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Adjuvants and Cytokines II - The Meaning of 'Reactogenicity'

by: SusanC

Fri Oct 23, 2009 at 20:28:32 PM EDT

"We typically see, for effective adjuvants, increased reactogenicity, an FDA term for feverishness, sore arm at the site, which we typically see with non-adjuvanted vaccines but often see more in the presence of an adjuvant.

"I want to point out it is very unclear whether these ever correlate with more severe adverse events.  You know occasionally they do.  But we have not found, to date -- (unclear) but the flip side is it would be difficult to find, for example, that increased local reactogenicity or feverishness down the road increases the commonality of some of the more severe adverse events that we might be concerned about such as neurologic events.  

"There just aren't those data."

Jesse Goodman, Chief Scientist, FDA, Dec 2008
Workshop on Adjuvants and Adjuvanted Preventive
and Therapeutic Vaccines for Infectious Disease Indications

Part 1 is here http://www.newfluwiki2.com/dia...

SusanC :: Adjuvants and Cytokines II - The Meaning of 'Reactogenicity'
Jesse Goodman is a man with a great deal of expertise and experience, in vaccines and the science behind vaccinations (see here and here).   When someone with such solid credentials speaks, we'd do well IMHO to listen.  His words are also important since the FDA has bucked the European and Canadian trends and has, to date, not yet licensed any vaccine containing non-alum adjuvants.  It may be instructive to get a glimpse of why.  

Goodman's comments center round the implications of increased reactogenicity, ie immediate short-term reactions to vaccines, and whether such reactions are indicative of problems in the future.  Clinical trials as currently designed are not very effective for detecting delayed adverse effects, let alone establishing causal relationship between them and vaccination.  (See examples here, here, and here.) Plus we are breaking new grounds with these new, non-alum adjuvants: there is no data anywhere, on the longer-term effects of such vaccines especially in non-elderly populations (and limited data even in the elderly), to guide us on such basic questions as what adverse effects to look out for, or whether they should or should not be considered 'possibly related to vaccination' (see below).  

We cannot assume that such powerful vaccines will only cause the same kinds of side effects as you would see in conventional vaccines. (Here's why) The experience of Vioxx should tell us that such assumptions can be dangerous - that powerful new drugs or vaccines can have unexpected but serious, even life-threatening, effects.  In the case of Vioxx, outside of those directly involved in that area of research, who would have thought that an arthritis drug would cause heart attacks?  And yet it did.  (There were in fact plenty of 'signals' - the issues were hotly debated within the FDA - but they were ignored by those whose fingers were on the button, at a cost of 28,000 extra heart attacks and sudden cardiac deaths.)  

Similarly, in the GSK trials for the AS03 vaccine, there were 2 cases of stroke within 6 months of vaccination among 500 clinical trial subjects aged 18-60.  (The expected risk of stroke for those aged 45-54 should be 0.6 in 500 persons per 6 months, less for younger people, but a bigger group is needed to test for statistical significance).  Were those related or unrelated to vaccination?  GSK says not, but do we know that to be the case?  We don't have any data to guide us.  Can we be comfortable assuming no causal relationship, when scientists are now telling us that inflammation plays a bigger role in strokes than we used to think? (Stoll 2006, Welsh 2008)

Another example is Cervarix, the HPV vaccine by GSK adjuvanted with AS04, which is a combination of alum and MPL, a derivative of bacterial endotoxin.  There are no hard figures (ie statistically significant ones) but the FDA meeting transcripts do show a fair amount of concern over possible excess of autoimmune and neurological conditions, and spontaneous abortions.  Some of these are not the kind of adverse events we would expect, (or look out for) in conventional vaccines, so it really is uncharted territory, what these new adjuvants may or may not cause months or years down the road.  With regards to AS03, the FDA has asked GSK to do a 2-year follow-up study of their clinical trial subjects, which I think is a good idea.  But it also gives you an idea of the kind of timescale we are talking about, before we have some vague idea of the range of risks (or lack thereof).

