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Adjuvants, Autoimmunity, and Vaccine Safety in a Pandemic IV - Safety of MF59

by: SusanC

Wed Oct 17, 2007 at 22:07:21 PM EDT


( - promoted by SusanC)

UPDATE: Novartis has finally confirmed what we suspected.  A review published by the company Safety of MF59™ adjuvant (Schultze 2008) states:

the results of Novartis' GLP toxicology studies performed to fulfil global health authority requirements for clinical testing or product approvals have not been published, to date.

Click on the links for

Exploring the safety data on MF59 and MF59-adjuvanted vaccines.

SusanC :: Adjuvants, Autoimmunity, and Vaccine Safety in a Pandemic IV - Safety of MF59
I always believe in giving people the benefit of doubt, and, at least in the first instance, always taking them at their word.  In examining the safety concerns about MF59, I believe the best approach is to look at the work of the most experienced scientists on such adjuvants, and see how the case for safety is made.

For that reason, I'm going to explore a couple of articles written by top experts and published in peer-reviewed journals on this subject.  Since these experts are also employed by manufacturer of MF59, Chiron previously and now Novartis, I believe we will not be in danger of ignoring any data that is favorable to their case.

I'm going to restrict my comments on issues of safety only, and will not address the efficacy of the vaccine discussed or potency of the adjuvant.  With one exception only, I am going to pick out all comments pertaining to safety of MF59 and examine the evidence presented.  The one exception is the use of MF59 in HIV vaccines, as I'm not clear whether host immune responses in these instances can be extrapolated to healthy subjects.  In addition, this attempt of mine is for public discussion and understanding only, and is limited by my inability to access all primary sources.

The following paper is written by one of the top experts on the subject (a cursory search on PubMed returns 89 publications over the last 20 years mostly on this and related subjects), appears to cover the topic very comprehensively, and makes as clear a statement as you can find in its title.  MF59 is a safe and potent vaccine adjuvant that enhances protection against influenza virus infection. O'Hagan, DT, Expert Rev Vaccines. 2007 Oct;6(5):699-710.

First of all, Finalcial & competing interests disclosure

Derek O'Hagan is Head of Vaccine Delivery Research, Novartis Vaccines and Diagnostics, Incl, MA, USA.
ABSTRACT:
In preclinical studies, MF59 adjuvant offered improved protection against influenza virus challenge and significantly reduced the viral load in the lungs of challenged mice. In humans, MF59 is a safe and potent vaccine adjuvant that has been licensed in more than 20 countries (Fluad [Novartis Vaccines and Diagnostics Inc., MA, USA]). The safety profile of an MF59-adjuvanted vaccine is well established through a large safety database. MF59 adjuvant has had a significant impact on the immunogenicity of influenza vaccines in the elderly and in adults who are chronically ill. MF59 has also been shown to have a significant impact on the immunogenicity of pandemic influenza vaccines. MF59 allows for broader cross-reactivity against viral strains not included in the vaccine. MF59 has been shown to be more potent for both antibody and T-cell responses than aluminum-based adjuvants. MF59 has broad potential to be used as a safe and effective vaccine adjuvant for a wide range of vaccine types.
  1. The first comment is not on MF59, but an older adjuvant, Freund's incomplete adjuvant or FIA. 
    Although w/o emulsions containing mineral oils, such as FIA, have also been used as vaccine adjuvants in humans, including in combination with influenza vaccines [4], they are generally considered as too reactogenic for routine human use [5].  Nevertheless, long-term follow-up in subjects who received immunization with FIA has established that there are no significant long-term adverse effects in humans with this adjuvant, although local reactogenicity was very common [6].
    Reference #6 refers to a paper that I cannot find but I posted the abstract and my comments here.  There is a different published review of this study which is discussed at some length here.  As you can see, both these reviews only compared mortality data, and there are some interesting findings eg cerebrovascular lesions and higher incidence of having a diagnosis of 'therapeutic misadventure' or 'late complications of therapeutic procedures' for the adjuvant group, that are not obvious from the gross data alone.

  2. There is quite an extensive paragraph on preclinical studies and toxicological studies, but with the glaring absence of any references for these remarks.  I would really have wanted to look at the original published findings of these preclinical studies showing the safety of MF59.
    In addition to immunogenicity studies, extensive preclinical toxicology studies have been undertaken with MF59, in combination with a range of different antigens in a number of species.  Prior to evaluation in clinical trials, pivotal toxicological studies were performed with MF59, including repeat-dose toxicity (including local tolerability), genotoxicity, embryo-fetal and developmental toxicity and sensitization evaluations.  No treatment-related safety issues were identified in these studies and findings were generally limited to inflammatory responses at the injection site, consistent with the use of an immunological adjuvant.  MF59 is neither genotoxic nor teratogenic, and does not cause sensitization in highly sensitive preclinical models.
    BTW In case you are wondering, this paper has a total of 73 references cited.  But nothing on preclinical safety or toxicological studies or any of the stuff that is just quoted! 
    In comparison, in the SAME section, on preclinical experience with MF59 the author gives 6 references (#25-30) for the efficacy/potency of MF59, but nothing on safety.  ;-(

  3. Next are the comments on Fluad, the vaccine licensed for the elderly.
    The registration of Fluad was based on the results of a large clinical development plan that demonstrated, in more than 20,000 subjects in company-sponsored clinical trials, that the adjuvanted vaccine is well tolerated and more immunogenic than conventional nonadjuvanted influenza vaccines.....Moreover, in the outpatient population, the use of MF59 was not associated with any significant increase in reactogenicity compared with conventional vaccines [34].

    Well, we've already come across one example where such large numbers as 10,000 aren't always what they seem.  Again, I wish they had included the references for that statement of 20,000 cos it would be great to go and check that data!  Anyway, it can't be helped...
    Now, reference #34 is this paper, which as you can see, covered 204 subjects in the Fluad group and 104 in the regular vaccine group.

  4. Next is one example that I've already mentioned, but is so important it bears repeating.
    Importantly, the addition of MF59 to the influenza vaccine did not affect the safety profile of the vaccine, which was very well tolerated in all clinical trials performed in elderly and nonelderly subjects [32]
    #32 is this study which as you can see is THE review of 10,000 elderly subjects.  Not nonelderly at all.  It could just be an oversight, cos we know that there is at least one study on nonelderly subjects, although we are not clear how 'nonelderly' those subject are, since the paper did not elaborate. 
  5. With more than 30 million doses distributed, the safety of Fluad is supported by extensive pharmacovigilance data that shows that vaccination with Fluad is associated with a very low frequency of adverse reactions [43].
    Unfortunately, reference #43 is something presented at a conference:

    D'Agosto V, Berardi S, Burroni D, Hennig R.  Tolerability and safety of an MF59-adjuvanted subunit influenza vaccine (FLUAD). IVW 2006 - the Second International Conference on Influenza Vaccines for the World, 18-20 October (2006).

    Which sort of makes it privileged information, you know.  Well, I KNEW I should be going to even more conferences....

The second paper that I would like to go through is chosen partly because it is cited by O'Hagan in the context of 'extensive preclinical experience of MF59' having been reviewed previously. MF59-adjuvanted vaccines: increased immunogenicity with an optimal safety profile. Podda A, Del Giudice G. Expert Rev Vaccines. 2003 Apr;2(2):197-203.

Audino Podda, Chiron Vaccines Clinical Research & Medical Affairs, Chiron Srl, via Fiorentina, 1 Siena, Italy. Giuseppe Del Giudice, IRIS Research Center; Chiron Srl, Via Fiorentina, 1, 53100 Siena, Italy.
ABSTRACT:
The need to enhance the immunogenicity of purified subunit antigens has prompted the development of several new adjuvants. However, many of these new molecules have demonstrated a reactogenicity profile that is not suitable for their inclusion in vaccines for human use. In this context, the adjuvant emulsion MF59 has been developed, tested in combination with different antigens in several animal models and subsequently evaluated in humans. Clinical trials with several MF59-adjuvanted vaccines have been performed in different age groups (from newborns to the elderly) and have shown an increased immunogenicity of coadministered antigens, associated with a high level of safety and tolerability. MF59 has been the first adjuvant to be licensed for human use after alum and, as part of an enhanced influenza vaccine for the elderly, is now available in the marketplace of several countries worldwide.
This paper has 47 references. 

  1. Again, the first place that we land in, is in preclinical studies.
    The adjuvant emulsion alone and/or in combination with different antigens (eg influenza, HSV, HIV and others) has been tested in several toxicological studies aimed at evaluating the safety profile of this compound before commencing clinical trials.  Toxicological studies, performed in rats, rabbits, dogs and other animal species, included acute toxicity studies, repeated-dose toxicity studies, mutagenicity studies and teratology studies.  The overall conclusions from this extensive toxicological evaluation was that MF59, either alone or in combination with different antigens, has an acceptable safety profile and can be safely administered to humans.

    Again, I wish they had put down the references.  I mean, by the sound of it, they probably spent a fortune and years on this, what is there to not share with as many people as possible?

