A Brief Overview On Early Life Immune Challenges And Why They (Might) Matter
Posted May 13, 2009on:
Hello friends -
My over riding idea set on vaccines is relatively complicated; but at the heart, I just am not confident that we are smart enough to understand all of the potential impacts of aggressively pursuing mass vaccination; it is too drastic a change from how every animal on the planet evolved to be taken as lightly as we seem to be. The indisputable success of vaccination, I fear, has made it difficult to even ask questions about the pragmatism of moving forward with breakneck speed to a place where we think are clever enough to take a shortcut over millions of years of evolution without even bothering to evaluate for unintended consequences. It isn’t that I think I am smarter than the immunologists who develop vaccines; it is that I think we as a species, are too dumb to understand the impact of our actions without quality evaluations; detailed analysis that is sorely lacking in the area of vaccines.
Before moving forward, it should be made clear that for a variety of reasons, the research regarding vaccines and autism that is available to us is has a very tight focus, either thimerosal content or its absence, or MMR. This is a statement of fact. There are no autism studies that evaluate anything else in the vaccination schedule other than these two components. There just aren’t. Anyone who tells you otherwise is either misinformed, or intentionally trying to deceive you for reasons of their own.
A common refrain heard in the debates over vaccinations and autism goes something like this: “We’ve studied it again and again, and every time, we see no association. It is time to move on and spend precious dollars and researcher hours elsewhere.” Also frequently used is the a variation on this quote: “Insanity is repeating the same thing and expecting different results.”
When I hear things like this, it drives me apeshit crazy; especially when it comes from the mouths of scientists, people who (supposedly?) understand the simplest foundation of the scientific principle, that you only learn about what you study. A study evaluating use of thimerosal vaccines and their non thimerosal containing counterparts has no mechanism of gaining insight into the effect cumulative early life immune activations; both vaccines have the exact same mechanism of action in that regard; otherwise, they wouldn’t be vaccines. In an ironic twist, continuing to study thimerosal, but claiming it gives us information regarding vaccination is, in large part, doing the same thing again and again and expecting different results. Likewise, studying the MMR has been useful, as we have learned much about the MMR; but it gives us precious little insight into the effect of other vaccines, including those given at much, much earlier ages.
If we did twenty studies on cigarettes with tar and those without tar, should the resultant pattern of epidemiological findings give us any reason to believe we should extrapolate our findings outside the realm of the impact of tar in cigarettes? Or, just because the MMR has been found to not to be associated with autism at eighteen months, should we also assume that other vaccines given at two months are therefore not associated with autism? This is absolutely analogous to what we are being told regarding our existing set of research.
That being said, it isn’t really enough to start questioning a massively successful health policy that has saved millions of lives just because some jerk on the Internet doesn’t think we’ve done enough looking into it and our existing studies have yet to tackle every imaginable combination of vaccine schedule, and genetic variation. The argument goes something along the lines of, “Yes, you are technically correct, but without some biologically plausible mechanism of action, we cannot keep on studying something just because there exists a temporal relationship between an increase in the vaccination schedule and an apparent increase in autism diagnosis.” Without any concept of how more, earlier vaccines could be having an adverse effect that is invisible to our existing studies, there is merit to this argument.
It is here that the research outlined below helps fill a gap in the discussion. Anyways, a few weeks ago I was reference backtracking, and wound up reading a set of research involving rather unexpected findings regarding the result of early life infectious exposure and resultant immune system activation. Looking through those references, it turns out, several research groups have been doing work regarding the effect of early development immune system activation and consequent alterations to a variety of biological realms, including effects on immune system functioning, altered stress responses, seizure susceptibility, and behavioral changes, into adulthood. In fact, many researchers have reported that a transient inflammatory response is capable of creating lifelong differences in exposed animals, if they are exposed during early development. The immune system is a work in progress in the prenatal and early post natal periods, and appears to be highly impressionable, and in some instances, unforgiving in response to disturbances. Note that the vast majority of the research below has only been published in the last couple of years; long, long after we started to aggressively increase the number of vaccines our youngest infants were receiving.