So, what Goodman is saying, is that we don't really know whether increased reactogenicity as observed in clinical trials, implies increased risk of longer-term serious consequences including, as he said, neurologic complications.  It may.  It may not.  But we don't know.  "There just aren't those data."

When the Chief Scientist of the FDA says that, we would be mad to not pay attention.

We do know that adjuvanted vaccines in general are more reactogenic.  For example, here's a chart (adapted from their EMEA file) showing the local adverse reactions following the GSK vaccine in adults, compared to controls receiving the unadjuvanted vaccine.  

Note that >50mm of swelling and/or induration (=hardness) is about the size of a tennis ball, which IMO is pretty darn big, for an injection site reaction.  Such strong local inflammation invariably results in disorderly cell death and release of intracellular contents, which, as we have seen, are processed by immune cells in the same way and at the same time as they are processing the vaccine antigen.  In the presence of a strong stimulatory environment generated by the adjuvant, is there a risk of activating autoimmune processes* against such self-antigens? There's no hard data to help us quantify that.  Immunologists studying the effect of infections and other triggers on autoimmune diseases, find that typically it takes a while (ie months or years) to progress from the first subclinical autoimmune reaction induced by a trigger, to eventual disease, so that by the time the patient has symptoms, the original trigger is long gone.  They call these 'hit and run' events.  (Christen 2004, Ma 2005, Krishnan 2006) The science would suggest that adjuvanted vaccines causing strong local reactions may act as such triggers for susceptible individuals, but again there's no data to tell us for sure and to what degree, one way or the other.

(*For more on cell death and autoimmunity, see Sauter 2000, Savill 2002, Kremer 2009)  

All that is for local reactions.  Let's look at systemic adverse events, ie those beyond the injection site.  Again, adjuvanted vaccines are more reactogenic.  For example, for the GSK vaccine, for adults aged 18-60 yrs, > 60% of those in the adjuvanted group complained of myalgia (ie generalized muscle pain unrelated to injection site), as compared to 20-30% in the unadjuvanted group.  Fever, fatigue, headache, and lymphadenopathy (swollen, painful, or inflamed lymph nodes) were also more frequent in the adjuvanted group.

Let's see what happens in kids.  There was a 3-staged clinical trial with the H5N1 vaccine on children aged 3-9, as follows.  Control groups were given the unadjuvanted seasonal flu shot.

I'm going to focus on the two groups (highlighted in red) most relevant to the current pandemic: those aged 3-5 yrs receiving half the adult dose in Phase A, because that is the dose that will now be given to kids 9 or younger.  And those aged 6-9 yrs receiving the full adult dose in Phase C, because that is the dose that will be given to anyone aged 10 or over.  (No trials were done for anyone from aged 10-18yrs.)

This first table shows AEs in kids aged 3-5 given 1/2 adult dose.  Grade 3 symptoms are defined either by size of local reaction, or as those causing some restriction in activity, or >39C in the case of fever.

And this for those aged 6-9 given a full adult dose:

The very first thing to note, is how the current unadjuvanted flu vaccine is quite well tolerated by kids (0% fever), in general, and how differently they react to the adjuvanted ones.  Let's look at some more comparisons of systemic symptoms:

As you can see, there is a huge excess of systemic symptoms, in both age groups.  It's remarkable that the younger kids (aged 3-5 yrs) had very little reaction to the unadjuvanted vaccine, but had some really strong reactions to the adjuvanted one.  In the older age group, the biggest differences are in fever and headache.  

But what do these symptoms mean?  Do they have any significance for the longer term, as Goodman seemed to be worried about?  I don't know the answer to that, but again science comes to the rescue.  The mechanisms behind these reactions, may give us some clue.

The following is a diagram (Perry 2003) of the acute phase response, which is your body's early/immediate response to injury of any kind, with or without concomitant infections.  Soon after such injury happens, the innate immune system swings into action, to contain and limit the damage, prevent further spread eg of an infection, and promote tissue repair.  Note that the acute phase response works the same way whether the trigger is an infection in the lung, as shown in the diagram, or a vaccine that causes your arm to swell up, or someone got hit by a car, or after surgery, or a non-infectious illness like acute pancreatitis.  (Gabay 1999, Gruys 2005) Such sharing of pathways has implications, but first let's look at how it works.