  2. This next is on the adjuvanted flu vaccine, this time on 12,000 elderly subjects.
    although the presence of the adjuvant is associated with an increased rate of local adverse reactions, particularly local pain, most of these reactions were mild in nature, of short duration and qualitatively similar to those induced by control vaccines [23-28]. 
    Phew! FINALLY we are getting some references! 
    Here are the links to these references, for y'all to browse, cos these ARE the adjuvanted flu vaccine studies!
    #23 is here but is also the same study discussed here
    #24 is here
    #25 is here
    #26 is here
    #27 is here
    #28 is here

    Good.  Now we know there's lots of data on the safety profile of Fluad in the elderly, notwithstanding all the caveats that we already discussed.

  3. Next we have clinical trial on a pandemic vaccine with H5N3, first there is this Phase 1 trial, subjects mean age around 28 years.  32 given MF59-adjuvanted vaccine, non-adjuvanted 33.  The second is when they rounded up the same subjects (found 26 of them) to study the effect of a booster shot.  15 of these individuals got the adjuvanted vaccine in this trial

    Anyway, for these 2 trials, here's the author's comment:

    From a safety point of view, the addition of MF59 was very well-tolerated and did not provide any evidence of clinically important reactogenicity.
  4. Other vaccines: Hepatitis B vaccine, link
    As expected, due to the presence of MF59, the adjuvanted vaccine induced a higher rate of mild local reactions (pain at the injection site was the most frequent reaction).  However, the incidence of systemic reactions did not significantly differ between MF59-adjuvanted and alum-adjuvanted vaccines.
  5. This is the interesting one, 2 studies on HSV vaccine - with 2 recombinant glycoproteins. 


    Several things to note about these 2 studies:

    • They both used MF59 as placebo.

    • Note the high drop-out rate 23% for the first study, 11% in the second.

    • Of these, 10 patients (7.3%) in the first study, and 8 (4%) dropped out specifically because of adverse reactions

    • The drop-out rates were the same for the 'vaccine' group and the 'placebo' group.

    Here I'm indebted to the work of Matsumoto, who provided the following information in his book.  Remember this chart from the first Tulane study

    Apparently, the 2 'NIH vaccine participants' on the chart came from these studies, I believe it is the second one.

    The story as written up by Matsumoto, is that one of the patients in the trial, patient X, a doctor who had received 'a placebo' went to the Senate Veterans Affairs Committee to report that he had developed symptoms that were very similar to what the Gulf War veterans were having - muscle and joint pains, twitching of muscles, rashes, fatigue, tingling in limbs, "possibly auto-immune peripheral neuropathy", had to stop working, etc.  Except of course he was not in the military, didn't get the anthrax vaccine, didn't have any of the exposures, etc.  The Senate Committee who knew of the work of Pam Asa at Tulane, sent him to see her.  He and another patient from the trials who got 3 doses of the vaccine and also got ill, both tested positive for anti-squalene antibody (ASA).

    The significance of this is, here you have 2 people KNOWN to have been given MF59, got sick shortly after being given those vaccines with symptoms of auto-immune disorders, and then tested positive for ASA. 
    Leaving aside the issue of whether this validates the ASA test, what else does this story tell us?  For me, the main purpose here is to arrive at some judgment as to how to interpret these papers published by Chiron and Novartis, like what does it take for them to tell you something went wrong?

    When I look at how the adverse reactions are described in the studies, even though they did admit to the patient drop-outs, and there's this whole list of adverse reactions, and the lengthy description in the paper itself, the authors still asserted that Vaccination side effects were limited in severity and duration.

    AND, despite all that, in this review of MF59-adjuvanted vaccines by Podda, you find this remark.

    Three immunizations with these proteins together with MF59 were very well-tolerated.

  6. One final trial I want to write about, Immunogenicity of a recombinant human cytomegalovirus gB vaccine in seronegative toddlers.

    As far as I can tell, this may be the first MF59 adjuvanted vaccine given to healthy toddlers except for those born of HIV-positive mothers.  The important thing to note is that the purpose of vaccinating kids against CMV is not to protect the kids, not the ones receiving the vaccines anyhow. 
    CMV is frequently transmitted by kids to caregivers, including pregnant women who may then give birth to babies with congenital CMV infection.

    I believe it is important to find ways of preventing congenital CMV, including vaccinating kids to protect the adults.  But does that justify giving an adjuvant for which we have scant data on large nonelderly adult populations, let alone kids and babies?

    Here's the chart showing the reactions of these kids.

    And the remarks from Podda's paper

    In this toddler trial, the CMV bG/MF59 vaccine was well-tolerated by all children and no significant systemic reactions occurred after administration of any of the three doses although transient local reactions were more frequent after the third dose.
    As with all the other studies, they only followed the kids for 7 days.

The rest of this series can be found via these links here part I, part II, part III, and part V.

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here's the 6 billion dollar question
What's with the preclinical data?

Anybody care to answer that?



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


actually
this is more than a rhetorical question.  ;-)  Anybody who finds such data/studies, please post!  Thanks!



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


[ Parent ]
This is Bizarre
I find discussion of potential adverse reactions to adjuvents that might possibly be used in an H5N1 vaccine that has a CFR of 60% to be bizarre.

it isn't bizarre at all to me
Walrus, I would very much like to know the state of scientific knowledge on exactly how safe MF59 is, and if it is at all implicated in autoimmune disorder.

I don't know what the CFR of the next pandemic will be, or if the next pandemic will be H5N1.

But ESPECIALLY if the next pandemic will be H5N1....we might have the possibility of using a pre-pandemic vaccine plus an adjuvant to make enough for most of the country.

We have some H5N1 vaccine right now.  We could stretch it with an adjuvant and give it out to lots of people.  Maybe it wouldn't be a perfect match, but it would be something, so maybe some people might not die but just get quite sick... but then they'd recover.

If I were convinced by sound scientific method that a pre-pandemic H5N1 vaccine/adjuvant was extensively tested and was "safe", had minimal, tolerable side effects (a little sore arm for a day) I might even volunteer to get one right now, if it were offered to me.

But, to be willing to accept a pre-pandemic vaccine, without knowing really anything, without knowing that the adjuvant had truly been tested for the long term, and in people my age?

For that, I just don't know, and for my KIDS?  I'd rather do everything I could just to keep them away and inside, for as long as possible, to be honest.

And autoimmune disorders can be mild, or they can be debilitating.  My friend suffers from one, and she can barely function; she can't work nor can she care for her child; she can't grocery shop, and she is in constant pain.  It's nothing to sneeze at; if it is a concern, it should be looked at seriously. 



GetPandemicReady.org - non commerical website with practical ways for families to prepare.


[ Parent ]
you are absolutely right
If we ever find ourselves in a high CFR pandemic with no other option available, I too would be willing to take many risks to stay alive.  But we are not in a pandemic now.  This is the time to find out.

My concern is the slippery slope.  That we are lulled into complacency by our fear of a high CFR pandemic, and that we will accept unjustifiable risks without scrutiny because of that.  It is not a theoretical risk, because for the US, for example, you have legislation that gives the Secy of HHS authority to use unlicensed vaccines in the case of emergency, under Emergency Use Authorization or EUA.  My concern is that it will be seen as a viable step and therefore they will be less vigorous in their efforts to find answers or alternative solutions.

And autoimmune disorders can be mild, or they can be debilitating.  My friend suffers from one, and she can barely function; she can't work nor can she care for her child; she can't grocery shop, and she is in constant pain.  It's nothing to sneeze at; if it is a concern, it should be looked at seriously.

Autoimmune diseases are not to be sneezed at.  Those who are healthy do not understand the devastation of not being able to function.



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


[ Parent ]
You and me both!
It's a mildly interesting diversion, but totally irrelevant to me it would be in the face of a high CFR pandemic virus running rampant.  I'd be rolling up my sleeve before they could draw it into a syringe - as if I thought in my wildest dreams that there'd ever be a vax for me anyway . . .

Which is just yet another reason that this whole discussion is a bit strange.  Not only does it seem silly to fret about possible sequelae in the event of survival, but sillier still due to the fact that most of us will never see an H5N1 vaccine in the first place - so worrying about what additives it might contain does seem odd . . .


[ Parent ]
My reply was to Walrus . . .
ACM posted while I was typing . . . :)


[ Parent ]
off-topic: i see coments in "flat + recentlast" mode but hitting "parent" shows who you're responding to
I prefer "flat + oldest first" because that's how "conversations in a room" happen in real life.  This can be adjusted using http://newfluwiki2.c...  My own "unread comments" appear in red, so it's easy enough to catch up.

I wonder how others like to read this forum.

As I said, an off-topic, but we might discuss it in the "community" diary.  Improving the user experience might not be trivial if we want to grow in number of users, that's why.

You arm yourself to the teeth just in case.  You don't leave the gun near the baby's hand.


[ Parent ]
Clawdia, we may or may not see a vaccine
The whole point of using an adjuvant is for dose-sparing, which means THAT is one way for most people to see a vaccine.

The choice of whether to accept a potentially dangerous vaccine vs a potentially fatal disease should be left to the individual, not decided for us by faceless men behind seemingly innocuous 'science'.

The danger also lies in the slippery slope.  Look at how the vaccine is being tested in babies for CMV now.  Is there any correlation between that and the need to take drastic measures in the interests of the individual being vaccinated?

Are we giving up our right to know too easily?  THAT is the issue we all need to consider.

For those of you who find this discussion irrelevant, I can respect that.  But there are those who do, and we need to respect that too, IMHO.