Most of the studies use a relatively standard component for initiating an immune response in the animals, Lipopolysacccharide, or shorthanded, LPS. All of them deal with observing changes in animals into adulthood after early postnatal activation of the immune system. Several were able to concurrently determine that the time of the immune activation was the determining factor in the animals persistent changes.
Once I started trying to create a list of all of the research into this area, it was quickly apparent that it was overly cumbersome to get through, and ran the risk of turning into a stream of consciousness style listing of papers without an over riding set of guide posts as to why they might have implications for our vaccination schedule and autism or other neurological disorders. With that in mind, I constructed a list of areas that these papers address and speak towards the blindspots in our existing vaccine research.
- Studies that took care to answer the question that the immune response was responsible for differential behavioral or physiological outcomes. For example, could the same outcome be achieved by administering inflammatory cytokines, as opposed to a bacterial or viral protein analog? Was there an attempt made to introduce inflammatory inhibitors that resulted in a negation of effects? This is an important distinction, as otherwise, the argument could be made that it was the LPS, as opposed to the resultant immune response that was responsible for the different outcomes.
- Studies that evaluated the effect of a time dependent effect on behavioral or physiological outcomes. For example, did animals have different outcomes if their was an immune challenge at one week, as opposed to one month? An extremely common refrain in this discussion is ‘the poison makes the dose’, unfortunately, it would seem that this is not necessarily the case.
- Studies that had findings that have correlations with known behavioral or physiological findings in autism. Of course, without any findings that have similarities to autism, this exercise would be largely futile for a blog about autism!
Before getting started, I’d like to be clear that I am not advocating that vaccines cause autism; but rather, that we haven’t studied the issue very well, and that we are gaining experimental evidence that our existing studies are inadequately designed to capture many potential unintended effects. My belief is that increased vaccination could impart a mild to moderate risk of autism diagnosis in some genetically predisposed individuals, and while I believe that a true increase in autism prevalence is occurring, that not all of this is caused by vaccination. A fuller detailing of these views if for another post, but the pertinent part here is that the studies outlined below tell us that we still have a lot to learn about how the immune system operates, especially during early development, and given that, proclamations that the vaccine schedule has been fully evaluated involve large leaps of faith.
That being said, lets take a look at some of the papers on the subject. In all instances below, the emphasis provided is my own. Many abstracts are snipped for space purposes.
There are critical postnatal periods during which even subtle interventions can have long-lasting effects on adult physiology. We asked whether an immune challenge during early postnatal development can alter neuronal excitability and seizure susceptibility in adults. Postnatal day 14 (P14) male Sprague Dawley rats were injected with the bacterial endotoxin lipopolysaccharide (LPS), and control animals received sterile saline. Three weeks later, extracellular recordings from hippocampal slices revealed enhanced field EPSP slopes after Schaffer collateral stimulation and increased epileptiform burst-firing activity in CA1 after 4-aminopyridine application. Six to 8 weeks after postnatal LPS injection, seizure susceptibility was assessed in response to lithium–pilocarpine, kainic acid, and pentylenetetrazol. Rats treated with LPS showed significantly greater adult seizure susceptibility to all convulsants, as well as increased cytokine release and enhanced neuronal degeneration within the hippocampus after limbic seizures. These persistent increases in seizure susceptibility occurred only when LPS was given during a critical postnatal period (P7 and P14) and not before (P1) or after (P20). This early effect of LPS on adult seizures was blocked by concurrent intracerebroventricular administration of a tumor necrosis factor (TNF) antibody and mimicked by intracerebroventricular injection of rat recombinant TNF. Postnatal LPS injection did not result in permanent changes in microglial (Iba1) activity or hippocampal cytokine [IL-1β (interleukin-1β) and TNF] levels, but caused a slight increase in astrocyte (GFAP) numbers. These novel results indicate that a single LPS injection during a critical postnatal period causes a long-lasting increase in seizure susceptibility that is strongly dependent on TNF.
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.
