box 1 protein in patients with autistic disorder

    BACKGROUND: High mobility group box 1 (HMGB1) is a highly conserved, ubiquitous protein that functions as an activator for inducing the immune response and can be released from neurons after glutamate excitotoxicity. The objective of the present study was to measure serum levels of HMGB1 in patients with autistic disorder and to study their relationship with clinical characteristics.

    METHODS: We enrolled 22 adult patients with autistic disorder (mean age: 28.1+/-7.7 years) and 28 age- and gender-matched healthy controls (mean age: 28.7+/-8.1 years). Serum levels of HMGB1 were measured by enzyme-linked immunosorbent assay (ELISA).

    RESULTS: Compared with healthy subjects, serum levels of HMGB1 were significantly higher in patients with autistic disorder (10.8+/-2.6 ng/mL versus 5.6+/-2.5 ng/mL, respectively, P<0.001). After adjustment for potential confounders, serum HMGB1 levels were independently associated with their domain A scores in the Autism Diagnostic Interview-Revised, which reflects their impairments in social interaction.

    Or, we could look at Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome

    Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. A potential role for immune dysfunction has been suggested in ASD. To test this hypothesis, we investigated evidence of differential cytokine release in plasma samples obtained from 2 to 5year-old children with ASD compared with age-matched typically developing (TD) children and children with developmental disabilities other than autism (DD). Participants were recruited as part of the population based case-control CHARGE (Childhood Autism Risks from Genetics and Environment) study and included: 97 participants with a confirmed diagnosis of ASD using standard assessments (DSM IV criteria and ADOS, ADI-R), 87 confirmed TD controls, and 39 confirmed DD controls. Plasma was isolated and cytokine production was assessed by multiplex Luminex analysis. Observations indicate significant increases in plasma levels of a number of cytokines, including IL-1beta, IL-6, IL-8 and IL-12p40 in the ASD group compared with TD controls (p<0.04). Moreover, when the ASD group was separated based on the onset of symptoms, it was noted that the increased cytokine levels were predominantly in ASD children who had a regressive form of ASD. In addition, increasing cytokine levels were associated with more impaired communication and aberrant behaviors. In conclusion, using larger number of participants than previous studies, we report significantly shifted cytokine profiles in ASD. These findings suggest that ongoing inflammatory responses may be linked to disturbances in behavior and require confirmation in larger replication studies. The characterization of immunological parameters in ASD has important implications for diagnosis, and should be considered when designing therapeutic strategies to treat core symptoms and behavioral impairments of ASD.

    If you are going to summarize my argument, please do not leave out its most important component; that if our parameter of interest is an immune response, the autism population has evidence suggestive of a susceptible population. This is an important point that despite my best efforts, seems to have eluded you; is there a particular reason you have decided not to include this in your summarization?

    pD’s extrapolation: Vaccines induce these responses whereas other antigenic exposures do not. His evidence for this? ……..Nothing.

    Please read my resonse to Bacon in post #238 where I said:

    I called it a faux infection, and our functional end point, generation of an inflammatory response, is the same from vaccination or wild infection.

    Infections generate an immune response. So do vaccinations. If you looked at the study I posted on 302, you will see that no detectable changes were found in children aged 3 to 60 months concerning baseline cytokine levels for why we have reason to believe that everyday exposure isn’t causing the same type of inflamamtory response that an infection, or a vaccine does.

    For the record, I’d clearly state that if my theory is to hold water, infections early in life would have the same propensity for harm. I have no problems with admitting this.

    In fact, we have some evidence for this, though it is conflicting. For example, we might use Infection in the first 2 years of life and autism spectrum disorders. which found:

    Children with subsequent diagnoses of autism do not have more overall infections in the first 2 years of life than children without autism. Data suggest that children with autism may have modestly elevated rates of infection in the first 30 days and that, during the first 2 years, children with autism may be at higher risk for certain types of infections and lower risk for others. Additional studies that explore the associations between prenatal and early childhood infections and autism may help clarify the role of infection and the immune system in the etiology of autism spectrum disorder.

    Or, we could look to Association of hospitalization for infection in childhood with diagnosis of autism spectrum disorders: a Danish cohort study which reports:

    A total of 7379 children were diagnosed as having ASDs. Children admitted to the hospital for any infectious disease displayed an increased rate of ASD diagnoses (HR, 1.38 [95% confidence interval, 1.31-1.45]). This association was found to be similar for infectious diseases of bacterial and viral origin. Furthermore, children admitted to the hospital for noninfectious disease also displayed an increased rate of ASD diagnoses (HR, 1.76 [95% confidence interval, 1.68-1.86]), and admissions for infection increased the rate of mental retardation (2.18 [2.06-2.31]).