If I was only concerned about whether I or even my kids should receive the vaccine, I would not be spending my hours and days researching this.  I look at this from the POV of how many millions of kids and young people might be affected, and how their lives may get ruined, and I believe we have a moral duty to ask some questions, that's all.



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


[ Parent ]
61% CFR is not the only posibility
At some point in the CFR scale, a say 5% probability of a life-long debilitating disease (if that's what we're talking about here) has to be weighed against a say 1% (CFR) * 30% (CAR) probability of death.  More so if things are very different for different age groups or previous health conditions.

The time to do such questions is now.

And of course we need to multitask as a not-even-a-hive entity (maybe we're a hive of hives, if we're anything at all).  So it's a good thing that some of the big "us" are looking into this.

You arm yourself to the teeth just in case.  You don't leave the gun near the baby's hand.


[ Parent ]
lugon, you are exactly right
the time to ask questions is now.

Yes, we ARE talking about life-long debilitating disease.  Severe chronic illness, disabling to the point of being unemployable. 

Those who dismiss these issues should find out what autoimmune and such related conditions are like, and ask whether those are acceptable trade-offs.  Google multiple sclerosis, systemic lupus erythematosis, rheumatoid arthritis, ALS, etc.



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


[ Parent ]
I have had MS
for twenty years. It does shrink your world in a big way. I'd hate for people to have to experience an autoimmune disease unecessarily.

Life is not so short but that there is always time enough for courtesy. Ralph Waldo Emerson

[ Parent ]
I totally agree
Most healthy people do not realize what it is like, to step from the realm where if you get sick, you go to your doctor and you expect to get well, into a realm of knowing that you will not get well for a very long time if ever.  That all the difficulties and discomfort and inconveniences do not have solutions, and you have to re-build you life AROUND them.

In some ways, particularly for those whose disability is not obvious to others, the realities and limitations that you have to live with, the distinctive personal experiences that you have gone through, can set you apart so much as to be isolating in and of itself.

Here's a poignant excerpt from the book "The Chronic Illness Experience", describing what it is like, to move from a 'nomal world' experience to the 'chronic illness' experience, a few short pages that are really worth reading.

http://www.amazon.co...



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


[ Parent ]
Autoimmune disorders
One of my daughters suffers from multiple disorders all linked to autoimmune disease.  She was healthy and leading a fully productive life until something triggered a reaction.  Though it is thought that some cases are a result of genetic damaged that lays dormant until a trigger activates it.  There are a whole series of diseases that are now recognized to be a result of autoimmune disorders.  In many cases, we many have recognized the disease but not the autoimmune root.  It is far more common than people recognize.

[ Parent ]
That's true.
Though it is thought that some cases are a result of genetic damaged that lays dormant until a trigger activates it.

Which is why the same trigger can produce devastating and life-long disease in some people and be fairly well tolerated by others beyond the transient discomfort. 



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


[ Parent ]
also true
that autoimmune conditions are a lot more common than most people realize.



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


[ Parent ]
Way too common!
I have one (or more) autoimmune conditions as well.  Sjogrens for sure, and something that acts like lupus but doesn't yield test results like lupus.  I was sick off and on for a good (bad) dozen years before getting that much of a diagnosis.
Well, I did get a diagnosis of chronic interstitial cystitis along the way, which may be related or may not, and that's another incurable condition.

It is indeed a far jump from expecting to get well to hoping, at best, for symptomatic relief or, if you get really lucky, some period(s) of remission.  I wouldn't wish anybody to have to move from the former status to the latter, unless doing so would improve the chances of surviving pandemic influenza, or something else equally significant.


[ Parent ]
Trigger
The first sign with my daughter was a small problem as a teen - explosion of problems after the birth of a child.

The pregnency could have triggerd the reaction...but she would not have changed her decision to have a child. We will all have to weigh our choices.


[ Parent ]
susan, you have mail!!!


You arm yourself to the teeth just in case.  You don't leave the gun near the baby's hand.

[ Parent ]
are you suggesting
that we give up holding tptb accountable just because a pandemic might have a 60% CFR?  How far are you willing to go with that line of thinking?  What, martial law?  Mandatory quarantine?  Just to name some things folks have talked about, not that i personally worry about those.

Whether a pandemic might have a CFR of 60% or 0.1%, science is still science.  We can decide whether we want to take extra risks in a high CFR pandemic.  But we shouldn't give up the right to make those choices with our eyes open, IMO.

And right now we are not in a pandemic.  There's no reason to stop any research into MF59 or other adjuvants.  But there's no reason to get some answers out of some rather complex and puzzling information either.



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


[ Parent ]
what I object to
is not adjuvant or MF59 per se, but the idea that just because something has been RESEARCHED by many many scientists that we should take their words for it without scrutiny.

Notice I AM taking them at their word, those who research and find the results acceptable.  What I would like to see is more open documentation of the evidence.

Maybe there's a lot of preclinical data somewhere, maybe I will find them.  Right now I find it puzzling if not disturbing that 2 of the most authoritative scientists on the subject, in writing REVIEWS of the whole issue, choose to not quote the data that supports their assertion that there is a lot of preclinical data that shows the safety of MF59.

I'm asking for 2 reasons:

  1. Other researchers, those not connected to vaccine companies, those working on autoimmune diseases, find these substances consistently capable of producing such diseases in animal models.
  2. I have found examples of misleading use of critically important supporting evidence, like this one, where a paper evaluating the safety of squalene as cosmetic ingredient is being cited as evidence of safety by scientists from the NIH, DOD, as well as the Institute of Medicine.

Now these are eminent scientists, and I'm a nobody.  But no one is infallible.  If mistakes had been made, then we need to point them out and make tptb accountable.

If mistakes have been made by me, then someone please point them out to me and make ME accountable.

But please do not tell me it is bizarre to ask these questions.  Show me where I'm wrong, is what I'm asking.  Please.  I would happily retract all of what I wrote if I can be convinced. 

Convince me.  By evidence, and scientific rationale.



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


a most timely discovery
on my part.  No, it is not about MF59 or vaccines or even pandemics, but a most excellent blog on denialism at scienceblogs.  http://scienceblogs....

Highly recommended!



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


Assessment of adjuvants from an industry publication
Here is a copy of something I posted at the PFI forum, and is relevant to this ongoing discussion.

This excellent review article about adjuvants contains a great deal of information not gathered in any one place. It is published in an industry journal, BioPharm International. Their "About Us" page tells us:

http://biopharminter...

BioPharm International magazine integrates the science and business of biopharmaceutical research, development and manufacturing. We provide practical peer-reviewed technical solutions to enable biopharmaceutical professionals to perform their jobs more effectively.

The article about adjuvants, which is quite approachable, gives an appraisal of the many types of adjuvants, their pros and cons. It also gives information about a new adjuvant ("Advax"), that they feel is much safer across the board for humans of all ages.

Because there is a strict copyright on the content of this article, I am not able to provide snips. Thus, I will cover some of the high points in my own words, and which article page to see for those items. Of course, the entire article is very interesting. The body of the article runs through pages 1-7; the large list of references goes from pages 8-14.

The article begins here.
http://biopharminter...

New-Age Vaccine Adjuvants: Friend or Foe?

A major unsolved challenge in adjuvant development is how to achieve a potent adjuvant effect while avoiding reactogenicity or toxicity

Abstract

Older vaccines made from live or killed whole organisms were effective, but suffered from high reactogenicity. As vaccine manufacturers developed safer, less reactogenic subunit vaccines, they found that with lower reactogenicity came reduced vaccine effectiveness. Somewhat ironically, the solution proposed to boost immunogenicity in modern vaccines is to add back immune-activating substances such as toll-like receptor agonists-the very same contaminants removed from old-style vaccines. This raises the question of whether the vaccine field is moving forward or backward. We propose that by avoiding adjuvants that work through toll-like receptor (TLR) pathways, and instead focusing on adjuvants stimulating B- and T-cell immunity directly, one can minimize inflammatory cytokine production and consequent reactogenicity. We present data on a polysaccharide-based adjuvant candidate, Advax, that enhances immunogenicity without reactogenicity, suggesting that potent and well-tolerated vaccines for both adult and pediatric use are indeed possible.
___________________

Other highlights from the article.

The review of oil-in-water emulsions begins on page 3 and continues to page 4. In general, the oil particles are considered to be irritants, causing local inflammation and macrophage invasion. The macrophages ingest the particles and travel to a nearby lymph node. Frequent adverse reactions are mentioned, along with possibility of excessive reactogenicity and toxicity. The authors also mention limited suitability for children.

A separate review of the oil in water adjuvant MF59 (which contains squalene oil) begins on page 4. It was surprising to read the authors' assessment (backed by references), that in influenza vaccines the adjuvant results only in a 25% increase of antibody levels in the elderly (they called it "modest"); and no increase in younger persons. They do not feel this adjuvant is truly antigen-sparing, which is one of the goals needed for pandemic flu vaccine production.

The authors also cite the evidence that squalene oil induces chronic inflammatory arthritis in susceptible animals; and that this susceptibility appears to be genetic. They raise the possibility that the same pattern could show in genetically prone humans if the adjuvant was used in a wide-spread manner.