This paper hits a lot of the sweet spots we defined above; there was a differential effect on depending on when an immune response was initiated, pro inflammatory cytokine administration alone was sufficient to cause the same effect, and furthering the link to the immune response, administration of tnf alpha antibodies negated any effects.
Of particular interest to our population of children, it is well established that children with autism grow up into adults with of epilepsy at far, far greater rates than their non diagnosed peers. One way to increase the likelihood of having more seizures, it appears, is to get a large dose of tnf alpha in early development. Having a seizure in the first year of life has been found to be very strongly associated with an autism diagnosis, however, with this type of study it is difficult to detangle the cause and the effect; i.e., are they having seizures because they have autism, or are they getting diagnosed with autism as a result of early life seizures? There are some studies on the long term effect of early life seizures that show chronic activation of the brains immune system; and again, the innate inflammatory immune response is implicated in causation.
Also of particular interest regarding autism is that the driving factor in this case was tnf alpha, a proinflammatory cytokine that has been shown to be elevated in several studies of children with autism. In fact, when researchers use drawn blood to determine immune responses, children with autism have been found to generate far more tnf alpha than controls in response to increasingly common (and scary) pollutants, common dietary boogeymen, and LPS. In other words, children with autism seem predisposed to creating more tnf alpha in response to a variety of environmental factors . In two studies that analyzed the brains and CSF of children with autism, highly elevated levels of tns alpha were observed.
Here is one with a great title:
Fever is an integral part of the host’s defense to infection that is orchestrated by the brain. A reduced febrile response is associated with reduced survival. Consequently, we have asked if early life immune exposure will alter febrile and neurochemical responses to immune stress in adulthood. Fourteen-day-old neonatal male rats were given Escherichia coli lipopolysaccharide (LPS) that caused either fever or hypothermia depending on ambient temperature. Control rats were given pyrogen-free saline. Regardless of the presence of neonatal fever, adult animals that had been neonatally exposed to LPS displayed attenuated fevers in response to intraperitoneal LPS but unaltered responses to intraperitoneal interleukin 1 or intracerebroventricular prostaglandin E2. The characteristic reduction in activity that accompanies fever was unaltered, however, as a function of neonatal LPS exposure. Treatment of neonates with an antigenically dissimilar LPS (Salmonella enteritidis) was equally effective in reducing adult responses to E. coli LPS, indicating an alteration in the innate immune response.In adults treated as neonates with LPS, basal levels of hypothalamic cyclooxygenase 2 (COX-2), determined by semiquantitative Western blot analysis, were significantly elevated compared with controls. In addition, whereas adult controls responded to LPS with the expected induction of COX-2, adults pretreated neonatally with LPS responded to LPS with a reduction in COX-2. Thus, neonatal LPS can alter CNS-mediated inflammatory responses in adult rats.
Here, again, the authors again went to some trouble to provide evidence that the effect was based on the resultant immune response by providing different bacterial proteins. We also observe long term, persistent alterations in COX-2 levels; essentially an indicator of changes to the immune regulatory system; inhibition of the COX enzymes is how pain relievers such as aspirin and Vioix work. Strangely, it seems that the treatment group had higher resting levels of COX-2, but reduced production in response to a challenge. The authors went on to perform a similar experiment on female rodents, with mixed similarities; the reduced fever response and response to challenge were observed as with the males, but, baseline levels of COX-2 were found to be the same between treatment and control animals. There are obvious correlations here with the sexual dismorphism in autism diagnosis here, if anyone has any thoughts on sexual dismorphic COX-2 profiles, please send me a comment.
I have not seen any papers directly measuring COX-2 in autism, but there are a great number on the related regulation of the immune system which show large differences between autism and control subjects. Polymorphisms in the genes responsible for COX-2 have been found to be highly transmitted in the autism population. I’ve been having some problems identifying the impact of this particular allele on circulating levels of COX-2. One study on colorectal cancer seemed to indicate a protective effect from the allele, which would seemingly be at odds with a inflammation promoter. Anyways, if anyone has any knowledge on this, please send it my direction.