    I believe there are other studies that show no relationship.

    It is dependent upon you pD to show that the human infant does not respond in this fashion to antigenic challenges. Many of the thousands of challenges infants face may be minor, true, and provoke muted responses which are not typically associated with significant proinflammatory cytokine production, but quite clearly many other challenges are not minor.

    Again, you’ll have to define ‘antigenic challenge’ in this regard for me. You’ve identified the biggest problem with your argument here, but don’t realize it when you say, ‘clearly many other challenges are not minor’. While this is technically true, to equate to our ~90% vaccination rate, “many other” needs to read in the range of four million children a year. Nearly every child is being vaccinated on their 60, 120, and 180 day from the womb (and a great many on their 2 or 3). Do you think you could provide evidence that such a similar profile exists for infections? Sure it happened to some infants in the past, but do you think it happened to 90% of them? This is a big change from how our ancestors evolved.

    The added challenge of vaccines would appear to be pretty insignificant in the grand scheme of things.

    And so, after all of this, lacking evidence, we are left with the assumption of no harm.

    – pD

  105. #105 Calli Arcale
    September 8, 2010

    I suppose the most trivial example would be colonization of the infant gut. That happens almost immediately after birth, and the gut flora changes completely several times in the first year as the child encounters new bacteria and the gut ecology gradually settles out. Given the massive immune system presence in the gut, I would think this to be significant, even if it’s not identical to a subcutaneous injection. It happens to 100% of babies. (Remember, it doesn’t need to be a massive and visually obvious infection to trigger an immune response.)

    And so, after all of this, lacking evidence, we are left with the assumption of no harm.

    Not exactly. We are left with no evidence of harm.

    Out of curiosity, if autistic children do, as you say, produce more pro-inflamatory cytokines than their normal peers, wouldn’t we expect to see a disproportionate rate of severe illness among the autistic population, and probably also of autoimmune disorders? I’ve heard it claimed that there is an increased rate, but have not seen any convincing evidence; mostly, I’ve heard anecdotes: “my child is autistic and has allergies!” which of course is useless, because lots of children have allergies anyway.

  106. #106 dt
    September 9, 2010

    @pD
    “If you are going to summarize my argument, please do not leave out its most important component; that if our parameter of interest is an immune response, the autism population has evidence suggestive of a susceptible population. This is an important point that despite my best efforts, seems to have eluded you; is there a particular reason you have decided not to include this in your summarization?”

    I have never mentioned autism, i have only dealt with the vaccination and immune challenge issue so far.

    All I am saying is that you have provided no evidence that vaccination provides a greater immune challenge in infants that the background incidence of natural infection, and the “antivax” argument is that vaccines are to blame.

    You say autistics have a higher rate of immune activation/proinflammatory cytokines, and the inference is this is somehow causal in the autism. I am not tackling that argument, merely asking for an important link in the evidential chain to be clarified – namely that this is something which disproportionately affects vaccinated infants (which seems to be where you are coming from). I see that rather than dealing solely with vaccination, you are approaching the problem now from the perspective of “immunoactivation causes autism, whether it be vaccination or infection” which is somewhat different from the argument I thought you were taking initially, what with your previous focus on the vaccine aspect.

    Your own cited evidence points to the fact that autistic kids do get infections, and indeed may get more infections that kids without autism. This might support the idea that immunoactivation is linked with autism, but says nothing about the role of vaccines. (It also doesn’t really support your idea that a fraction of the population is hypersusceptible, and this is why they get autism – that might be the case if you showed autistic kids had equivalent rates of infections to other kids – but you have shown they get more infections, which indicates a cumulative “load” effect rather than a hypersensitivity).

    I would argue that since the immune response to vaccines is far narrower and often less robust than the challenge of a natural infection, that vaccination could reduce cases of autism, as overall it would lessen the immune burden.

    Taking this where I know you will go next, you will say that the challenges from vaccines occur at an earlier age than the natural challenges, so this must be bad. Yet I have indicated that the challenges to the infant immune system are frequent and significant, even in early infancy. (And don’t forget that the bete noir vaccine wrt autism, the one which is meant to make kids regress/change withing hours of recieving it, is the MMR which is not given in the first year)

    Let’s take RSV for example. This is only one of literally dozens of viruses that an infant will get during its first year of life. Not only can the infant catch it once, but several times, as little immunity is engendered. Two thirds of infants get this in their first year, and it is one in which virtually all the harm caused is by virtue of the host immune response, which is varied and complex.

