1. Characterize the immune response from vaccines in the general pediatric population.
What sort of characterisaton do you think is needed?
I think we need to more specifically characterize the innate immune response, in other words we should have a very good understanding of changes in particular cytokines after the administration of a vaccine or combination of vaccines.
Originally Posted by Skeptiquette
2. Characterize the immune response from vaccines in certain subpopulations, using various genetic and epigenetic profiles as our criteria.
I'm not sure how this would help. It's already known that there is a small percenatage of non-responders to any vaccine, herd immunity gets round that.
Actually, this would help in understanding why certain individuals have a very meager or non-response to a vaccine, which will ultimately result in the development of more effective vaccines. More importantly, from a safety standpoint, we would be able to understand the particular genetic determinants which influence the generation of an innate immune response. We would be able to understand why(if it even happens: see point #1) some infants have a more robust inflammatory response to a vaccine than others. Thus, we would be able to predict a negative outcome to a vaccine more accurately.
Originally Posted by Skeptiquette
3. Understand the differences between the immune response generated by natural infection vs. vaccine.
In most cases I'd say there is a good knowledge of that already. Vaccines are developed mostly by unravelling the immune response of individuals who have recovered from an infection. Or by looking for correlates of protection in animal models.
Hmm. I guess I should have clarified this whole post. I am mainly interested in the immediate immune response of the individual to the vaccine. So, let me ask a question.
Is the innate immune response of an individual infected with pertussis, the same, from a qualitative, quantitative and kinetic standpoint, as the innate immune response of an individual injected IM with DTaP?
Does the immune system “perceive” the threat differently if it is injected IM, rather than subjected to the mucosal immune system, which it has evolved to interact with over millennia?
This idea gets tossed around “skeptic” circles and made fun of, but I am serious.
I think a good example can be derived from a recent study, which differentiates the innate immune response in an animal model between a vector (mosquito) delivered virus, vs. a sterile needle delivered virus. One would think that this would be the model where we should be able to predict a very similar response if not congruent, because the virus is normally transmitted via a mosquito “needle stick” into the skin. This is not the case, however, the innate immune response between these two modes of delivery is completely different. We have the same exact virus, but a completely different immune response when the mouse has the virus injected subcutaneously, rather than via the mosquito “injection”. I don’t want to extrapolate from here and say that, therefore every immune response is different when elicited via vaccination vs. natural infection, I just want to highlight that this concept is not as simple as many “skeptics” seem to understand it. It comes back down to meticulously characterizing the innate immune response to vaccination, we simply need more data!
Originally Posted by Skeptiquette
4. Study the impact of vaccination and the immune response during critical periods of brain development.
The brain is an immunologically privileged site. The blood brain barrier prevents the immune response from doing harm.
Umm… no. Is the simple answer, I will try to be brief about this, but this idea has been meeting significant resistance for the past two decades and has been effectively discarded. Here is a question you can ask yourself and think critically about.
How does infection of the periphery (influenza for example) coordinate the behavioral changes(“sickness behavior”) typically experienced by the infected individual?
The blood brain barrier (BBB) acts as an interface between the periphery and CNS, the major players involved in this interface are cytokines (immune system signaling proteins). The BBB is not only capable of transporting cytokines from the bloodstream into the CNS and visa versa, but also, secreting cytokines from its abluminal side (CNS side) into the CNS due to cytokine induced receptor activation from its luminal side. Cytokines also modulate the integrity of the BBB to permeability of other proteins and molecules. Based on this we understand that the BBB provides multilayered mechanisms to mediate neuroimmune interactions.
One can imagine the peripheral immune system as another facet of the peripheral nervous system, in that it is responsible for sensing the presence of micro organisms, their by-products, products from cellular damage or injury, etc. We all understand that the nervous system is responsible for relaying messages acquired by the well known “six senses” to the brain, so that the organism can react accordingly. Well, the immune system is also responsible for relaying messages to the brain and is doing this continuously whether the organism is experiencing an overt infection or not. As I have stated above, one of the ways the immune system does this is through cytokine signaling (directly interfacing with the brain), the other way is via cytokine signaling interfacing with the peripheral nervous system, which interacts with the brain. Obviously, we could go into much more detail regarding the specifics of all of this, but suffice it to say the BBB does not preclude the immune response, but rather acts as an interface integrating immunological information to the brain.
Originally Posted by Skeptiquette
5. Study the outcome of vaccination on various epigenetic parameters of immune activation.
I don't know of an issue that would warrant this.