Here are the basic steps, following the numbered arrows in the diagram.  

  1. Cells of the innate immune system, like neutrophils and macrophages, respond to signals of injury.  They move into the area and start the 'clean-up', eg by phagocytosis.  In the process, they become activated and secrete a number of cytokines, IL6 being one of the earliest ones strongly triggered.  Over a certain threshold of inflammation, cytokines and cell debris spill over into the blood, and travel to other parts of the body.

  2. In the liver, IL6 triggers the production of a large number of proteins (eg C-reactive protein, fibrinogen) into the blood, and causes a reduction in other proteins.  These are collectively called acute phase proteins.  Here's a list which also gives you some idea of what these proteins do.

  3. IL6 and other cytokines also have effects on the brain, which results in the symptoms that we recognize as being 'sick', eg fatigue, headache, loss of appetite, or myalgia, plus fever.

  4. The bone marrow is also stimulated to produce more white blood cells, to fight the infection.

The acute phase response is fundamental to all systemic immune responses, including when someone gets infected by flu.  Cytokines play important roles in severe or fatal influenza eg ARDS or influenza-related encephalopathy, but we'll save that for another day.   For right now, let's take a closer look at fever as a marker of systemic reaction to adjuvanted vaccines.  The following diagram (Eccles 2005) gives some more clarity on how cytokines induce fever.  

You can see that cytokines, including especially IL-6 (Chai 1996), are an essential component in the pathway for induction of fever.  Whether these cytokines work by directly passing into the brain, or by stimulation of the vagal nerve (probably both), they have to be present in the circulation, even if transiently, for fever to occur.  (Leon 2002, Rummel 2006)  In other words, people don't get fevers unless they've had a systemic cytokine response, and IL-6 is an essential part of that.  

Now, does this constitute 'proof' that AS03-adjuvanted vaccines induce a systemic cytokine response?  No, not unless and until it's measured and the data published.  However, for the purpose of non-specialists who are more concerned about whether to take the vaccine than the finer points of science, there IS a strategy called making an educated guess.

So what is an educated guess?  Let me use an analogy.  You know that your car battery needs to be working in order for you to start your car, right?  When you get up in the morning, climb into your car, and turn on the ignition, and the car starts nicely and easily, what does that tell you?  It tells you that you've got a battery that is working (well, at least not totally dead!!)  Notice you didn't have to go look under the hood and test the battery; you can 'test' it (and 'prove' it) indirectly by turning on the engine.  In the same way, there are certain biological phenomena that logically follow one upon the other, where the mechanism is well established.  Just like a functioning battery is a requirement for the car to start, a systemic cytokine response, however transient, is a requirement for fever and other systemic symptoms after vaccination such as headache, myalgia, fatigue, etc.

Note however that such 'educated guessing' is useful only on the conceptual level, ie to answer the question of whether, in principle, an AS03-adjuvanted flu vaccine can or cannot induce serum cytokines.  Whether that does happen in a particular person, is a lot harder to tell, because individual cytokine responses vary over a wide range, partly due to genetic factors. (Bennermo 2004, Hildebrand 2005) Which means it's much harder to make an educated guess as to how you specifically might be affected by such vaccines, even though we might think, statistically, (eg from the relative frequency of 'reactogenicity'), that if you vaccinate a large population with an adjuvanted vaccine, you're probably more likely to have some people who have stronger and systemic cytokine responses, than if you use an unadjuvanted vaccine.

In addition to the chronic illnesses that might be induced by a high or dysregulated IL-6 response, as mentioned in the previous diary, would a strong surge of systemic cytokines affect concurrent illness, eg influenza infection?  I haven't found any data that specifically addresses this issue, but there are some interesting models that I hope to explore at another time, if only to improve our understanding of influenza as an illness.  For the next diary, let's turn out attention to the implications for pregnancy.  