The review of "Advax" adjuvant begins on page 7. The active component is inulin, a polysaccharide derived from a plant source. The advantages of inulin include a very high safety profile; it can be prepared in very pure form free of contaminants and toxins; and that it is excreted unchanged in the urine. The disadvantages cited by the authors, are that the vaccine community equates adjuvant strength with "inflammation and reactogenicity", which they assert is not necessary to achieve an immune response.

The summary should be read by everyone (also on page 7), particularly the brief last paragraph which is very critical of the current state of research on adjuvants as compared to vaccine antigens, and urge immediate support of funding for this technology, to address this imbalance.
____________________

Comment

The evidence from this article that external squalene can be an irritant and is ingested by macrophages suggests that not all squalene is seen by the body as equal. Previous critiques from various sources that squalene is "all natural" because it is a molecule in the human body and a precursor to cholesterol, just does not hold up anymore. There may be slightly altered formations of the molecule that the body sees as "foreign". Hopefully future research will shine light on this issue.


thank you
yes this is a good article.  I'm planning on writing an overview summarizing the big picture issues raised in this document.

But specifically on MF59, which is what this diary is focused on, you are right in that the improvement in efficacy in the influenza vaccine is very modest.  The main advantage they are touting is dose-sparing in a pandemic.  I haven't examined very closely the efficacy issue yet, so I'm going to keep an open mind. 

The issue right now is, assuming a pandemic or prepandemic vaccine adjuvanted with MF59 is effective, how much risk are we willing to take in order to have that vaccine?  Does the documented science justify the optimism (on safety)?  Does our experience so far of human trial data tell us these trials can be depended upon to give us that confidence about safety in young people?



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


[ Parent ]
squalene-related references from above article

Here is more, reposted from my PFI submissions.  Susan has, I believe also reviewed the second reference in this post, which addresses immunogenicity (how well the adjuvant enhances antibody titers post-vaccination).  Immunogenicity is a separate issue from safety, as Susan has previously mentioned; but both deserve attention, especially considering the potential risks from squalene - it a cost versus benefit type of consideration.

***************************************************

There were two references given in the article posted above (#4 and 45), addressing antibody production with the FLUAD vaccine which contains MF59 (squalene). Here are the abstracts from these articles. Unfortunately, I am unable to access full-text articles at this time.
_______________________________________________________

Prescrire Int. 2004 Dec;13(74):206-8.

Influenza vaccine with squalene adjuvant: new preparation. No better than available products.

[No authors listed]

(1) Injectable influenza vaccines reduce morbidity and mortality in people over 65 years. (2) A new influenza vaccine, with an adjuvant (MF59C.1) based on squalene, is now marketed in France for people over 65, and especially those with chronic conditions at risk of influenza complications. (3) The clinical evaluation dossier contains data from about twenty immunogenicity studies in more than 4000 elderly subjects. According to a meta-analysis of these studies, there is no firm evidence that the MF59C.1 adjuvant vaccine is any better than other vaccines at inducing immunity in elderly people with chronic conditions.  (4) A retrospective analysis of mortality among subjects enrolled in immunogenicity studies showed no significant difference between groups receiving the squalene adjuvant vaccine and groups receiving another influenza vaccine, either in the general population or in subsets of patients with relevant chronic conditions. (5) Local adverse effects (pain, rash, induration) and systemic adverse effects (malaise, myalgia, headache) were significantly more common after the squalene adjuvant vaccine than after other influenza vaccines. Pharmacovigilance data collected by the company show no unexpected adverse events. (6) In practice, there is no reason to prefer the squalene adjuvant vaccine to existing vaccines for elderly people, whether or not they have underlying chronic conditions.

PMID: 15599987
__________________

Vaccine. 2003 Oct 1;21(27-30):4234-7.

Frey S, Poland G, Percell S, Podda A.
Saint Louis University School of Medicine, Saint Louis, MO, USA.

The adjuvanted influenza vaccine FLUAD is composed of subunit influenza antigens combined with the MF59-adjuvant emulsion. The vaccine was developed primarily for use in elderly populations, but non-elderly individuals might also benefit. To evaluate this hypothesis, 301 healthy adults were assigned randomly to receive two intramuscular injections of either FLUAD (150 subjects) or a non-adjuvanted vaccine, Fluzone (151 subjects), in two trials conducted at a 1-year interval. Injections consisted of 15 micrograms per 0.5 ml dose. Vaccine composition was A/Texas/36/91 (H1N1), A/Johannesburg/33/94 (H3N2), and B/Harbin/7/94 for the first injection and A/Texas/36/91 (H1N1), A/Nanchang/933/95 (H3N2), and B/Harbin/7/94 for the second injection. Immunogenicity was evaluated at 28 and 180 days post-immunization. FLUAD was generally well tolerated in healthy adults when compared with Fluzone. FLUAD was associated with increased pain at the injection site after immunization. A statistically significant increase in the incidence of injection-site warmth, chills, myalgia, and analgesic/antipyretic use occurred in the FLUAD group after the first injection but not after the second injection. In both groups, most of these local and systemic reactions were classified as mild. FLUAD was more immunogenic than Fluzone following both injections. After the first injection, statistically significant differences were found in the percentage of subjects with four-fold rises in hemagglutinin inhibition (HI) titers at 28 days post-immunization for the B antigen. After the second injection, the FLUAD group had significantly higher HI titers, a significantly higher percentage with a four-fold increase in titer, and a significantly greater percentage of subjects with titers >/=160 for the H3N2 antigen at 28 days. Only minor immunogenicity differences between the two groups were seen at 180 days.Compared with Fluzone, FLUAD was associated with increased immunogenicity and mild post-immunization reactions in healthy adults.  The magnitude of increased immunogenicity in healthy adults was less than that seen in elderly populations.

PMID: 14505903
______________________

Comment: In the second abstract, it appears that while the FLUAD vaccine produced higher titers 28 days post-injection, there was no significant difference between the MF59-adjuvanted and the non-adjuvanted vaccine titer levels at 180 days. It would have been interesting to see what the titer levels were showing post-60 or post 90 days. This study took place in healthy adults.


[ Parent ]
title of article

Sorry! I neglected to include the title of the second article above, from the journal "Vaccine":

Comparison of the safety, tolerability, and immunogenicity of a MF59-adjuvanted influenza vaccine and a non-adjuvanted influenza vaccine in non-elderly adults.


[ Parent ]
your first abstract
is from an interesting source. 

Prescrire International (a new quarterly journal)

In 1981 La revue Prescrire was launched to offer French-reading physicians expert, objective, and documented synoptic information on diagnostic and therapeutic options. Opened with a grant from the French Ministry of Health that lasted until 1992, it has otherwise been supported entirely by subscriptions. It has not carried advertising in order to maintain the needed independence.

Now an English-language quarterly version is available that carries selected articles from the French version. The articles may cover individual drugs, drug classes, adverse effects, and other practical topics. The documentary basis for judgments is included as references; the range of journals surveyed is international.

source: Annals of Internal Medicine



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


[ Parent ]
Lancet article describes a more recent study
This was from cidrap -- I didn't read the actual study-- a little while back, which seemed to indicate that recent studies are saying MF59 does improve immunogenicity.  Doesn't it?

http://www.cidrap.um...

"Writing in the Aug 18 issue of The Lancet, Isabel Leroux-Roels and colleagues reported that the lowest dose of adjuvanted vaccine, 3.8 micrograms (mcg), induced immune responses after two doses that met or exceeded all US and European criteria for vaccine licensing. Further, more than 75% of volunteers who received this low dose of adjuvanted vaccine, based on a clade 1 H5N1 virus, were shown to have neutralizing antibodies against a clade 2 strain. Equal doses of the vaccine with no adjuvant yielded significantly weaker responses.

The new report fleshes out preliminary results that GSK released in July 2006 and March 2007. The British company's 2006 report raised hopes that adjuvants could substantially boost the supply of prepandemic H5N1 vaccines by reducing the amount of antigen (active ingredient) needed in each dose. Several vaccine trials have shown that the hemagglutinin, or H, component of the H5N1 virus triggers a weak immune response in humans, so vaccines must contain relatively large amounts of it.

Seasonal flu shots typically contain 15 mcg of antigen for each of three flu strains, about four times as much as the lowest dose in the GSK vaccine trial. The first H5N1 vaccine licensed in the United States, made by Sanofi Pasteur, required two 90-mcg doses to induce a good immune response in about half of volunteers. With an adjuvant, the vaccine was shown to induce a good immune response in about two thirds of volunteers who received two 30-mcg doses.

The Lancet report describes, apparently for the first time, GSK's proprietary adjuvant. It is described as an oil-in-water-based emulsion, with the oil portion containing DL-alpha-tocopherol, or vitamin E, and squalene, an oil found in some fish oils, and the water portion containing a small amount of polysorbate 80, a nonionic detergent.

The vaccine used in the study was a split-virus formulation derived from a clade 1 H5N1 strain isolated from a Vietnamese patient in 2004. The trial was conducted in Ghent, Belgium, and involved 400 healthy men and women between the ages of 18 and 60. The volunteers were randomly assigned to receive one of eight vaccine formulations-3.8, 7.5, 15, or 30 mcg, with or without adjuvant. Each person received two doses, 21 days apart.