Also interest here, though I am having problems articulating the precise issue, is that IL1 or prostaglins did not result altered responses. This, to me, could potentially speak towards a preferential training of the Toll Like Receptors, as opposed to a downstream functional area.
We have reported that neonatal infection leads to memory impairment after an immune challenge in adulthood. Here we explored whether events occurring as a result of early infection alter the response to a subsequent immune challenge in adult rats, which may then impair memory.In experiment 1, peripheral infection with Escherichia coli on postnatal day 4 increased cytokines and corticosterone in the periphery, and cytokine and microglial cell marker gene expression in the hippocampus of neonate pups. Next, rats treated neonatally with E. coli or PBS were injected in adulthood with lipopolysaccharide (LPS) or saline and killed 1-24 h later. Microglial cell marker mRNA was elevated in hippocampus in saline controls infected as neonates. Furthermore, LPS induced a greater increase in glial cell marker mRNA in hippocampus of neonatally infected rats, and this increase remained elevated at 24 h versus controls. After LPS, neonatally infected rats exhibited faster increases in interleukin-1beta (IL-1beta) within the hippocampus and cortex and a prolonged response within the cortex. There were no group differences in peripheral cytokines or corticosterone. In experiment 2, rats treated neonatally with E. coli or PBS received as adults either saline or a centrally administered caspase-1 inhibitor, which specifically prevents the synthesis of IL-1beta, 1 h before a learning event and subsequent LPS challenge. Caspase-1 inhibition completely prevented LPS-induced memory impairment in neonatally infected rats. These data implicate IL-1beta in the set of immune/inflammatory events that occur in the brain as a result of neonatal infection, which likely contribute to cognitive alterations in adulthood.
Another instances where the authors used inflammatory inhibitors to obtain evidence that the behavioral outcomes were dependent on the immune response by administering inflammatory inhibitors. And again, we see drastic differences in behavior and immune response between animals that had an immune response early in life, and those that did not. This looks to be part of a multiple paper study, the initial paper can be found here. Increased levels of IL-1beta have not been observed in children with autism; though some researchers have found that in response to LPS, children with autism produce more IL-1Beta than their non diagnosed counterparts.
It was titles like this that really got my head spinning early on when I started to realize just how much information there was on this subject.
If you believe in reincarnation, I wonder just how bad a person you need to be in order to wake up as a Sprague-Dawley rat the next time? Anyways, here we can see different results depending on the timeframe of immune activation. And again, we see modifications to immune system regulation and behaviors.
Neonatal exposure to an immune challenge has been shown to alter many facets of adult physiology including fever responses to a similar infection. However, there is a paucity of information regarding its effects on adult behaviours. Male Sprague-Dawley rats were administered a single injection of the bacterial endotoxin lipopolysaccharide (LPS) at 14 days old and were compared, when they reached adulthood, with neonatally saline-treated controls in several behavioural tests of unconditioned fear and anxiety. There was no effect of the neonatal treatment on performance in either the elevated plus maze, modified Porsolt’s forced swim test or the open field test. However, neonatally LPS-treated rats did show significantly reduced exploration of novel objects introduced to the open field arena, indicating an effect of the neonatal immune challenge on behaviours relating to anxiety in the adult.
Here, we see that early life exposure to endtoxin was seen to alter behaviors, including reduced exploration, indicative of increased anxiety.
Another great title! In this case, the authors used straight tnf alpha and observed ‘long term disorders of behavior’. For our particular subset of children, who have been shown to create tnf alpha at highly exaggerated rates compared to their non diagnosed peers, the triggering mechanism has particular salience.
By this point, the hows of what they did are probably pretty straightforward. Snipped from the abstract:
Taken together, these data indicate that early infection strongly influences the induction of IL-1beta and BDNF within distinct regions of the hippocampus, which likely contribute to observed memory impairments in adulthood.
This is the oldest paper I have come across so far, published in 2000.
