Adjuvants, Autoimmunity, and Vaccine Safety in a Pandemic II - Reasons for Concern

additional thought

on this frequently raised argument that squalene is a naturally-occurring substance, like olive oil or milk or whatever.  And that it's been used with no apparent adverse effects in cosmetics etc.

Well, here's the key.

You can drink milk and ingest olive oil.  You can put lotions on your face.  Does that mean you can inject them?



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

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by: SusanC @ Sun Oct 14, 2007 at 12:44:52 PM CDT

abstracts available

of some of the studies on MF59 and immunogenic effects.

Hat tip to beehiver at pfi!

http://www.singtomeo...


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

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by: SusanC @ Sun Oct 14, 2007 at 15:08:30 PM CDT

to illustrate the lack of reliability of VAERS

or Vaccine Adverse Events Reporting System, in this report ANTHRAX VACCINE GAO's Survey of Guard and Reserve Pilots and Aircrew, they found respondents reported more than double the adverse reactions than published in the product insert. 

More worryingly, 24% of reported symptoms are systemic, about 100 times more than estimated in the product insert. 

We found that most of the reactions were not reported to the military chain of command through official channels (military medical personnel), informal channels (supervisors), or FDA's VAERS....We estimated that about 67 percent of those who experienced side effects or reactions were unaware of VAERS. As a result, about 6 percent of those who experienced a reaction reported it to this system.

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

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by: SusanC @ Sun Oct 14, 2007 at 22:30:10 PM CDT

inject

Hmm, Well  you can inject Botox but you'd better not injest it.  You can breathe air, injest it (makes marvelous, grand burps) but I'm thinking air is not something one wants injected : )

Is there something about the chemical make up of squalene that is of interest here?  Any insights into WHY and HOW squalene may be kicking off an auto immune response?

In layman's terms, pretty please. . . .

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by: Olymom @ Sun Oct 14, 2007 at 23:32:09 PM CDT

it's not just squalene

Is there something about the chemical make up of squalene that is of interest here?  Any insights into WHY and HOW squalene may be kicking off an auto immune response?

The effects seen in animal studies appear to be characteristic of this whole group of substances.  In fact, squalene appears to be the LEAST toxic of them, which is the reason why so far only one product MF59, has made it into any human vaccine.

As to why it kicks off autoimmune response, I can't answer it from the biochemical point of view.  I can only say that researchers have been using this group of substances to boost immune responses for a variety of reasons eg to see if they can stimulate the immune system sufficiently to make some vaccines that are weakly immunogenic work better, AND to induce immune reactions for experimental purposes when they want to study autoimmune responses in animals, which, as you can see, are basically 2 sides of the same coin.

The problem has always been that substances that tend to be immunogenic for vaccine purposes ie stimulate enough immune response to protect against whatever infectious agent you are trying to make into a vaccine, also tend to be most reactogenic ie cause activation of other undesirable processes in the immune system.


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

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by: SusanC @ Mon Oct 15, 2007 at 07:41:45 AM CDT

[ Parent ]

Here's a study

that might answer your question.

Freund's adjuvants: relationship of arthritogenicity and adjuvanticity in rats to vehicle composition.  Available online for free.  The following table can be viewed here except you have to rotate it.

Note the rest of the oils tested, including Johnson's baby oil.  The table on this page shows similar ability of a whole range of regular household oils such as olive oil to cause disease when injected.


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

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by: SusanC @ Mon Oct 15, 2007 at 10:44:58 AM CDT

[ Parent ]

the author of this study Michael Whitehouse

in a telephone interview with Matsumoto (source: Vaccine A, G Matsumoto p 54) said "most oils are dangerous."

Here's the excerpt (NB mine):

In the early 1970s, scientists at UCLA Medical Center, including one of the most respected rheumatologists in the country at the time, Carl M. Pearson, started looking for a less toxic alternative to Freund's (NB adjuvant, the original one tested for these purposes).  They ran a series of experiements with a variety of edible oils on the assumption that because they were "metabolizable" the body could process them safely.  In other words, if you could ingest them, you could inject them.  Intuitively, this premise seems somewhat dubious: your body could metabolize a cheeseburger, for instance, but you couldn't liquefy it in a blender and inject the resulting slurry, and then expect to feel well in the morning.  Pearson's associates, Michael White house and France w. Beck, injected more than a dozen of these metabolizable oils into rats, including castor oil, coconut oil, olive oil, sesame seed oi, cottonseed oil, corn oil, wheat germ oil, safflower oil, cod liver oi, oleomargarine, and the commercial lubricating oil, silicone.  Then these were mixed with heat-killed Mycobacterium tuberculosis, the UCLA groups got results it didn't expect.  All the oils were toxic; they all induced arthritis in rats with varying degrees of severity.  The data changed Whitehouse's views on the safety of metabolizable oils. "To summarize very simply, I think most oils are dangerous." (telephone interview 01/28/02)

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

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by: SusanC @ Mon Oct 15, 2007 at 11:04:43 AM CDT

[ Parent ]

btw please also note

that all supporting information that I'm quoting are from either published peer-reviewed journals or US government official documents eg GAO reports.

Matsumoto's book contains 57 PAGES of notes and references, including 48 articles from peer-reviewed journals on squalene alone.  I have checked through many of these, and the points that he made are borne out by the references that I checked so far. 

This is far from 'internet conspiracy theory'.  Is there enough to convince us that MF59 is DEFINITELY DANGEROUS?  I can't say, but, as I said, we ignore this to our peril.