This is a rather large can of worms that needs to be opened immediately and sorted out.
Here is the issue, Capsid. The human newborn(as well as all other animals) has the capacity to adjust how it reacts to its environment, at the level of the gene, upon sampling the environment. This is the concept of developmental plasticity, a very important concept in evo devo biology. We obviously know that an organism does not have the capacity to change its genes, but it does have the capacity to change how the genetic information is packaged and thus how it is expressed. This is one facet of epigenetics, which is referred to as the “histone code”, DNA methylation would also fall into this category.
My contention is that upon vaccination the human newborn, being in a state of developmental plasticity, has the capacity to formulate a predictive-adaptive response, in order to better suit itself to a future environment. This adaptive response would be predicated on the innate immune response to the vaccines given during this developmental period. There exists a (quickly) growing body of evidence that exposures to various “immune activators” at developmentally sensitive periods can have a programming effect on the innate immune system (in animal models). Once again, the organism is not changing its actual genetic make up, but rather, modifying various epigenetic parameters to predict a positive adaptive outcome.
This makes perfect sense, really. The organism is sampling from its environment and attempting to adapt itself to better suit its future environment, hence, the term predictive-adaptive response. This is obviously a great feature of a developing organism, but it can have negative consequences. When the organism, initiates a predictive-adaptive response that does not match its future environment than there can be problems, this is typically referred to mismatching.
This is the issue that would warrant understanding the epigenetic parameters, which are modulated by vaccinating during a developmentally plastic timeframe.
Originally Posted by Skeptiquette
6. Study the outcome of vaccination on patterns of infant microbial colonization.
. The specificity of the immune response should not inhibit microbial colonisation.
Sorry, this was poorly worded.
I think there may be a couple different issues here worth discussing.
1) How does the elimination of Bacteria, such as S. pneumonia, a commensal of the large proportion of humans impact the colonization of other bacteria such as S. aureus? What are the downstream effects of this substitution? Or, How does the elimination of another transient commensal, B pertussis, affect host defense to influenza virus?(A recent journal article I read, where the experimenters inoculated mice with an attenuated strain of B. pertussis and demonstrated a very reduced course of infection with influenza. Somehow, directly, indirectly, the presence of B. pertussis attenuated the course of infection from influenza. Interesting!)
2) How does the state of the immune system, due to vaccination, and more precisely TLR expression influence microbial colonization patterns of the infant.
This particular point relies on many of the other points I made and is hard to discuss due to the theoretical nature, but nonetheless, It will become more important and more attainable as we start to define some of the other unknowns that I have postulated.
Originally Posted by Skeptiquette
7. Study the kinetics of immune activation in various subpops and the general pop. due to vaccination.
What do you mean by immune activaton?
I think you know what I mean by now, but, to reiterate innate immune system activation. In this context, how long do we see innate immune system activation? Then, once again, How long do we see innate immune system activation in various sub-populations?
Originally Posted by Skeptiquette
8. Study the impact of vaccination on pregnant women, in particular maternal immune activation (MIA).
I'm not sure what you mean by immune activation.
Somehow this perplexes me, since you say you work in the vaccine field… but I believe you.
Same thing, innate immune system activation in pregnant women, and the potential impact on the developing fetus. Here is a link to a recent abstract which will clue you in to what I am referring to.
http://www.ncbi.nlm.nih.gov/pubmed/20924155
An emerging area of research in autism spectrum disorder (ASD) is the role of prenatal exposure to inflammatory mediators during critical developmental periods. Epidemiological data has highlighted this relationship showing significant correlations between prenatal exposure to pathogens, including influenza, and the occurrence of ASD. Although there has not been a definitive molecular mechanism established, researchers have begun to investigate this relationship as animal models of maternal infection have support- ed epidemiological findings. Several groups utilizing these animal models have found that activation of the maternal immune system, termed maternal immune activation (MIA), and more specifically the exposure of the developing fetus to maternal cytokines precipitate the neurological, immunological and behavioral abnormalities observed in the offspring of these animals. These abnormalities have correlated with clinical findings of immune dysregulation, neurological and behavioral abnormalities in some autistic individuals. Additionally, researchers have observed genetic variations in these models in genes which regulate neurological and immunological development, similar to what is observed clinically in ASD. Altogether, the role of MIA and cytokine dysregulation, as a key mediator in the neuropathological, behavioral and possibly genetic irregularities observed clinically in autism are important factors that warrant further investigation.