We have investigated whether exposure to Gram-negative bacterial endotoxin in early neonatal life can alter neuroendocrine and immune regulation in adult animals. Exposure of neonatal rats to a low dose of endotoxin resulted in long-term changes in hypothalamic–pituitary–adrenal (HPA) axis activity, with elevated mean plasma corticosterone concentrations that resulted from increased corticosterone pulse frequency and pulse amplitude. In addition to this marked effect on the development of the HPA axis, neonatal endotoxin exposure had long-lasting effects on immune regulation, including increased sensitivity of lymphocytes to stress-induced suppression of proliferation and a remarkable protection from adjuvant-induced arthritis. These findings demonstrate a potent and long-term effect of neonatal exposure to inflammatory stimuli that can program major changes in the development of both neuroendocrine and immunological regulatory mechanisms.
On the basis of our data, it does appear, however, that activation of endocrine and immune systems during neonatal development can program or “reset” functional development of both the endocrine and immune systems. In this respect it is noteworthy that exposure to steroids during immunization schedules in early life can alter the development of immune tolerance, and that animals raised in pathogen-free environments have increased susceptibility to inflammatory disease (20, 29–31). The environment in which a mammal develops is often the environment in which it must survive throughout life, and developmental plasticity must surely be of adaptive advantage. We suggest that “immune environments” during development not only can alter inflammatory and neuroendocrine responses throughout life but also may alter predisposition to stress-related pathologies associated with HPA activation.
There are some other papers out there that have failed to find a relationship between early life immune activation and subsequent HPA axis modulations.
Thus, a single bout of inflammation during development can programme specific and persistent differences in NR mRNA subunit expression in the hippocampus, which could be associated with behavioural and cognitive deficits in adulthood.
The author reports highly variable NMDA expression changes in animals tested over a variety of timeframes. Changes to NMDA receptors have been reported in autism, as well as in animals treated prenatally with valporic acid; which has been shown to greatly increase risk of autism diagnosis.
Four days after TNBS treatment, plasma corticosterone was unaltered in all groups; however, TNF-alpha was significantly increased in adult TNBS-treated rats that had LPS as neonates compared with all other groups. In conclusion, neonatal, but not later, exposure to LPS produces long-term exacerbations in the development of colitis in adults.This change is independent of HPA axis activation 4 days after TNBS treatment but is associated with increased circulating TNF-alpha, suggestive of an exaggerated immune response in adults exposed to neonatal infection
Again, we see tnf alpha implicated as a mediating factor; in this case, animals treated with LPS during development went on to develop much more severe colitis symptoms when drug induced. These changes were only apparent if the immune insult occurred during a specific timeframe. An increased baseline level of tnf alpha is also something that has been observed in the autism population.
Here, researchers performed an experiment to determine if immune stimulants other than LPS could generate ‘neonatal programming of the rat neuroimmune response’, so they used PolyIC; a viral protein analog during early life. What was observed was that animals treated on postnatal day 14 showed attenuated febrile responses into adulthood, coinciding with altered
There are other papers available with similar findings, but this set is a large chunk of what is out there. Our summarization is as follows:
- 12 studies showing analyzing the effect of early life immune activation on rodents with findings into adulthood on behavior differences, seizure susceptibility, colitis susceptibility, HPA Axis modifications, and immune system changes.
- 1 study observed behavioral results from administration of tnf alpha alone. (Zubareva OE, 2009)
- 1 study observed physiological results from administration of tnf alpha alone. (Galic, 2008)
- 3 studies used inflammatory inhibitors to validate the immune response was responsible for the physiological changes (seizure susceptibility), behavioral changes (memory impairments), and immune function. (Galic, 2008, Ellis 2006, Bilbo 2005).
- 2 studies found that the timing of the immune activation was a mediating factor in causing persistent changes (Spencer, 2006, Galic, 2008).
- 7 studies found persistent changes to the immune system. (Boisse, 2004, Spencer 2006, Bilbo 2008, Shanks 2000, Spencer 2007, Ellis 2006, Walker 2009).
- 1 study finding changes to brain receptor structures. (Harre 2008).