    This review is quite enlightening:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258918/pdf/1625-07.pdf

    Now if kids are getting frequent “significant” antigenic challenges such as this throughout their infancy, I can see no logic in ascribing the added small immune burden of vaccination (which might actually help lessen the overall burden by reducing the risk of natural infection) as being significant enough to induce autism.

    Your concept, that infection-induced immunoactivation is the trigger for autism, would if taken to its logical conclusion, lead to a “bubble” mentality of isolating all infants from others for the first year of life to reduce chances of getting any infections, and promote the search and use of vaccines for RSV, rotavirus, ECHO viruses, corona viruses, coxsackie viruses, flu and paraflu, rhinoviruses… (thats hundreds and counting).

    I hardly think that as a strategy to reduce the incidence of autism that this would find favour, particularly among the type of mothers that both hate vaccines and espouse the hygeine hypothesis.

  107. #107 dt
    September 9, 2010

    Clarification on RSV: “Not only can the infant catch it once, but several times, as little immunity is engendered.”

    By this I mean little long lasting protective immunity. The initial acute immune response is very active and significant, as I indicate.

  108. #108 passionlessDrone
    September 9, 2010

    Hi Callie Arcade –

    Out of curiosity, if autistic children do, as you say, produce more pro-inflamatory cytokines than their normal peers, wouldn’t we expect to see a disproportionate rate of severe illness among the autistic population, and probably also of autoimmune disorders?

    It is not as I say, it was as the data says. I have provided some references in post #275 on this. Further

    As far as severe illness in the autism population, there are a few studies on this that I believe are negative; i.e., no differences were found. There was the paper in 305 I linked to that showed an increase in hospitilization in the ASD group, though I’m not sure if that fits the classification of severe illness or not. (?)

    Regarding auto immune disorders, there is one negative study, Atopic features in early childhood autism. [PMID: 18272414] that I know of. It does not seem to have been studied too well.(?) The linkage to parental autoimmune disorders seems strong; see my post at 199 for some studies that fit this criteria.

    – pD

  109. #109 Calli Arcale
    September 9, 2010

    Sorry, I didn’t mean to imply anything ugly; just trying to be clear that I was referencing you. I was too lazy to go up and do another blockquote for what was more a case of curiosity than anything else. (It was late; I was tired. I sorta turn into a pumpkin after 10PM.)

    I guess my real question is whether, if there isn’t increased rate of other illnesses, whether the pro-inflammatory cytokines in autistic children in that data is actually meaningful. Just because something is more doesn’t mean it’s doing anything. *shrugs* I’m out of my depth on that question.

  110. #110 passionlessdrone
    September 9, 2010

    Hi dt –

    I have never mentioned autism, i have only dealt with the vaccination and immune challenge issue so far.

    It was my hope that by this point you will have noticed that the overwhelming majority of my links have been related to autism.

    All I am saying is that you have provided no evidence that vaccination provides a greater immune challenge in infants that the background incidence of natural infection, and the “antivax” argument is that vaccines are to blame.

    Why is it that the complete and seemingly undisputed lack of studies on the innate immune response in regard to vaccination is my problem? This is the heart of my concern; we don’t have quality data on this. I cannot provide links to studies that do not exist; and in the line of my arguement, as you seem to sense later on in your response, ‘greater’ is only part of the potential problem; timing is also important.

    Regarding ‘the “antivax” argument’, I have stated with some clarity that I have no problems with a myriad of other causes.

    I have absolutely no problem with a bazillion other mechanism of action; pure genetics, the environmental ubiquity of endorcrine disruptors, pesticides, and other chemicals, the fattening of the populace, actually getting a viral or bacterial infection, difficulties in birthing and/or gestation, epigenetic alterations from any combination of the above, whatever. My worldview is far, far away from a place where vaccines are the only potential problem.

    (Post 231)

    You say autistics have a higher rate of immune activation/proinflammatory cytokines,

    That isn’t what “I say”; it was what the data says.

    and the inference is this is somehow causal in the autism.

    I am saying this is possible. Big difference. See my post in 229 for more on this.

    I am not tackling that argument, merely asking for an important link in the evidential chain to be clarified – namely that this is something which disproportionately affects vaccinated infants (which seems to be where you are coming from). I see that rather than dealing solely with vaccination, you are approaching the problem now from the perspective of “immunoactivation causes autism, whether it be vaccination or infection” which is somewhat different from the argument I thought you were taking initially, what with your previous focus on the vaccine aspect.

    You are over simplifying my position. I am saying that immunoactivation may lead to autism. Please find a single place where I have made the causation claim. As evidence of a nuanced position on my end, regarding both causation and infections, I could quote myself from this thread:

    I cannot make the claim to prove that immune dysfunction in autism is causal. Similarly, I cannot prove that vaccination can cause autism.