Here is an article from the Washington Post, which I think does a reasonably fair job representing the subject
http://www.washingtonpost.com/wp-dyn/content/article/2007/11/23/AR2007112301327.html
Note, Paul Patterson an expert in this field, says:
"Obviously, the safe thing to do is to go with the experts, and the experts are the CDC," said Paul Patterson, a professor of biology at the California Institute of Technology and one of the leading researchers into the link between maternal infections and schizophrenia. "However, if it was my wife, I would not [want] her vaccinated."
I don’t want this to be abused as a appeal to authority fallacy, but, I think this highlights why we need more research into this area if we want to make safe informed decisions.
Originally Posted by Skeptiquette
9. Study the impact of the immune response generated by vaccines on various behavioral correlates.
I don't have a view on this. It's not something discussed in the vaccine field.
I understand this isn’t too much of a priority to a vaccine manufacturing company.
I think that this can be highlighted by a recent double-blind randomized crossover study which investigated the effect of typhoid vaccination on innate immune parameters and further on a behavioral endpoint, depression.
I would actually consider this a good model of a study that we need to adapt to a younger cohort. (since the study used healthy adult male volunteers). Here is a link and abstract.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2885494/pdf/main.pdf
Abstract
BACKGROUND: Inflammatory cytokines are implicated in the pathophysiology of depression. In rodents, systemically administered inflammatory cytokines induce depression-like behavior. Similarly in humans, therapeutic interferon-alpha induces clinical depression in a third of patients. Conversely, patients with depression also show elevated pro-inflammatory cytokines.
OBJECTIVES: To determine the neural mechanisms underlying inflammation-associated mood change and modulatory effects on circuits involved in mood homeostasis and affective processing.
METHODS: In a double-blind, randomized crossover study, 16 healthy male volunteers received typhoid vaccination or saline (placebo) injection in two experimental sessions. Mood questionnaires were completed at baseline and at 2 and 3 hours. Two hours after injection, participants performed an implicit emotional face perception task during functional magnetic resonance imaging. Analyses focused on neurobiological correlates of inflammation-associated mood change and affective processing within regions responsive to emotional expressions and implicated in the etiology of depression.
RESULTS: Typhoid but not placebo injection produced an inflammatory response indexed by increased circulating interleukin-6 and significant mood reduction at 3 hours. Inflammation-associated mood deterioration correlated with enhanced activity within subgenual anterior cingulate cortex (sACC) (a region implicated in the etiology of depression) during emotional face processing. Furthermore, inflammation-associated mood change reduced connectivity of sACC to amygdala, medial prefrontal cortex, nucleus accumbens, and superior temporal sulcus, which was modulated by peripheral interleukin-6.
CONCLUSIONS: Inflammation-associated mood deterioration is reflected in changes in sACC activity and functional connectivity during evoked responses to emotional stimuli. Peripheral cytokines modulate this mood-dependent sACC connectivity, suggesting a common pathophysiological basis for major depressive disorder and sickness-associated mood change and depression.
Originally Posted by Skeptiquette
10. Study the impact of the immune response generated by vaccination on particular protein expression in the brain, I am most interested in understanding the potential impact on MHC I expression during postnatal development.
Why MHC class I?
Briefly, MHC class I has recently been discovered to play a pivotal role in brain development. It has been found to be involved in the pruning of synapses in the developing brain. We know that in the peripheral immune system MHC I expression is upregulated due to immune activation, particularly TNF-alpha. We know that TNF-alpha can be transported across the BBB and impact expression of MHC I in the brain. It would be interesting to see if a vaccination event also alters the expression of MHC I in the brain, to what extent and how long this lasts.
What is even more intriguing about this is that a common morphological feature of the brains of children with Fragile X, and autism, is increased dendritic spine density (location of synapses), which could be due to alterations in pruning activity associated with MHC I.
This is probably a good segue into a post about how immune proteins are involved in normal physiological operations of the human brain, including memory and learning, synaptic plasticity, synaptic pruning, and how alteration in expression of these proteins(cytokines, MHC I, etc.) can alter normal physiological processes of the brain.
Therefore, I will go into more detail at another time and another post, when I have time.
What exactly do you think we should be allocating money to research in terms of vaccine safety?
Vaccines are safe, the money would be better spent on developing new vaccines.
I think this statement embodies your lack of critical thinking about this subject.
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