In the meantime, I'll leave you with some food for thought - a slide from Dr Goodman's presentation.  Note especially where he underlined the text:

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some good abstracts and quotes
Wisse 2004 The Inflammatory Syndrome: The Role of Adipose Tissue Cytokines in Metabolic Disorders Linked to Obesity

Circulating IL-6 is the single most important factor controlling the hepatic acute-phase response.

Kobayashi 2004 Shielding the double-edged sword: negative regulation of the innate immune system.

Proinflammatory cytokines mediate a positive feedback loop on the innate immune system, and overproduction of cytokines, if unchecked, is hazardous to the host and may cause severe outcomes such as hyperthermia, organ failure, and even death in extreme cases. Moreover, if the overproduction of proinflammatory cytokines persists, it may cause chronic inflammatory diseases.

Bennermo 2004 Genetic predisposition of the interleukin-6 response to inflammation: implications for a variety of major diseases?

BACKGROUND: A single-nucleotide polymorphism (SNP) in the promoter region of the interleukin-6 (IL-6) gene at position - 174 (G>C) has been reported to be associated with a variety of major diseases, such as Alzheimer disease, atherosclerosis, and cardiovascular disease, cancer, non-insulin-dependent diabetes mellitus, osteoporosis, sepsis, and systemic-onset juvenile chronic arthritis. However, authors of previous in vitro and in vivo studies have reported conflicting results regarding the functionality of this polymorphism. We therefore aimed to clarify the role of the - 174 SNP for the induction of IL-6 in vivo.

METHODS: We vaccinated 20 and 18 healthy individuals homozygous for the - 174 C and G alleles, respectively, with 1 mL of Salmonella typhii vaccine. IL-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) were measured in the blood at baseline and up to 24 h after vaccination.

RESULTS: Individuals with the G genotype had significantly higher plasma IL-6 values at 6, 8, and 10 h after vaccination than did individuals with the C genotype (P <0.005). There were no differences between the two genotypes regarding serum concentrations of IL-1beta and TNF-alpha before or after vaccination.

CONCLUSIONS: The - 174 G>C SNP in the promoter region of the IL-6 gene is functional in vivo with an increased inflammatory response associated with the G allele. Considering the central role of IL-6 in a variety of major diseases, the present finding might be of major relevance.

Kanzler 2007 Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists

Some functions are specific for microorganisms or viruses, others are less discriminating, and some, such as NK killing, specifically target infected host cells. Consequently, innate responses have the potential for causing significant tissue damage, locally and systemically3,34. Most often a rapid defense justifies this cost; however, responses that are too intense or prolonged can lead to acute or chronic inflammatory disease states.

All 'safety concerns' are hypothetical.  If not, they'd be called side effects...

toxicity in rabbits
with some signs of systemic inflammation, from the GSK file:

There was evidence of an inflammatory response in haematology, clinical chemistry and pathological parameters. Increases in fibrinogen and white blood cell counts were noted in temporal association with the erythema and oedema noted on observing the rabbits. Relative to body weight, the spleen weight was increased in all groups compared to the control (7 - 41%). This difference was much less marked from rabbits killed on Day 71, 28 days after the last injection, indicating reversibility.

Frequency and severity of fasciitis was higher in rabbits from the vaccine group.  This toxicity was attributed to the adjuvant.

Note that fibrinogen is one of the acute phase proteins made in large quantities during the acute phase response.  Ditto high white count.  Increased spleen weight is also a sign of excessive immunostimulation.  Source: Nonclinical evaluation of unexpected immunostimulation

All 'safety concerns' are hypothetical.  If not, they'd be called side effects...

I'm looking at the AEs for kids
in the tables I made above.  You know, it's so obvious when the data is presented like this.  But it isn't how it's presented in the EMEA file.  They have some data from other trials in table form, but this part was all in paragraphs, like this one for Phase A:

Phase A

In the 6-9 years age stratum, the overall incidence of AEs by subject was 96.1% in the AS03 group and 88.9% in the control group. The incidences of general symptoms were comparable between vaccine groups but local symptoms occurred more often in the AS03 group. There was no increased reactogenicity in either vaccine group after the second dose compared with the first dose.