    (Post 229)

    I am worried about the resultant immune response, and you get one of those if the disease is real or not.

    (Post 256)

    In other words, perhaps an actual infection creates a more vigorous immune response than a vaccination;
    I’d say this is certainly possible, but barring any studies, we cannot know for sure. The studies I mentioned regarding synergistic effects of stimulating multiple toll like receptors simultaneously makes this a difficult problem.

    (Post 275)

    Do you have some particular reason that despite all of this, you continue to pigeonhole my position as advocating causation can be proven and ignoring infection?

    I would argue that since the immune response to vaccines is far narrower and often less robust than the challenge of a natural infection, that vaccination could reduce cases of autism, as overall it would lessen the immune burden.

    The extended immune response, sure; but if I were to ask you, or anyone, to post something that details the inflammatory cytokine response from vaccination, no one has seen fit or able to do so. You are making an assumption without data; that’s a bad way to handle systems as complicated as this.

    Taking this where I know you will go next, you will say that the challenges from vaccines occur at an earlier age than the natural challenges, so this must be bad. Yet I have indicated that the challenges to the infant immune system are frequent and significant, even in early infancy. (And don’t forget that the bete noir vaccine wrt autism, the one which is meant to make kids regress/change withing hours of recieving it, is the MMR which is not given in the first year)

    I am saying that we have evidence that time can have a sigificant effect; but I do like how you’ve picked up on that component of my thoughts. Regarding the MMR, please refer to my post 260 where I said:

    While the people who claim to have witnessed dramatic regressions in their child following MMR vaccination are definitely vocal; my concerns are more along the lines of subtle changes. The more we learn about things like exposures during development, it seems that our conclusions towards no effect are forced downwards as we learn apply finer filters.

    Let’s take RSV for example. This is only one of literally dozens of viruses that an infant will get during its first year of life.

    This is a ridiculous statement. I don’t know if you’ve ever had children, but I have, and they do not get sick ‘dozens’ of time in the first year of life! Lets say each viral infection lasted two days; at two dozen infections, that would be forty eight sick days in the first year of life alone; one seventh of the infants first year of life! Does anyone out there have a baby? Have they been sick anywhere close to one day a week?

    What if we were to see what the oft quoted Paul Offit says about the frequency of infection in Vaccines and Autism: A Tale of Shifting Hypotheses?

    Further, vaccines represent a minute fraction of what a child’s immune system routinely navigates; the average child is infected with 4–6 viruses per year [32].

    The figure you have provided, “dozens of viruses” is, conservatively, several orders of magnitude greater than what Mr. Offit claims! Could you please provide any evidence at all that infants are infected with “literally dozes of viruses during its first year of life”? I’d hate to think you pulled this number from nowhere in an attempt to try to minimize the frequency of vaccinations, so why not just let everyone know from where you got this astoundingly high figure. As I’ve stated repeatedly, this is a forum where you are expected to substantiate your claims, and this one is a whopper of a claim. This thread has been an absolute exercise in people making claims and then refusing to back them up with data. Not this time. Where on Earth did you get this idea?

    Not only can the infant catch it once, but several times, as little immunity is engendered. Two thirds of infants get this in their first year, and it is one in which virtually all the harm caused is by virtue of the host immune response, which is varied and complex.

    I think RSV is a great example of exactly the type of potential problem I am proposing; immune disturbances early in life having difficult to predict consequences!

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258918/pdf/1625-07.pdf

    This is a pretty neat paper. Unfortunately, your assertion that ‘virtually all of the harm is caused by the virtue of the host response’ seems to be at odds with the conclusions of the paper, however.

    The relative contribution of viral versus various host factorsto RSV pathogenesis remains controversial.

    In most cases, however, there may not be a single predominantfactor. Instead, there may be different relative contributions from the various interacting viral and host factors that will depend on the speed and magnitude of viral replication,
    the effectiveness of the host response, underlying predispositions toward aberrant, exaggerated, or deficient aspects of the host response, maturational state, and other factors.

    Now if kids are getting frequent “significant” antigenic challenges such as this throughout their infancy, I can see no logic in ascribing the added small immune burden of vaccination (which might actually help lessen the overall burden by reducing the risk of natural infection) as being significant enough to induce autism.

    Define ‘frequent’ and “significant”. Also, please provide evidence that such “significant” antigenic challenges are “frequent”. And finally, provide some evidence that demonstrates the robustness of the inflammatory cytokine response of pediatric vaccines. Until you can start backing your assertions up, I don’t see how to proceed. My biggest concern is over a lack of data, and you seem to think that just telling me things without backing them up is sufficient. It isn’t good enough, especially when it seems that your own references seem to disagree with your conclusions, or your claims are several times the value of other claims made by others.