- 3 studies finding increased anxiety and / or fear responses. (Zubareva 2009, Spencer 2006, Spencer 2005)
In developing some of these ideas online, I ran into several arguments as to why we these findings have no bearing on our existing research into vaccination taking into consideration the a time dependent effect of immune activation. Below, as near as I can remember, is a cataloging of these complaints, and my take on their validity, and in what ways the studies above provide information.
1) Vaccines are already tested for safety and efficacy.
Technically a true statement, but one that very quietly attempts to substitute safety testing for evaluation of autism. Most of the safety studies, even those that follow participants for several years, are not designed to capture either neurological outcomes like autism, or more subtle changes such as persistent changes to immune system markers. For verification of this, all one really needs to do is take a look at what happened in reality, and apply a primitive logical filter. When it was posited that the MMR might be causing autism in some children, there was a flurry of retrospective studies performed on children who did or did not get the MMR. Whatever your position on the quality of those studies, the fact is, those studies were necessary only because the existing set of safety and efficacy studies were not sufficient to answer the question of if there was an association with the MMR and autism. In other words, why bother with retrospective studies if the existing literature already had evidence of no link?
As for testing of immune system changes, you will be very hard pressed to find studies on the existing vaccine schedule for children that takes into consideration pre and post cytokine or related immunological measurements. If anyone has any studies that I haven’t seen (which is two), please let me know. One that I have found, Modulation of the infant immune responses by the first pertussis vaccine administrations has some rather startling findings.
Many efforts are currently made to prepare combined vaccines against most infectious pathogens, that may be administered early in life to protect infants against infectious diseases as early as possible. However, little is known about the general immune modulation induced by early vaccination. Here, we have analyzed the cytokine secretion profiles of two groups of 6-month-old infants having received as primary immunization either a whole-cell (Pw) or an acellular (Pa) pertussis vaccine in a tetravalent formulation of pertussis–tetanus–diphtheria-poliomyelitis vaccines. Both groups of infants secreted IFN-γ in response to the Bordetella pertussis antigens filamentous haemagglutinin and pertussis toxin, and this response was correlated with antigen-specific IL-12p70 secretion, indicating that both pertussis vaccines induced Th1 cytokines. However, Pa recipients also developed a strong Th2-type cytokine response to the B. pertussis antigens, as noted previously. In addition, they induced Th2-type cytokines to the co-administrated antigen tetanus toxoïd, as well as to the food antigen beta-lactoglobulin. Furthermore, the general cytokine profile of the Pa recipients was strongly Th2-skewed at 6 months, as indicated by the cytokines induced by the mitogen phytohaemagglutinin. These data demonstrate that the cytokine profile of 6-month-old infants is influenced by the type of formulation of the pertussis vaccine they received at 2, 3 and 4 months of life. Large prospective studies would be warranted to evaluate the possible long-term consequences of this early modulation of the cytokine responses in infants.
Now this doesn’t mean that DTaP causes autism, but it does tell us that we are largely operating based on our findings of reduced disease and empirical measurements of seriopositivity, as opposed to a true understanding of all of the effects of vaccination; this study was conducted eight years after DTaP was licensed for use. Clearly our existing set of safety and efficacy tests for DTaP were not sufficiently designed to capture this kind of information. If anyone tells you that have the slightest fucking clue as to the result of such cytokine shifts in a generation of infants, you are being lied to. This study also casts a relatively poor light on argument 3.
Strength of argument: Zero.
2) The vaccination hypothesis cannot explain X characteristic of autism. (Where X is a ‘characterization’ of autism, such as improved spatial skills)
What this argument really says is that the person making cannot imagine a way in which characteristic X could be caused by vaccination, and therefore, the hypothesis is invalid. Of course, of the few accepted causes of autism, such as prenatal exposure to ruebella, there is also no well defined mechanism by which such an event could lead to most of the characteristics that this argument utilizes. An even biggest problem with this argument is that it mandates that every person with autism has characteristic X, when in fact, autism is characterized in part by large heterogeneousness. And if we were to expand our premise from, ‘vaccines may cause autism through early life immune activation’, to, ‘autism may modify the behavioral or immune system functioning through early life immune activation’, this argument falls to complete irrelevancy without making our existing set of research any more robust.