In the 3-5 years age stratum, AE rates were generally lower than in older children. Incidences of general symptoms per subject were comparable between vaccine groups but rates of local symptoms per subject were higher in the AS03 group. There was no increased reactogenicity in either vaccine group after the second dose compared with the first dose.

The incidence of grade 3 AEs was generally low with no difference between the vaccine groups in older children but with rates of 13.7% versus zero in children aged 3-5 years. The incidence of AEs with causal relationship to the vaccination in the subjects aged 6-9 years was 94.1% in the Half HA/Half AS03 group compared with 83.3% in the control subjects. However, rates were comparable among subjects aged 3-5 years (66.7% and 61.1%).

In the 6-9 year-olds the rates of pain were 61% for Fluarix and 76.5% for AS03 vaccine after the first dose (none and 5.9% with Grade 3) but were comparable after the second dose (none and 4% with Grade 3). In the 3-5 year-olds the rates of pain were higher with AS03 vaccine after both doses but very few had Grade 3 pain.

Rates of solicited general symptoms per subject as shown below were not markedly different between vaccine groups in the 6-9 years age stratum. The rate of any fever (> 37.5°C) after dose 1 of AS03 vaccine was 5.9% but no subject had Grade 3 fever (> 39°C) and no subject in the Fluarix group had any fever. The rates for any fever after the second dose were 16.7% for Fluarix and 10.2% for AS03 vaccine while rates for Grade 3 fever were 5.6% and zero. The per-dose rates for any antipyretic use were 8% in both vaccine groups with per subject rates of 17% and 14% in respective groups.

In the 3-5 years age stratum rates of solicited general symptoms per subject were higher than in the control group. The rate of any fever after dose 1 of AS03 vaccine was 9.8% but 3.9% had Grade 3 fever (> 39°C). The corresponding rates after the second dose were 6% and zero. No subjects in the Fluarix group had fever after either dose. The per-dose rates of taking any antipyretic were 9% for Fluarix and 19% for AS03 vaccine, with per subject rates of 17% and 35%.

Unsolicited AEs reported up to 51 days after the first vaccination showed no particular signal or clinical pattern in any vaccine group.

Who has the time to pick through this kind of paragraphs to extract the information?  Assuming anybody KNOWS to look for that file on the EMEA site.  That's one way to 'bury' information....

All 'safety concerns' are hypothetical.  If not, they'd be called side effects...

You made the tables yourself!
I didn't catch that the first time I read it.  They should hide their heads in shame!  They omitted tables for the children's reactions because they knew it was bad news?  And presumably no one called them on it....  Or if someone did, they were shut down.
:-x  [stifling rant]

"The truth does not change according to our ability to stomach it."  Flannery O'Connor

[ Parent ]
yes, I made the tables
I had to extract the data from those kinds of paragraphs.  

All 'safety concerns' are hypothetical.  If not, they'd be called side effects...

[ Parent ]
The Bennermo paper lists common diseases associated with IL-6 genetic
variation, if I understand the abstract.  Is this an indicator of how common this variation is and/or who should be concerned with taking an adjuvanted vaccine?  (IOW, is it a hint about who should be cautious, i.e., anyone with those diseases in self or family?  It's probably too slight to be called proof.)  Or is this just one little piece of the unknowns?

A single-nucleotide polymorphism (SNP) in the promoter region of the interleukin-6 (IL-6) gene at position -174 (G>C) has been reported to be associated with a variety of major diseases, such as Alzheimer disease, atherosclerosis, and cardiovascular disease, cancer, non insulin dependent diabetes mellitus, osteoporosis, sepsis, and systemic onset juvenile chronic arthritis.
CONCLUSIONS: The - 174 G>C SNP in the promoter region of the IL-6 gene is functional in vivo with an increased inflammatory response associated with the G allele. Considering the central role of IL-6 in a variety of major diseases, the present finding might be of major relevance.