    Your concept, that infection-induced immunoactivation is the trigger for autism, would if taken to its logical conclusion, lead to a “bubble” mentality of isolating all infants from others for the first year of life to reduce chances of getting any infections, and promote the search and use of vaccines for RSV, rotavirus, ECHO viruses, corona viruses, coxsackie viruses, flu and paraflu, rhinoviruses… (thats hundreds and counting).

    Please replace “is the trigger for autism”, with “could be one of many triggers for autism”. I’m not advocating anything except an intellectually honest conversation about what we know, and what we don’t. If you can start providing evidence regarding the magnitude of the immune response after vaccination, that would be a good start. There are things we can meaningful control (the rate, and schedule of vaccination), and things we cannot meaningfully control (exposure to the world). I’m saying we should evaluate looking at things we can control, not that we try to change things for which we have no control.

    I hardly think that as a strategy to reduce the incidence of autism that this would find favour, particularly among the type of mothers that both hate vaccines and espouse the hygeine hypothesis.

    I do not hate vaccines, and I think the hygeine hypothesis has some intriguing possibilities.

    – pD

  111. #111 Dangerous Bacon
    September 9, 2010

    titmouse: “Regarding the autism-vaccine hypothesis, the first evidential hurdle is a real correlation between vaccination and autism. Until that’s present, the biochemical details are pretty moot.”

    This reminds me of the homeopathy advocate Orac sometimes lampoons, the eminent Dr. Lionel Milgrom. This guy publishes journal articles containing fabulous equations and models showing how homeopathy might produce its wonderful healing effects. All of this mumbo-jumbo is predicated on the conviction that homeopathy actually works beyond placebo effect, but is a waste of time and electrons considering that such evidence of effectiveness is lacking.

    Similarly, one can weave a jargon-filled connect-the-dots narrative about how the immune response to vaccines (unlike the immune response to “natural” infectious assaults on the body occurring on a daily basis) imperils children and makes an autism-vaccine link rational; lost in all of this is the ample evidence that vaccines do not cause autism. So having a pretty collection of irrelevant cytokine anecdotes does not make for a convincing argument.

  112. #112 Sid Offit
    September 9, 2010

    The repeated use of Paul Offit’s canard, “we’re challenged by billions of bacteria everyday” as a way to excuse the possible adverse effects of vaccination is beyond ridiculous. It’s like saying eating a cup of Activa is the equivalent of receiving a MMR injection.

  113. #113 dt
    September 9, 2010

    pD:

    “It isn’t good enough, especially when it seems that your own references seem to disagree with your conclusions, or your claims are several times the value of other claims made by others.

    My own statement regarding RSV was that “Two thirds of infants get this in their first year, and it is one in which virtually all the harm caused is by virtue of the host immune response, which is varied and complex.”
    You dispute that the paper indicates that the host immune response causes most of the damage. Perhaps I was wrong to suggest “virtually all” the damage was through immunopathogenesis. I was trying to emphasise to you that RSV does provoke a very brisk immune response (like many other viruses do) The review does admittedly present evidence for direct viral cytopathogenesis, but also significant evidence for immunopathogenesis, eg:

    Several observations suggest a substantial contribution of host immunity to RSV disease. For example, clinical observations (as noted above) and in vitro studies (described later)showed that RSV is not highly cytopathic or invasive.///When cotton rats with an established
    RSV infection were administered a neutralizing antibody that reduced pulmonary virus replication more than 1,000-fold, there was little effect on pulmonary pathology; the
    addition of anti-inflammatory glucocorticoid therapy was necessary to reduce pathology (122). A similar lack of clinical improvement was observed for intubated children with an established infection, for whom antibody therapy reduced viral shedding 30-fold compared to controls (97). The inability to block disease progression by sharply reducing virus replication is suggestive of immunopathology rather than direct viral cytopathology. Finally, genetic polymorphisms that increase expression of the IL-4, IL-8, and (tentatively) CCR5 genes were associated with an increased frequency of severe pediatric RSV disease, suggesting that these host factors can contribute
    to pathogenesis

    and

    Excessive T-lymphocyte cytotoxicity is one potential mechanism
    of immune-mediated pathogenesis…..depletion of CD4 or CD8 T cells reduced disease, and depletion of both resulted in long-term infection without illness…. T-cell reconstitution dramatically reduced viral shedding but also resulted in a dramatic increase in pulmonary disease …..A role for Th2-biased responses in RSV pathogenesis was
    suggested by (i) the Th2-mediated disease associated with FIRSV discussed above, (ii) the Th2 bias of the young infant
    (discussed later), in whom severe disease is more frequent, and (iii) the association of Th2 responses with asthma, which involves small airway constriction, mucus plugging, and wheezing similar to patterns seen with RSV disease.