Strength of argument: One.
3) Infants are bombarded with antigens all the time and their immune system is not overwhelmed. Vaccination is no different.
Again, this argument starts with a kernel of technical truth; infants are forced to deal wifth a variety of bacterial and viral antigens from the moment they are born. However, in the first place, the simplest commonsense logical tests tell us that there is a big difference between ‘everyday exposure’ and the contents of a vial. For starters, your child comes equipped with an array of defense mechanisms to keep bacteria and viruses outside of their bodies, namely the skin, mucous, tears, and gastric acid. When we use a needle to penetrate the skin and inject the antigens into the tissue, all of these natural defense barriers are immediately bypassed. Secondly, the antigens in a vaccine aren’t alone; they come with aluminum based salts that are designed to enhance the immediate innate immune response. Funny enough, the mechanism by which these chemicals achieve their function is still under investigation, but they are absolutely necessaray for a vaccine to initiate a sufficient immune response for the body to develop antibodies. If we simply evaluate what regulatory agencies tell us; that low (or high) grade fevers are a common side effect of vaccination, between 5% and 30% of the time depending on the vaccine, we are forced to acknowledge that our children do not develop fevers anywhere close to the same frequency. Or, we can look at the DTP / DTaP study above, where we observed highly differential immune profiles between different vaccines. If all of the thousands or millions of antigens these children were exposed to in the intervening months were having a meaningful impact, it should have been impossible to identify one group from another; and yet, the different profiles were strikingly clear. If everyday exposure is equivalent, how can we resolve these seemingly paradoxical findings?
Strength of argument: Three. Even though vaccination is very different, the strawman argument of an ‘overwhelmed immune system’ is nicely defeated by this argument. In our studies above that dealt with observed immune system alterations, however, it is not an “overwhelming” of anything that was observed, but rather, a persistent modulation with wide ranging effects.
There are several frequent answers to these counter arguments.
3a) Just because you sometimes have a fever after vaccination doesn’t mean your immune system isn’t activated the rest of the time.
Again technically true, but it leaves out the fact that a fever indicates a more robust immune response. Any effect that is dependent on the relative strength of immune activation forces us to conclude that we cannot draw equivalencies between normal immune system activation and what happens when you get a vaccine. We can consider all of the animals from the studies above for insight; they were all exposed to plenty of bacteria on their own, they were rats after all; and yet, only those that received LPS, PolyIC, or tnf-alpha were seen to have changes. In other words, if common immune system activation was sufficient to cause differential effects, with all of that background immune activation there should have been no ability to tell which animals were in the treatment group. And again, we can refer to the DTP/DTaP study for insight as to our ability to discern vaccine exposure and everyday exposure with measures beyond single pathogen seriopositivity.
3b) The immune response generated by the actual diseases are far more robust than that from vaccination. Considering this, it is even more important to vaccinate children earlier.
If one of the concerns we have applies to the timing of the immune response, this answer is only sensible if we had a reasonable expectation that an infant will become infected with diptheria, tetanus, pertussis, hepatitis b, rotavirus, haemophilus influenza, and/or polio by the age of two months, and again at four and six months of age. While such a situation would no doubt have very poor outcomes for the child in question, the chances of any one of these things happening is very low. On the other hand, the chances of an infant having an immune response initiated via vaccination at this age is approaching 100%. Furthermore, this argument is frequently based on duration of response (a measure of bacterial or viral persistence, as opposed to strength of response), but several of the studies above found that a single, transient immune activation was sufficient to cause differences into adulthood.
4) None of the studies above test vaccination. (sometimes coupled with: they test exposure to LPS)
Whatever the trigger, there is only one innate immune system to generate a response, and the gatekeepers of the immune response, the toll like receptors, are the components responsible for initiating the innate immune response be it by vaccination or wild bacterial/viral exposure. It should be noted that there are times when both arguments 3 and 4 will be used nearly simultaneously. For anyone concerned with an over reliance on LPS, we have several studies where viral analogs were used, and others where straight tnf-alpha achieved similar results. Likewise, we have three studies showing that the use of inflammatory inhibitors resulted in amelioration of effects; strong evidence that the trigger of the immune response is relatively unimportant compared to the immune response itself.