"The truth does not change according to our ability to stomach it."  Flannery O'Connor

there's a lot of ongoing research
on the genetic angle.  The - 174 SNP is one big item.  There are some interesting findings, especially correlation with IL-6 level and adverse outcomes.  But I don't think there's enough information to actually inform a particular individual about their risks.  It's more useful, again, on the conceptual, collective (ie if you fire a shotgun at the barn door, how many buckshots are going to hit?) and policy level, and much more difficult to evaluate for any individual.

All 'safety concerns' are hypothetical.  If not, they'd be called side effects...

[ Parent ]
There Is An Element of These Presentations That Is Critical..........And Missing.
There is an element in these presentations that is missing....and it is important if one is to make sense of the data.

That is the use of statistics and most importantly the use of statistical hypothesis testing.

SusanC says it herself.

"there were 2 cases of stroke within 6 months of vaccination among 500 clinical trial subjects aged 18-60.  (The expected risk of stroke for those aged 45-54 should be 0.6 in 500 persons per 6 months, less for younger people, but a bigger group is needed to test for statistical significance). "

What that actually means is that we have absolutely no way of knowing if the strokes were in any way caused by adjuvants or were merely a cluster of random events.

To put it another way, in a given weekend in this State, lets say that there are Five car accidents that result in say, Seven deaths. The Newspaper immediately runs an opinion piece under the Headline "Road Safety Is Declining". The reality is that without applying a statistical test, we have absolutely no way of knowing if road safety is declining, staying the same, or in fact improving!

When a scientist says "We don't know" about adjuvants, what he is actually saying, being a good and precise scientist, is "We do not know because we have not done a trial that is big enough to detect anything that is statistically signifigant." This is because if the effect or outcome you are looking for occurs in a vanishingly small number of cases, the sample size to validate your theory runs into the Tens or Hundreds of Thousands of subjects.

The design of clinical trials is a widely studied subject. The trials are designed, and must be designed, to pick up outcomes down to levels that are acceptable to the approving authority like the FDA. These numbers are not absolute either, for example, if a disease is known to be 100% fatal, a 10% death rate from side effects of the drug that treats it may be judged acceptable, but I wouldn't know. On the other hand if you are going to vaccinate millions of people the FDA tolerance for side effects, including death, would be a lot smaller.

Of course, even assuming absence of criminal behaviour or simple negligence, accidents can and do happen where the adverse effects of a drug do exist, but are so rare that it requires hundreds of thousands of users before a statistically valid conclusion about the drugs safety can be reached, there was one drug I was told about that was approved, in Britain I think, that had a side effect - blindness, that was completely missed because the sample size was not big enough.

What we can say about adjuvants is that in all the clinical trials of all vaccines using them, no one to my knowledge has detected a statistically significant adverse response that was big enough, considering other known risks, to preclude their use.

Or, to put it another way, I might be run over and killed by a truck while leaving a clinic after being vaccinated. So was my death a side effect of vaccination?

good point
about statistical significance.  The problem we are facing, in some countries, is that tens of millions (at least) of people are going to be vaccinated in a very short time.  Normally, when you license a vaccine, initially there may not be enough safety data, to a statistically significant degree, but neither are we vaccinating so many people in such a short time.  There is some time to collect information on the inital vaccinees which would, theoretically (but see below) give us some idea of the ballpark level of safety (remembering that all safety is relative).  In the absence of such information, how are people supposed to evaluate the risk/benefits of getting vaccinated vs not getting vaccinated?

Therein lies the dilemma.  If it was statistically significant, it would be 'proof', and it would not be a 'safety concern', but a known risk.

To get an idea of what it takes to find statistically significant correlations that can demonstrate or exclude causal relationship between some adverse events and some vaccines, just take a look at Cervarix.  It has been licensed for 2 years in many countries, but if you read the recent (Sept 2009) transcripts of the FDA advisory committee meeting, the data was not sufficient to demonstrate or exclude causal relationship between some very serious AEs such as autoimmune and neurological events, and early pregnancy loss (aka 'spontaneous' abortion).  

More here http://www.newfluwiki2.com/sho... or you can follow the link to read the transcripts yourself!

All 'safety concerns' are hypothetical.  If not, they'd be called side effects...

[ Parent ]

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