    But enough quibbling over that particular split hair…..

    pD:

    “It isn’t good enough, especially when it seems that your own references seem to disagree with your conclusions, or your claims are several times the value of other claims made by others.

    This is a reference to Paul Offit’s remark that “the average child is infected with 4–6 viruses per year” and your dislike that I said infants are infected with dozens of viruses.

    Would that you so readily believed everything that came out of Offit’s mouth….. 😉

    I think that his estimate is an underestimate. Apart from RSV (already covered) we have:
    Rhinovirus
    Human metapneumovirus
    Influenza
    Parainfluenza A/B
    CMV
    Herpes viruses – types 1, 3, 4, 5, 6, 7.
    Rotavirus
    Adenovirus
    Coxsackie (several subtypes)
    ECHO (several subtypes)
    Coronavirus
    and the rest

    Admittedly I cannot instantly lay my hands on a source giving the exact incidence of each of these these in infancy, suffice to say that they do occur and chances are most infants will be exposed to and infected with many or most of these, and a few others I haven’t mentioned to boot.
    That time your kid was a bit grizzly and hot for a couple of hours? Could have been an ECHO virus.
    That time your kid just seemed off colour, and din’t even have a fever? Could have been adenovirus.

    We are not talking about severe clinical disease/hospitalisation here, just an infection sufficient to engender an immune response. Not every infection provokes a bad clinical response. And most viral infections in infancy are asymptomatic/subclinical.

  114. #114 Todd W.
    September 9, 2010

    @Sid

    Straw man. No one is saying that the daily antigenic challenges are the same as vaccination or that it excuses vaccine AEs.

    However, if someone is going to claim that vaccines “overwhelm” the immune system, or that they have some other major deleterious effect on the immune system, then they need to show a) that such effects do not occur from normal exposure to environmental challenges or b) that such effects occur with greater severity and/or regularity than environmental challenges.

  115. #115 dt
    September 9, 2010

    Apols – HHV-5 is CMV. Didn’t mean to list it twice.

  116. #116 dt
    September 9, 2010

    @Sidtroll:

    “The repeated use of Paul Offit’s canard, “we’re challenged by billions of bacteria everyday” as a way to excuse the possible adverse effects of vaccination is beyond ridiculous.”

    Nice to see you are paying such close attention to the actual discussion Sid. Now be a good boy and go play with some matches near another strawman, will you?

  117. #117 Sid Offit
    September 9, 2010

    I would argue that since the immune response to vaccines is far narrower and often less robust than the challenge of a natural infection, that vaccination could reducecases of autism, as overall it would lessen the immune burden.

    You’re expending considerable effort to not see this but

    “far narrower and often less robust” i.e. different may very well be the problem. As you must know, the immune system is quite complex and has evolved to behave in a specific and synergistic way. Different, less robust or not, may therefore lead to deleterious consequences.

  118. #118 Calli Arcale
    September 9, 2010

    But *does* it? That’s the question. I’m not inclined to get terribly worried about something until there’s data. I appreciate PD’s point about “if nobody does the studies, we won’t know”, but I’m still not going to live my life in fear of all the things we don’t know yet. Maybe having an aquarium is bad for your health in some way which hasn’t yet been studied; I’m still not going to get rid of my guppy/pleco collection.

  119. #119 passionlessDrone
    September 9, 2010

    Hi dt –

    Perhaps I was wrong to suggest “virtually all” the damage was through immunopathogenesis. I was trying to emphasise to you that RSV does provoke a very brisk immune response (like many other viruses do)

    OK. But the details in this discussion are important, had I decided not to respond anyone reading might have taken your words as accurate, when clearly, they are still a point of some contention. It isn’t that I care about RSV in particular, I care that it seems to be a recurrent theme; making statements that subsequently cannot be substantiated, or for which we have evidence that is the opposite.

    I’m in general agreement that the immune response to RSV is brisk, and available evidence says that the immune response is responsible for future outcomes.

    your dislike that I said infants are infected with dozens of viruses.

    I dislike that you seem to have the propensity to say things that you cannot substantiate with evidence and how elbematic this is for the entire vaccine / autism discussion. Again, had I not asked you to substantiate this value, what is to keep a future reader from actually believing that an infant gets ‘dozens’ of viral infections their first year? The fact that there are other infectious disease experts (who appear not to know much about autism), that claim staggeringly lower values isn’t something to sneeze at, to use a pun.