The researchers assessed humoral immunity by measuring hemagglutination-inhibition (HI) antibody titers and also testing for the presence of antibodies that could actually neutralize the H5N1 virus in the lab.

All eight vaccine formulations were well-tolerated, and no serious adverse events were reported. Pain at the injection site was the most common symptom in all groups but was more common in those who received the adjuvanted vaccine. General symptoms such as fatigue and headache also tended to be more common in the adjuvant group.

The adjuvanted preparations induced significantly stronger immune responses than the nonadjuvanted preparations at all doses, the report says. The 3.8-mcg dose with the adjuvant yielded HI antibody titers of 1:40 or higher in 84% (95% confidence interval [CI], 70.9% to 92.8%) of volunteers and fourfold increases in neutralization titers in 86% (95% CI, 72.8% to 94.1%). Without adjuvant, 3.8 mcg of vaccine induced similar results in only 16% and 37% of vaccinees. Even at the highest dose, 30 mcg, vaccine without adjuvant triggered similar HI titers and increases in neutralization titers in only 43% and 65% of vaccinees, respectively, the report says. "

(more)

GetPandemicReady.org - non commerical website with practical ways for families to prepare.


[ Parent ]
thank you, ACM ;-)
See my comment below.  Let's hold those studies on the different vaccines and whether they work and how much dose reduction we can get, for the next diary.  Let's just stay on evaluation of safety for this diary please,  Thank you!



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


[ Parent ]
will do, but note safety was mentioned
"All eight vaccine formulations were well-tolerated, and no serious adverse events were reported. Pain at the injection site was the most common symptom in all groups but was more common in those who received the adjuvanted vaccine. General symptoms such as fatigue and headache also tended to be more common in the adjuvant group."

I would like to know more about this fatigue and headache... did it cause anyone to drop out of the study? 

GetPandemicReady.org - non commerical website with practical ways for families to prepare.


[ Parent ]
I don't know about this particular one
but headache, malaise, muscle pain etc are commonly cited in all the studies.  They admit that, and I don't have a problem with them per se.  We have to accept some degree of reaction to some vaccines IMHO.  What I AM concerned about is longer term side effects that are not picked up by those 7 days of reporting, which is what most of the studies rely on.

As for dropping out, not every study reports how many people drop out, so I don't know. Suffice it to say that I didn't see that information on ANY of the ones that I went through, except for the 2 on HSV, which as I said was connected to this controversy of 'patient X'.

btw, this patient actually took the NIH to court for failure to inform properly in the consent form.  He lost, but did the publicity, and the fact that 2 patients that dropped out due to severe and prolonged adverse reaction and got tested by Tulane have anything to do with the fact that they DID eventually report the drop-out rate?  Remember studies take a long time to get published, so at the time of publication, this controversy would have been full-blown, at least to those involved, and it would be quite hard to NOT put it down in the data, don't you think?

The question is, were there others that got seriously ill that have not come to our attention?  That's what we don't know.



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


[ Parent ]
I guess my question was this
I'm attuned to tiny differences in wording now, I admit -- but the abstract mentions first, that this vaccine meets or exceeds all licensing standards in the US and Europe.  (So, it has to be "safe"?)  And second, that "The adjuvanted vaccines induced more injection-site symptoms and general symptoms than did the non-adjuvanted vaccines, but most were mild to moderate in intensity and transient in nature."

A lot of the wording of the other vaccine trials you reviewed were not as strong as this, it seems to me.  "Most were mild to moderate in intensity" -- OK, that doesn't mean ALL. 

So, some reactions were neither mild nor moderate.  Which leaves -- severe?  I'd like to know how severe, and what happened to them a year or two later... and how many are we talking about?

GetPandemicReady.org - non commerical website with practical ways for families to prepare.


[ Parent ]
I don't have a Lancet subscription
It'll cost me $30 to read the study, so I'm hoping someone else will do so for me and see if the answers are there as to how severe these "few" reactions were.

Susan, I hope you don't think I am hijacking your thread.  I know you are looking for preclinical animal studies, but this topic also seems completely on topic for this part of the discussion.  This is a very important report, published in a highly reputable journal, about a promising adjuvant for use with a pandemic or prepandemic vaccine.  It was tested for safety in a non-elderly population.  And There WERE more side effects in the adjuvanted group than the non-adjuvanted group.  And MOST reactions were mild or moderate, and transient.  not just at the injection site, but in general i.e. systemically. 

GetPandemicReady.org - non commerical website with practical ways for families to prepare.


[ Parent ]
well, not just pre-clinical
anything on safety and adverse reactions.

met or exceeded all US and European criteria for vaccine licensing

The problem with clinical trial data is that if the 7 days of recording symptoms and whatever VAERS (vaccine adverse reaction reporting system) etc are the regulatory standard, the question becomes, are those standards good enough to exclude the kind of issues that we are talking about?  In the absence of animal model toxicology data? 

THAT was the question that I have been asking both officials and industry experts (note my comment at the very end of the top diary in part 1) and I never got a sense that there are better ways of monitoring.  If you look at the 1951 study, 16-18 years after, even looking at mortality data, how sure are we that things were ok for those vaccinated?

Remember that GAO report on how the incidence of adverse reactions were much much higher than that quoted on the product inserts?  Of course I'm not saying we have to aim at 100% safety.  It doesn't exist.  OTOH, if the current regulatory safeguards are not sufficient, then we need to beware of complacency.

If clinical trial results and VAERS have serious limitations, and they do, then preclinical animal data becomes critical to our evaluation of safety.

The point here is, you cannot experiment in humans AND find out exactly what happens to them afterwards.  The most thorough studies, I'm sorry to say, involve injecting animals and then sacrificing them and looking at post-mortem changes, such as these changes in the brain or the observation of clinical diseases such as allergic encephalomyelitis, as well as the numerous studies we have posted on induction of arthritis and lupus-like antibodies and illnesses. 

Another practical problem even if we were to disregard ethics is that humans have longer life-span and correspondingly diseases often take longer to manifest than small animals.  Certain animals are particularly useful for tests for many reasons, one of which includes the speed with which problems manifest.  It's a rather unpleasant discussion, but it IS the reality.



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


[ Parent ]
I'll see if I can find the paper later n/t




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


[ Parent ]
I agree with you about risk vs benefit
and we should deal with both.  OTOH, the arguments for and against using adjuvants are already very complex.  Notice how much I have to write to get to this point!

What I'm trying to do is to discover where exactly is the line with regards to safety, separately from efficacy. 

Because what you will find is every time you try to raise the issue of safety as a standalone question, people will drag you into the efficacy debate and CFR debate and all the emotive reasons why we should be taking more risks.  And the safety issue disappears in the middle of that.  You will have a hard time getting and keeping people's attention.  We see that on this forum as well, whenever we try to present too many sides of the problem all at once.

That's why right now, I just want to lay out clearly and with as little ambiguity as possible, the evidence for safety vs evidence for toxicity.  Irrespective of efficacy.

So if you don't mind, please let's hold those ideas for now, and save them for the next part that I'm going to write, ;-) which is going to cover the totality of the considerations.



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


[ Parent ]
again if you haven't already
and if you don't mind me saying this, check out that link I posted earlier, about denialist tactics.  We need to learn them and beware of getting sucked into them, even in our own arguments.  lol

http://scienceblogs....



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


[ Parent ]
the issues highlighted here
involve more than adjuvant or vaccine safety.  It challenges our trust in people and especially institutions.  For example, how far can we trust even peer-reviewed journal publications?  We have been trained to trust them, and they are by-and-large reliable, but what if on occasion they are misleading or misrepresenting information?

It's not just on vaccines or adjuvants.  How many times have we come across new study results announced with great fanfare, only to find on closer examination that things are not what they seem?  Like this diary for example.

It's sobering, it's dispiriting.  It's shocking even, sometimes, but I'd like to think for those of us who have been examining pandemic issues for a while that we have at least learned that scientists are fallible and can be disingenious or even dishonest, and we need to take due care on important issues.



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


as I said
I'm going to give everyone the benefit of doubt.  I'm continuing to search for data from preclinical or animal studies whether conducted by Chiron or anyone else, that support their claim of extensive toxicological studies showing the MF59 is safe.

They must be somewhere.  I'm still looking.  And I'm not being cynical here, but a real call for help.  If anybody find anything that SUPPORTS safety (we already have a lot against) please either post or email me.  Thanks!



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


[ Parent ]
With The Greatest Respect, I think Concerns are Misguided - Take what you are offered
Witht he greatest respect to everyone here, and of course I am not pointing a finger at anyone, there is a huge body of Malarkey, Horsefeathers, Tripe, Rubbish, Bunkum and Garbage produced on the subject of Vaccines, Vaccination and Adjuvents promoted by people with either vested interests or personal convictions. I would therefore like to respectfully suggest that anyone wanting to quote studies be very careful in understanding the sources of the information they quote and the motives of the people who supplied the information.

I speak from direct experience of running a company that poured over two million dollars over five years into an AIDS vaccine project involving scientists with impeccable reputations from world renowned household name institutions.

If you wish to quote a scientific study, first look at the background of the scientists who have done the work, and who they work for. Is there qualification real of did it come from the on line University of Phoenix? Is the institution they work for credible and do they have an ongoing expertise in the area of science discussed?