None the less, this argument has some validity in that it is difficult to compare the immunological strength of the response between dosages of LPS, PolyIC, and tnf-alpha with what happens after standard childhood immunizations. Unfortunately, the reason such a comparison is impossible to perform is that we have no values to use as comparisons from the end of vaccination. If someone could provide a study showing pre- and post- cytokine levels after common childhood vaccinations, please post a link. Even with our studies that tell us that children with autism have a tendency to respond more vigorously to immune stimulants than their non diagnosed peers, this is a large unknown. It would be very tricky to capture excellent in vivo comparison information here, as it would require injecting infants with LPS in order to gauge the immune response; there are all kinds of problems with that. Animal models and in vitro may be the only options available.
Strength of argument: Five.
5) Humans grew up in dirty environments; they were exposed to viruses and bacteria all the time. What is different about the most recent generation than the thousands of generations past?
This is a pretty strong argument, after all, in general, conditions in the past were, generally, germier than they are now. The issue, to my mind, is that even with a dirtier past, our actions have skewed what was once a distribution. We have taken efforts to insure that every infant gets a robust immune response, and earlier in life; as opposed to what used to be some infants. In other words, even if there was a fifty percent chance of a two month old having generated a strong immune activation in generations past, the chances are now much closer to one hundred percent. The same thing happens at four months, and six months. With the insane well meaning introduction of the Hep-B vaccine at the day of birth, this radical alteration to this distribution is unmistakable. Part of the problem with gauging this argument is that there seems to be a wide range of ‘average’ infections reported in infants during their first year of life; with ranges from 0 – 12; and even with these, it is impossible to get a measure of the strength of the response. Our ability to understand what the average was just a few generations ago completely futile.
There are also large problems with drawing equivalencies between the other components of the environment of previous generations and the current generation.
Strength of argument: Seven.
6) The model is wrong, there is just too much difference between human and rat physiology to be worried.
The strongest contributor to this argument is uncertainty in our ability to accurately interpret the jump from prenatal to postnatal immune activation between rodents and humans. But again, this is driven in large part by a relative paucity of information as opposed to a deeper understanding of the differences between the two. After all, any amount of intellectual honesty tells us that the researchers in the experiments above are not overly concerned over the question as to if rats develop immune system differences into adulthood following early development immune activation; these experiments are being funded and performed because there are things to be learned about human physiology from the results. To put another way, if researchers and funding agencies were confident that there was no way the same transient inflammatory episodes could have similar effects on people, would any of these studies actually been funded or performed? The effect size also speaks towards the complexity of going from rodent to humans.
Strength of argument: Eight. There is a real chance that all of the effects observed here in rodent models only have experiments to pre-natal exposures in humans. Likewise, it is acknowledged that the rodent model is useful in many areas but that frequency that results that look good in rodents and then poor in people, is very large. Unfortunately, to my mind, this does not constitute evidence of lack of effect of our vaccination schedule, just one reason why it might not be having an effect. It is the assumption of no effect, as opposed to the presence of quality analysis.
I’ve never actually had this argument made to me, strangely enough, but it does strike me as a very large question mark.
The fact that these experimentsare being carried out at all, with the findings being described as novel, should be enough to tell us that for all practical purposes, we still are gaining an understanding of the effects of early life immune activation, some twenty years after we began to aggressively increase the number of vaccines our infants receive. Just because the effects that were observed are sometimes very subtle does not mean that they cannot have profound ramifications, and if our existing analysis was not designed to capture subtle effects, drawing far reaching conclusions from them is worthless, and indeed, potentially dangerous.
With that in mind, is it possible to have a rational discussion about the possibilities of finding ways to gain more insight into the potential outcomes of earlier and more vaccination without invoking vitriole, charges of scientific illiteracy, the big pharma gambit or accusations of child abuse?