    Here is an example; lets say I were to claim that kids got ‘literally dozens’ of vaccines at their check ups, I’d get crucified with ridicule; yet you make the claim that kids get dozens of viral infections in their first year and it’s no big deal, something I ‘dislike’. Is accuracy important or not? Is the ability to substantiate a statement important or not? I thought I’d wandered into someplace where that was important; maybe I was wrong.

    I further dislike that you consistently misrepresent my position, though I cannot tell if that is intentional or not.

    I think that his estimate is an underestimate.

    Well, OK. For the sake of argument, I could just as easily say that his estimate is an overestimate and we’d both be in the same place; without anything to back it up. If you can find something, anything that approaches two viral infections a month, please push up a link.

    We are not talking about severe clinical disease/hospitalisation here, just an infection sufficient to engender an immune response.

    Can you tell me if this fits as “significant” in your model above (Post 307), or not? That would be a big help.

    Tragically, we are back to the same place we’ve been for a long time; your inability to demonstrate that we understand the strength of an immune response from vaccination. Without that, attempting to make equivalencies between asymptomatic presentation, and everyday exposure are at best, educated guesses. I think that is a problem, but I guess others don’t. I’m not sure how we move on from that. (?)

    – pD

  120. #120 passionlessDrone
    September 9, 2010

    Hi Calle Arcade –

    I appreciate PD’s point about “if nobody does the studies, we won’t know”, but I’m still not going to live my life in fear of all the things we don’t know yet.

    I am quite pleased that someone has, apparently, received at least one of my messages. I’d also add that I’ve always very much appreciated your writing style and usually find your posts quite thoughtfull.

    – pD

  121. #121 Calli Arcale
    September 9, 2010

    *blushes* That’s very kind of you to say, pD. I find you very articulate and thoughtful, and I often learn something from your posts. You’re also a warm-hearted person, and that’s always a good thing to find on the Web, where anonymity tends to encourage harsher expressions of opinion.

  122. #122 dt
    September 10, 2010

    pD, I rather feel this discussion is inexorably descending into a “tit for tat” exchange of nitpicking. I hope not and will try and prevent it from becoming one.

    “Here is an example; lets say I were to claim that kids got ‘literally dozens’ of vaccines at their check ups, I’d get crucified with ridicule; yet you make the claim that kids get dozens of viral infections in their first year and it’s no big deal”.

    There is a difference. Firstly, antivaxers do say this about vaccines, and the important thing to note is that they keep saying it even when corrected. The claim is one that is easily verified and quantified.

    My claim that infants get dozens of viral infections is an estimation based upon knowledge of the existing medical literature, personal and professional experience (and I am open to the possibility that this may be an overestimate). It is unlikely to be able to be definitively proved without a rather comprehensive prospective (and invasive) microbiological surveillance study being carried out on infants, which would be difficult to justify.

    But let me say why I think there is supporting evidence that infants get frequent infections in infancy, of which most will be viral.

    Firstly you have quoted one study yourself (Infection in the First 2 Years of Life and Autism Spectrum Disorders)which indicates the frequency of infections in infants, comparing this to those with and without autism. The methodology indicates that infections are only recorded if they were serious enough to result in “inpatient, outpatient, emergency,and referral visits” (ie they will miss less serious infection episodes, which common sense will tell you will greatly outnumber the episodes for which medical care is sought). The mean number of infections in the first 2 years of life were 8.7 and 8.9 for cases and controls respectively.

    Another prospective study, entitled “Serial viral infections in infants with recurrent respiratory illnesses” looked for viral infections in infants up to 1 year who had a parent/both parents with asthma. If it was thought that the child had a respiratory infection, this was assessed and all episodes which were deemed moderate or greater severity (MSI) were then clinically assessed, and nasal sampling carried out for viruses. Also routine nasal washings were carried out in some children in the study, regardless of symptoms.
    Results show that these kids had a median of 2 “moderate to severe” respiratory illnesses in the first year, and the analysis goes on to focus on the subset of infants who had recurrent illnesses.