Has the author you are quoting published considerable volumes of work in "Nature" or other "Peer Reviewed" scientific publications? "New Scientist" and Readers Digest don't count. Neither does having a book entitled "Vaccines, the hidden dangers" published.

Does the Scientist you wish to quote have a body of work in the field he is speaking on? For example, Professor James Watson yesterday said that Africans are less intelligent people - he is the discoverer of the structure DNA - what does he know about IQ tests? 

Is the Scientist you wish to quote looking for a grant or running short of research funds? This is the source of all those "I've found a cure for cancer" stories that end with "all we need is funding for five more years of research, we are almost there. It is also the source of the old medical science joke "If you are a mouse and you get cancer, we can take very good care of you".

Are you quoting directly from the Scientist or relying on someone else's account of what the scientist said?

It is only after you have ticked all these boxes, that you know you are quoting from a credible source.

Then there are the incredible sources - people who have an axe to grind or money to make, or perhaps simply a religious or other conviction. Usually a simple Google search will flush these people out - look for endless articles in magazines and newspapers about "The Dangers of (name your medicine), and appearances on TV shows, their own website and perhaps their own book or natural healing remedies like colloidal silver.

In my book, if it ain't peer reviewed and published in a reputable scientific journal (bear in mind that there are some scientific journals with low reputations that will publish almost anything for a fee) then it didn't happen.

And to those who say "well they can still be wrong", yes, that is correct, but two heads are better than one, and the liklihood that you are right and they are wrong is vanishingly small unless you are another scientist working in the field.

Sorry for the rant, but I don't have time to patiently go through the stuff thats around on adjuvents and suchlike and track every prairie dog back to its hole.

Thank you for reading this.


actually you are absolutely right
I read through what you wrote 3 times, and I can't fault your logic.

thank you.

Sorry that you don't have time to patiently go through the stuff thats around on adjuvants.  Otherwise we can actually have a conversation with you on the subject.  But thanks anyway for your contribution.  ;-)



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


[ Parent ]
Thank You for Your Coment SusanC
The point I was trying to make is that I think this is an academic debate, which it of course your perfect right to have.

My view is that we will have to take what is presented to us in the way of vaccines in a Pandemic and I would guess that the decisions, at least down here in Australia, on the use of adjuvents, and which adjuvents, is already decided, purchased, and incorporated in the template paperwork for the approval of the vaccine which is already completed.

To put it another way, if they used sulphuric acid as an adjuvent for the only vaccine available in a Pandemic with a 60% CFR, neither I, nor anyone else I can think of, is going to quibble.

But then again Australia has the capability to vaccinate its entire population in less than a year, and I believe that will be what TPTB will do once we know we have an effective vaccine against a pandemic strain.

I'm not sure where our H5N1 vaccine is at the moment, (last I heard was phase III trials) because its development enraged the Indonesians and I think CSL will be keeping it very quiet as will the WHO coordinating Flu Centre at The University of Melbourne.


[ Parent ]
yes, we will have to take what is presented
in a pandemic.  But we are not in a pandemic yet, and the decisions are not made yet. 

Politicians and governments are supposed to be accountable.  Professionals are supposed to be accountable.  I appreciate that you don't want to spend your time going through the details of adjuvant science, and we are no experts here, but neither are the decision makers in government.  They depend on their advisors who in turn look up the science, to advise them what to do.

THAT kind of function is not beyond the capability of a well-informed public.  A lot more complicated policies have been overturned because of the dedication of private citizens to find the truth, to help educate each other, and educate the very busy decision makers who would otherwise be given only one side of the argument.

We may not be experts, but I'd like to think we are perfectly capable of seeing through spurious arguments when we encounter them.  That depends on a good deal of investment of time and effort in self-education.  Which is what we are doing here. 

We sow what we reap, is what I personally believe. 



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


[ Parent ]
Antidote needed.
I am from Canada and so will likely be given GSK's vaccine with its squalene based adjuvant. As I understand it Canada has a 10 year contract with GSK to supply pandemic flu vaccine (I don't know details).

I find this series of threads informative, so please don't stop just for the sake of it. There appears to be systemic efforts in obfuscation or dismissing the adjuvant safety issue as a red herring, or a done deal (in my case in Canada it probably is). However, no one seems to have quoted credible evidence that squalene is safe enough. I also accept that if a pandemic arrives soon enough with a high CFR, there may not be a better choice than a risky adjuvant.
That option of using a risky vaccine I think is already available to regulators without declaring it safe if it isn't.

I think two things need to happen:

1. continued research in safer alternatives

2. research into 'antidotes' for the autoimmune disorders aftermath

On the second point, I understand a long term debilitating disease is very expensive to care for. We have political debates in Ontario whether our public health care system should pay for long term treatment or therapy for kids with autism. My recollection of order of magnitude costs per kid is $80,000 per year. Ontario has said no because the government run health care system can't afford it.

Speaking of CSL in Australia, I checked their website and found out that they are marketing to the U.S. and has just announced approval for their flu vaccine for over 18 year olds.

What is more interesting is that they sell antidote for some immune disorders such as GBS (remember swine flu?). Now should their pandemic vaccine with their proprietary adjuvant cause autoimmune disorders (hypothetically), then would they offer free autoimmune disorder therapy for life?

http://www.cslbehrin...

Perhaps other vaccine companies have similar outfits. Does any one know?

This also brings up an ethical question. Is it OK for a vaccine company to sell a product that causes harm, and then sells a cure afterwards, hypothetically of course?

Thanks in advance. Back to lurking.



You want perspective. I want perspective. Let's talk. We don't have to agree on every thing. If we do, one of us is redundant.


it may be a done deal
but it's not a red herring.

And thanks again for the precautionary principle links from a while ago. I have used them to good effect repeatedly.  ;-)


[ Parent ]
I don't think it's a done deal
It isn't until it is licensed, and there are still lots of technical issues to overcome.

My concern for the near term lies in complacency in tptb, that thinking they have the adjuvant option which they can push out without license in an emergency then they will slacken in their efforts or fall prey to the lobbyists who will give all their arguments in support of their interests.

All I'm doing, as far as I'm concerned, is giving voice to another lobby, that of private informed individuals in general and as parents in particular.

As I always said, we may not succeed, but I sure ain't gonna quit without at least giving us a voice!



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


[ Parent ]
there are no antidotes
to autoimmune diseases.  If they exist, these would not be chronic life-long conditions, would they?

If a company has discovered an antidote to autoimmune disease, they will make so much money out of it they hardly need to create such a convoluted way of making a profit!  There are enough patients with autoimmune conditions right now who will pay very high prices to get that sort of 'antidote'!



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


[ Parent ]
The researchers

If there is any question about the quality of the research or researchers that have performed the immune-related studies on oil emulsion adjuvants, here is information that may shine light on that picture.

The bulk of the research articles about potential safety concerns with oil emulsions have come from research teams in immunology and rheumatology.  They dig into what are the pathways of disease at the molecular and genetic level (often lupus, rheumatoid or inflammatory arthritis, Sjogren's syndrome, etc).  This is complex work.  One of the well-accepted models for inducing the disease in rats & mice, which then allows testing of the molecular and genetic pathways, is injection of pristane and/or squalene.  Looking at just the article abstracts from the researchers, indicates over and over again that pristane, squalene, or mineral oil are just to induce disease.

Three of the primary and long-standing research teams working in this area(there are probably others) are from:
- Karolinska Institute in Sweden
- University of Florida Department of Medicine (Gainesville, FL), Division of Rheumatology and Clinical Immunology
- Medical Inflammation Research Dept. at Lund University
________

Karolinska is a highly respected research, medical, and teaching institution. The Nobel Prize in Physiology/Medicine is announced from Karolinska.  See http://en.wikipedia....
or Karolinska's website http://ki.se/ki/jsp/...

Dr. Johnny Lorentzen at Karolinska leads a research group working with oil-emulsion adjuvants and closely-related immunology since the mid-1990s.  Here is his webpage at the Institute:
http://www.ki.se/med...
And this describes a current research project:
http://kiim.ki.se/re...
_________

Here are a couple of relevant faculty pages from University of Florida Department of Medicine (Gainesville, FL), Division of Rheumatology and Clinical Immunology.  (There are others who are working with this research team).

Westley H. Reeves, M.D.
http://www.medicine....
Dr. Reeves' and associates' research focuses on the mechanisms of autoimmunity in systemic autoimmune diseases such as systemic lupus erythematosus (SLE), polymyositis, and Sjogren's syndrome. They have found that the hydrocarbon oil pristane induces a lupus-like syndrome in normal mice characterized by the production of high levels of antinuclear antibodies specific for SLE as well as immune complex-mediated glomerulonephritis and arthritis. Using cytokine knockout mice, they have found that pristane-induced lupus is strongly dependent on IL-6 and interferon-g . The hypothesis that different manifestations of lupus (clinical and serological) result from the overproduction of these and other cytokines is being investigated in patients from the UF Lupus Research Center and in animal models in order to understand the interrelationships between genetic predisposition and environmental triggers of autoimmune disease.

Dr. Minoru Satoh
http://www.medicine....
Dr. Satoh has been working on the mechanisms of autoantibody production in systemic lupus erythematosus, scleroderma, polymyositis, and other systemic rheumatic diseases using murine model of lupus as well as samples from autoimmune disease clinic. The laboratory has established a new murine model of lupus, in which lupus-related autoantibodies and immune-complex glomerulonephritis are induced in normal strains of mice regardless of their genetic background by the hydrocarbon oil, pristane. Recent studies focus on the role of antigen presenting cells (macrophages, dendritic cells, B-cells) and cytokine abnormalities in pristane-induced lupus compared with genetically-determine murine lupus in NZB/W F1 and MRL mice.
_____________

The Medical Inflammation Research Dept. at Lund University in Sweden is led by Dr. Rikard Holmdahl.  He has worked with immunity and auto-immunity since the 1980s.

An overview of the work is here:
http://www.inflam.lu...

And Dr. Holmdahl's curriculum vitae, with includes 346 articles, is here:
http://www.inflam.lu...
___________

Perhaps this will give a better idea of the complexity of work being performed, along with the qualifications of some of the major researchers.


italics & correction

I seem to have a talent for locking bold, or italic, or ?  into ON mode when I make posts. :-)  Sorry!

And a correction to the last sentence in 2nd paragraph, which read: "Looking at just the article abstracts from the researchers, indicates over and over again that pristane, squalene, or mineral oil are just to induce disease."

But should read:
Looking at just the article abstracts from the researchers, indicates over and over again that pristane, squalene, or mineral oil are used to induce disease.


[ Parent ]
Beehiver, I'm afraid I fail to understand the logic of your Post about Pristane.
With the greatest respect Beehiver, your post about these two papers demonstrates what I am trying to explain. You are taking these papers out of context.

It may well be that the use of Pristane to induce autoimmune diseases is a well known laboratory technique used to trigger autoimmune disease in mice - thats why Pristane is an adjuvent - it challenges the immune system and supposedly amplifies the immune response from the vaccine component.

The first paper is about autoimmune disease in mice, in particular IL-6 and Interferon G - it is NOT about Pristane.

The second paper is about a new mouse model that has been created for research by using Pristane - it is NOT about Pristane itself.

So yes, I would expect that Pristane, Squalene and every other adjuvent is going to trigger an autoimmune disease in mice - if it is given in large enough quantities - thats what it is supposed to do - create an immune system response.

The research teams are NOT experts in the use of adjuvents or the creation of vaccines, they are by their own admission, studying autoimmune disease.

To put it another way, and using exactly the same logic as you have proposed, if I produced two research papers about the treatment of burns, that does NOT mean that I can argue from that that we should therefore eat our food raw in future because fire is too dangerous.


[ Parent ]
well, here's the thing
if there are lots  of papers suggesting that squalene, pristane, and similar adjuvants produce autoimmune disease i mice, I would very much want to see studies showing how they decided it was safe to use such substances in humans.  Aren't animal models an important part of the process of determining toxicity?  How many other pharmaceutical products a year are rejected because they cannot pass animal tests?  Have we applied the same standards with regards to MF59?  I'm not saying we haven't, I just haven't been able to find the relevant studies.

I assume that you are suggesting that these substances are safe at lower doses, as suggested by your following statement:

"So yes, I would expect that Pristane, Squalene and every other adjuvent is going to trigger an autoimmune disease in mice - if it is given in large enough quantities - thats what it is supposed to do - create an immune system response."

Please enlighten us whether the "if it is given in large enough quantities" is based on scientific data or your guesstimate?  Do we HAVE any data on whether at low doses these substances do or do not trigger autoimmune diseases?'

More importantly, do we have any data on whether these substances given in doses equivalent to or higher than what is found in vaccines, are safe, and in 2 different animal models, as is required for preclinical data by the FDA?

"To put it another way, and using exactly the same logic as you have proposed, if I produced two research papers about the treatment of burns, that does NOT mean that I can argue from that that we should therefore eat our food raw in future because fire is too dangerous."

Unfortunately, the relevant points in those papers are not about treatment of autoimmune diseases, they are about the induction or production of autoimmune diseases.  And yes, if you discover that fires cause burns, that I would say that we need to be careful about fires, how exactly to use them and how not to use them.  Just as you would not try to grill a burger by holding it with your fingers, but use tongs or whatever instead, maybe the answer for squalene is that it is safe to put on your face, in your stomach, but not injected into your body!

The burden of proof in vaccine and pharmaceutical products should be, and is, on proving the absence of harm before use, NOT assuming safety until proven otherwise!



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


[ Parent ]
Walrus, you speak like a criminal defense lawyer,
asking for proof beyond a reasonable doubt that these adjuvants are unsafe.

I think the burden of proof should be on the seller of the product. As long as there are red flags, we need to be cautious. What beehiver posted are reasonable red flags that call for more tests before these adjuvants should be approved as 'safe' products.

If adjuvants are so safe, why aren't there arms-length tests conducted? All we see is systemic avoidance of arms-length safety studies. What are vaccine makers afraid of? Why dance around the issue? Why not get a truly arms-length study properly done to clear the name?

Being 'experimental' doesn't mean the adjuvants cannot be used if a pandemic arrives tomorrow. It just means that no misleading assurance should be given to the public, especially when the vaccine makers have already been exempted of liability, which the public should also know.

I would ask you to read the Final Report of the SARS Commission and I quote below:

The Commission therefore recommends:

? That the precautionary principle, which states that action to reduce risk need not await scientific certainty, be expressly adopted as a guiding principle throughout Ontario's health, public health and worker safety systems by way of policy statement, by explicit reference in all relevant operational standards and directions, and by way of inclusion, through preamble, statement of principle, or otherwise, in the Occupational Health and Safety Act, the Health Protection and Promotion Act, and all relevant health statutes and regulations.

? That in any future infectious disease crisis, the precautionary principle guide the development, implementation and monitoring of procedures,
guidelines, processes and systems for the early detection and treatment of possible cases.

? That in any future infectious disease crisis, the precautionary principle guide the development, implementation and monitoring of worker safety procedures, guidelines, processes and systems.


You want perspective. I want perspective. Let's talk. We don't have to agree on every thing. If we do, one of us is redundant.


[ Parent ]
italics off

test



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


[ Parent ]
I think its fixed
For future reference, I used < /i > twice (without the space)



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


[ Parent ]
test




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


"Absolute Proof is impossibe to find!"
With respect SusanC, I think you are asking for an impossible standard of proof when you state:

"The burden of proof in vaccine and pharmaceutical products should be, and is, on proving the absence of harm before use, NOT assuming safety until proven otherwise!"

Safety in use of all medicines is inducted from trials and statistical analysis, and even with the rigorous protocols already in use sometimes they get it wrong.

Safety is inferred "on the balance of probabilities" by testing statistical hypothesis about safety at about the  99.995% level. In other words we are never sure that something is perfectly safe, just 99.995% sure that its safe.

Now these trials typically take about five years, first phase 1 - safety and tolerance i.e the drug won't kill you.

Phase 2 is activity - does the drug, in this case a vaccine, produce a response in people and at what dosage?

Phase 3 - Efficacy - the last and most expensive, involving thousands of people and seeing if the drug actually does something useful. It usually takes at least a year.

At this point the drug is a candidate for approval once all the paperwork is complete and efficacy proved.

Of course, these trials cannot tell if another five years down the track, after literally hundreds of thousands of people have been using it continually for five years, that side effects from long term use appear, and there are plenty of drugs where they have - and the drugs have either been withdrawn or their use changed or restricted. This is what epidemiological studies are all about. Viox, Paracetamol, Viagra, and goodness knows what else, have been shown to have side effects, but they weren't apparent of foreseeable at the time the drugs were approved.

The real answer to you question about the safety of these adjuvents appears to be, as far as I can tell, is that epidemiological studies have been done on these adjuvents and there is no observable demonstrable statistical link between the use of them and any disease in humans at this time.

Furthermore, if you are familiar with the entire system of ethics committees, safety panels, peer review, etc.,it is pretty hard to screw up or falsify data without getting caught.

As for the mice thing, thats why I posted that joke ("If you are a mouse and you get cancer, we can take very good care of you") because there are lots and lots of drugs, vaccines and treatments that work really really well in mice during research but completely fail to do anything useful in humans, as a lot of venture capitalists have found to their sorrow.

P.S. We spent two million with some very clever scientists and collaborated with the worlds most prestigious organisation in the field of vaccination and produced an AIDS vaccine that worked great in a test tube, but nowhere else as far as we could tell;)

But this is beside the point, even if there was a PROVEN 1.0% chance that an adjuvent would cause an autoimmune disease later, are you going to deny your kids vaccination in a pandemic with a 30% attack rate and a 60% CFR?


[ Parent ]
nobody is asking for absolute proof
I'm just asking for proof of what the manufacturers are stating, for example, in the 2 papers I quoted in the top diary.

O'Hagan 2007:

In addition to immunogenicity studies, extensive preclinical toxicology studies have been undertaken with MF59, in combination with a range of different antigens in a number of species.  Prior to evaluation in clinical trials, pivotal toxicological studies were performed with MF59, including repeat-dose toxicity (including local tolerability), genotoxicity, embryo-fetal and developmental toxicity and sensitization evaluations.  No treatment-related safety issues were identified in these studies and findings were generally limited to inflammatory responses at the injection site, consistent with the use of an immunological adjuvant.  MF59 is neither genotoxic nor teratogenic, and does not cause sensitization in highly sensitive preclinical models.