    “Viral detection rate increased with the severity of illness: 29 (45%) out of 65 in asymptomatic infants, 14 (67%) out of 21 in infants with mild illness and 136 (91%) out of 150 in infants with MSI”

    Now I’d like to drill down into this sampling of “asymptomatic” kids for a moment. The study did sampling of kids and grouped them according to the frequency of Moderate to severe illnessess in the year (MSIs). Overall, there were 193 samples done on asymptomatic kids. 63 were positive for one virus (32%), and some were positive for more than one virus.
    http://erj.ersjournals.com/content/32/2/314/T1.expansion.html (see near bottom of the table)

    I mention this to show that viruses are detected quite frequently in infants, and that even asymptomatic infants when randomly sampled, show evidence of a respiratory viral infection nearly a third of the time. Now when one considers the limitations that this study had in detecting viruses (they did not sample for Human bocavirus, CoV HKU1 and respiratory polyomaviruses), the conclusion must be that respiratory viral infection is quite frequent/prevalent in infants if random/sporadic sampling can reveal evidence of same in a minimum of a third of apparently well children.

    These studies give some indication of the frequency of infections in early childhood. The bulk of infections may be due to respiratory or gastrointestinal viruses, but other nonspecific viral illnesses also occur. A check on the epidemiology and clinical data on the dozens of potential individual virus infections reveals that these viruses are commoner than one would believe at first sight. For example, have any of you heard of Sapovirus or Astrovirus? They both can cause diarrhoea, and a survey looking for them in non-hospitalised infants with gastrointestinal upset found them in 4.7% of cases (Epidemiology and molecular characterization of sapovirus and astrovirus in Japan, 2008-2009.)

    I mention this last study to demonstrate that viruses we have never even heard of can be found in kids, but only if one is able to look for them using sophisticated molecular diagnostics. Claiming, as I do, that infants can be infected with “dozens” of viruses hardly seems far fetched, indeed it seems highly probable. Unless every infant is screened for every known virus it is unlikely that we will be able to accurately determine the incidence of infection. Certainly some better known respiratory viruses seem pretty prevalent, being found in a third of well infants.

    I cannot find other prospective studies at the moment which demonstrate the incidence of infant viral infections – my googlefu is weak today. I am happy to try and hunt more down next week (I am pretty busy this w/e).

    How does one rate infection significance? That depends. Most infections have a spectrum of clinical presentations, from subclinical to severe, but the immune response to the infection does not necessarily correlate with clinical severity. Any and every exposure to an infectious agent will result in an immune response, and if this is very effective, then the infection may not even be noticed by the child’s parent or person infected.

    So immunologically significant (but clinically insignificant) infections may be occuring all the time in all of us. This is something else you need to consider in your model.

  123. #123 passionlessDrone
    September 11, 2010

    Hi dt –

    pD, I rather feel this discussion is inexorably descending into a “tit for tat” exchange of nitpicking. I hope not and will try and prevent it from becoming one.

    OK.

    I cannot find other prospective studies at the moment which demonstrate the incidence of infant viral infections – my googlefu is weak today. I am happy to try and hunt more down next week (I am pretty busy this w/e).

    I’m super busy too and have already let my tenaciousness get the better of me on this thread. I do have some thoughts on what you have presented, but want to do some more reading, and some more real life in before I get fired up again. I’ll check back in a few days.

    – pD

  124. #124 Drivebyposter
    September 11, 2010

    The repeated use of Paul Offit’s canard, “we’re challenged by billions of bacteria everyday” as a way to excuse the possible adverse effects of vaccination is beyond ridiculous. It’s like saying eating a cup of Activa is the equivalent of receiving a MMR injection.

    How exactly do you come to that conclusion?
    It’s more like…
    “Saying a quote means something other than what it actually means makes you an ass”

    I’m fairly sure you know this, but the immune system deals with a lot of challenges on an average day. A vaccine wont doesn’t add that many more than it’s used to. If you’re used to running 15 miles a day, running an extra 200 feet probably won’t matter.

  125. #125 skeptique
    October 4, 2010

    DT’s argument:

    The immune responses from natural sources is at least greater than or equal to the immune responses from vaccination, and therefore, an immune response elicited by vaccines is unlikely to contribute in anyway to behavioural or neurodevelopmental changes.

    I see a problem with this argument.

    Basically, how can we understand if the immune response elicited by vaccines is contributing to behavioural or neurodevelopmental changes by arguing that the natural exposure to viral and bacterial antigens elicits a far greater response than vaccines?

    you can’t

    I can see using this type of logic to determine the relative risk of an increased immune response via vaccination vs. the increased immune response from natural infection on the outcome of neurodevelopmental disorders consistent with autism.

    But first wouldn’t we have to study the relationship between vaccination and various parameters of immune response(both adaptive and innate) and how these values correlate with behavioral changes or neurodevelopmental changes?

    sorry to bring this back from the dead, but seemed like a decent conversation was taking place, and I had some thoughts.

    BTW, in reference to some earlier posts regarding TLR stimulation. the pertussis toxoid used in childhood vaccines is an agonist of the TLR4/tlr2 pathway (just like LPS) interesting!

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