No reference quoted.

Podda 2003:

The adjuvant emulsion alone and/or in combination with different antigens (eg influenza, HSV, HIV and others) has been tested in several toxicological studies aimed at evaluating the safety profile of this compound before commencing clinical trials.  Toxicological studies, performed in rats, rabbits, dogs and other animal species, included acute toxicity studies, repeated-dose toxicity studies, mutagenicity studies and teratology studies.  The overall conclusions from this extensive toxicological evaluation was that MF59, either alone or in combination with different antigens, has an acceptable safety profile and can be safely administered to humans.

NO reference quoted.

I am happy for them to prove me wrong, that there is no need to worry, cos then we will have a happy ending.  But the thing is, the longer I try to find that evidence, the more disturbed I become.

Maybe I'm pretty clueless in finding journal papers.  If someone else finds them, please post them.  I've asked that repeatedly.  I'm open to all evidence, this is an open forum.  So if you find evidence that supports their claims, please let us know.



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


[ Parent ]
A Comment on Sqalene.
here is one article (not a scientific paper)that comments on  the Squalene hoax which is at the basis of these anti vaccination/adjuvent rumblings.

[url]http://www.slate.com...[/url]

We had enough frightened parents here about five years ago that the Federal Minister for Health has made vaccination compulsory for all kids, else there are no federal child benefits paid, and as well, the kid cannot go to pre school or school.


[ Parent ]
this is not about anti-vaccination
or even anti-adjuvant.  I've been very clear about this right from the beginning.  See my disclaimer here.

This is about scrutiny of scientific evidence. 

It's very simple.  The vaccine companies are saying it's safe.  All I'm saying is somebody please help me find the data upon which that assertion is made.  We found the clinical trials.  Fine.  But I am having a real problem finding the preclinical data.

THAT is the issue under discussion.  Not about frightening parents.  Not about anti-vaccination, etc etc.

Let's stay with what is under discussion here please.



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


[ Parent ]
Walrus, Slate reads like National Enquirer, or NPR
so if this is all you could come up with to try to persuade us  that Squalene is safe, while you insist that beehiver's red flags are unfounded since they are not done by what you call 'vaccine experts', then you really haven't convinced me Squalene is safe. As for 'vaccine experts', don't most if not all of them work for vaccine companies directly or indirectly, immediately or in a future career, perhaps to get research funding, and can only tout the company line, or can only research approved issues, safety not being one of them? Last I read, vaccine experts use squalene safety in cosmetics to prove that it is safe in vaccines.

Walrus, you wrote this:

http://www.newfluwik...


In my book, if it ain't peer reviewed and published in a reputable scientific journal (bear in mind that there are some scientific journals with low reputations that will publish almost anything for a fee) then it didn't happen.


You want perspective. I want perspective. Let's talk. We don't have to agree on every thing. If we do, one of us is redundant.


[ Parent ]
There are no third party safety tests. Never mind absolute proof.
Right now, arguments are put forward that since a CFR may be 60%, there is no need to look at safety.

The vaccine makers are avoiding any third party tests for safety. If you don't look for the evidence, you won't find them.

I think we need the third-party tests done to look for auto-immune disorders specifically. Then we know what the risk factors are. Armed with that information, along with the actual CFR during a pandemic, reasonable decisions (not disastrous decisions) can be made based on risk/reward ratio. 


You want perspective. I want perspective. Let's talk. We don't have to agree on every thing. If we do, one of us is redundant.


[ Parent ]
I don't need third party
not right now.  I'm happy to just FIND what the companies have done.  They must have published them somewhere/  I'll have another go at searching over the weekend, but I'll tell you, I've spent a fair amount of time at this, before I wrote this up.  That, the difficulty of finding what they suggested they have done, and the various examples of, what? misrepresentations?  are very disturbing to me. 

Particularly this one, where a claim is made that "Both squalene and squalane can be metabolized and have a good record in toxicological studies." in a paper that is clearly titled as discussing squalene use as adjuvant is referenced to a review of squalene used in cosmetics, and then the same reference is used here in a compendium for adjuvants written by experts from the NIH and DOD for vaccine researchers, and then finally, used as reference for a report by the highest experts in the land, The Institute of Medicine.

Are we still comfortable with taking their word completely for granted?  Without scrutiny and verification?

Who was it who said, "Fool me once, shame on you.  Fool me twice, shame on me."?




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


[ Parent ]
Purely Unscientific
But I read this and realize, finally, what must have happened to a close member of my family many years ago (probably in the 1950s-60s).  This person developed autoimmune disorders -- first lupus (very odd, as the individual is male, and there is NO genetic history in the family for this) and then severe rheumatoid arthritis (also no family history for this, and no "markers" or occurances in later generations).  The progress of the autoimmume problems was, briefly -- started appearing approximately 7 - 10 years after suspected immunization(s), then became progressively worse over the next 30 years.  Has been quite debilitating to this individual.

Why I can't be more specific:  this individual worked in classified research and still is unable to divulge specifics.  Some of this is logical guesswork on my part, tying together time periods, basic knowledge of what he was working with, and where work was done.  I do know that he received vaccines ("experimental", without a doubt), but I cannot know exactly what.  So was it the vaccine, the adjuvant, or what??? Still, the affects are so textbook close to what is reported about squalene, etc. that I feel there is a connection somewhere.

Why does this matter?  Because I think that some of the long-term research studies and facts Susan and others may be seeking are not available due to the classified nature of some of the research and institutions involved.  In other words, it was never published due to the sensitive nature of the research being conducted. 

Just my two cents -- I may be way off base here, but I do know of one instance where the true facts cannot be known or proven due to classified status. 


as an fyi on adjuvants
the current CIDRAP series has adjuvants on as scheduled for Part 4.

http://www.cidrap.um...


and I'm fairly neutral re adjuvants
I don't think they're established yet as either harmful or safe, and the idea of testing for safety as well as efficacy pre-pandemic makes sense to me.

Should a pandemic hit, the odds might shift.


[ Parent ]
Homeless people die after bf vaccine trial
cross posted from July 2 news. http://www.newfluwiki2.com/sho...

Poland - Three Polish doctors and six nurses are facing criminal prosecution after a number of homeless people died following medical trials for a vaccine to the H5N1 bird-flu virus.

The medical staff, from the northern town of Grudziadz, are being investigated over medical trials on as many as 350 homeless and poor people last year, which prosecutors say involved an untried vaccine to the highly-contagious virus.

Authorities claim that the alleged victims received £1-2 to be tested with what they thought was a conventional flu vaccine (Snip)

(Snip) Mieczyslaw Waclawski, told a Polish newspaper that last year, 21 people from his centre died, a figure well above the average of about eight. http://www.telegraph.co.uk/new...





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


another article appears to suggest the vaccine was Fluad
cross posted from July 3 news.  http://www.newfluwiki2.com/sho...

7-2-08 http://www.dziennik.pl/wydarze...

Ten people died

Wednesday, 2 July 2008 03:09

Vaccine for avian flu are tested for the homeless

Luis Romero for each new specyfikiem vaccinating against the flu with the homeless Grudzi?dza dostawali from surgery after 5-10 gold. They did not know, however, that it did not mean to ordinary influenza, unlike siej?c? destruction in the world with avian influenza. Ten people died. Are their death was linked to tests? The shocking information has reached a reporter for "Fact Finding" TVN. The behavior of doctors condemned the minister of health Ewa Kopacz.

Homelessness argue that they do not know that their szczepi? against avian influenza. In April 2007 grudzi?dzka clinic "good practice" to send them your query, which was provided free of charge for the transmission of the vaccine against ordinary flu called VAXIGRIP. For every vaccine they had to get the money, so some zaszczepili even a dozen times. Only now it appears that they received two doses of vaccine FLUAD-H5N1, which has been assessed in this study a vaccine against the dangerous H5N1 influenza virus.

Shortly after the vaccination more than a dozen people died. It is not known whether the test vaccine was the cause of death for the homeless. Many of them are people schorowane and wycie?czone lifestyle for which such experiments can be dangerous. Statistics, however, gives much thought.

"In 2004, four homeless people died from our centre" - admits in an interview with "Faktami" Mieczyslaw Wac?awski, head of St. shelters them. Albert in Grudzi?dz Brother. However, in the years 2005 and 2006 a total of 16 people died, in 2007 - the year in which they tested the vaccine - as many as 21 According to TVN24, victims may be even 350 people. About 150 of them - are homeless. The rest are ordinary citizens, zwabieni zarobkiem.

The management of GP weapons is that all patients signed consent to the vaccination and knew, against which the szczepi?.

Yesterday I received a court to Torun indictment against three doctors and six nurses. As investigations showed, they broke, they not only patients but also the pharmaceutical company, which instructed the vaccination. Prosecutor alleges the forgery of documentation, urging witnesses to make false confessions and certifying Defamation, as well as misappropriation of property. The allegation of endangering the health and life of the homeless but the indictment did not act in November.

Zachowaniem doctors oburzona is the minister of health. "The doctors who conducted these tests should not return to the occupation" - as doctors assessed the accused in the programme "Facts after Faktach" Ewa Kopacz. "In the interest of all doctors is that those who zawinili, suffered a penalty" - she added.



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


[ Parent ]
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