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

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by: SusanC @ Mon Oct 15, 2007 at 11:11:57 AM CDT

[ Parent ]

you can also

get an idea of the range of topics covered in this piece of investigative journalism, by looking at the index of the book on amazon. http://www.amazon.co...

btw, just in case, I'm not promoting the book, just telling you where to look for the info!


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

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by: SusanC @ Mon Oct 15, 2007 at 11:22:33 AM CDT

[ Parent ]

safety of squalene

Here's an important source that I would suggest you download and save.  A Compendium of Vaccine Adjuvants and Excipients (2 Edition)  The implications of what is said in this authoritative compendium are such that it is worth examining it in a bit more detail.

AUTHORS:
Frederick R.. Vogel, Vaccine and Prevention Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,
Michael F. Powell, Sofinnova, Inc.,  San Francisco, California 94105,
Carl R. Alving, Department of Membrane Biochemistry, Walter Reed Army Institute for Research, Washington, DC 20307.

On page 1:

Since the advent of modern immunology twenty years ago, hundreds of natural and synthetic compounds have been evaluated as vaccine adjuvants. After extensive safety and toxicity testing, many of these novel adjuvants have proven to be acceptable for clinical evaluation. During the same time, investigations into the mechanisms of action of adjuvants have increased. Today, a major goal of adjuvant research is to apply the increased understanding of basic immunobiology to adjuvant development.  Improved understanding of  adjuvant mechanisms of action will provide a basis for the rational selection of adjuvants for use with new vaccines. The purpose of this compendium is to provide a reference for investigators interested in accessing information on the numerous adjuvants available for study, and to foster collaboration between basic and applied vaccine researchers with adjuvant developers. This compendium is extensive but by no means complete. It is our hope that vaccinologists, will find this a useful resource and that it may help to advance adjuvant development as an integral part of a rational vaccine design.

COMMENT: This is a reference written by scientists from the NIH and DOD, for the purpose of helping investigators find information.  It doesn't say whether this is for human vaccines but the institutions involved would suggest that is the intention.

Now, let's look at what it says about MF59 and squalene

on MF59, page 62 of the pdf file

COMPONENT/ADJUVANT NAME:  MF59

OTHER NAME(S): None

STRUCTURE: Squalene/water emulsion. Composition: 43 mg/mL squalene, 2.5 mg/mL polyoxyethylene
sorbitan monooleate (Polysorbate 80), 2.4 mg/mL sorbitan trioleate (Span 85).

[SNIP]

SAFETY/TOXICITY: Minor reactogenicity upon intramuscular injection of humans in combination with HSV or HIV antigens.

on page 105 of the pdf file:

COMPONENT/ADJUVANT NAME:  Squalene

SAFETY: May be harmful by inhalation, ingestion or percutaneous adsorption. Oral LD50 5 g/kg, IV LD50 1.8 g/kg.

Christian, M. S., 1982, Final report on the safety assessment of squalane and squalene. J. Amer. Coll. Toxicol., 1:37-56.

ADJUVANT PROPERTIES: Squalene itself is not an adjuvant. See monograph on MF59.

• Sanchez-Pestador, L., et al., 1988, The effect of adjuvants on the efficacy of a recombinant herpes simplex glycoprotein vaccine, J. Immunol., 141:1720-1727.
  
• Van Nest, G. A., et al, 1992, Advanced adjuvant formulations for use with recombinant subunit vaccines in:
  Vaccines 92, Ed by F. Brown, RM. Chanock, H. S. Ginsberg and R. A. Lerner, Cold Spring Harbor Press, Plainview, NY, pg 57.
  
• Van Nest, G. A. et al., 1995, MF59: Design and evaluation of a safe and potent adjuvant for human vaccines, in: Vaccine Design M. F. Powell and M. J Newman (Eds.) Pharmaceutical Biotechnology Series, Plenum Publishing Corp., New York.

COMMENT: In this instance the only study quoted on safety is based on one study on squalene. 

I am indebted to the most excellent journalistic prowess of Matsumoto, who relentlessly tracked down this hard-to-find paper by Christian in the Journal of American Toxicology, and discovered that ... drum rolls please... this was  based on a review of squalene as a cosmetic agent.

I couldn't find the paper, not unexpectedly, but I did find an online summary here, http://portalmarket....

Cosmetic Ingredient Review
Final Report on the Safety Assessment of Squalane and Squalene

Summary
Squalane and Squalene have been identified as a natural components of human sebum. Both ingredients are used at concentrations ranging from =< 0.1 to >= 50 percent in a variety of cosmetics. Because cosmetics containing Squalane and Squalene are applied to all body surfaces, these compounds may potentially enter the body through the skin, eyes, lungs, mouth, or other routes. Squalene can form peroxides on exposure to air, while Squalane is stable to air and oxygen. Animal studies indicate Squalane is slowly absorbed through the skin, while both compounds are poorly absorbed from the gastrointestinal tract. Squalene is a metabolic precursor of cholesterol and other steroids.
The acute toxicity of these ingredients by all routes in animals is low. At 100 percent concentrations, both compounds are nonirritants to rabbit skin and eyes. According to clinical evidence of formulations containing Squalane, the compound is not a significant skin irritant or sensitizer.
Limited contact sensitization tests indicate that Squalene is not a significant contact allergen or irritant. Reversible depilation is reported from topical application of Squalene to animals, but limited human studies did not show any such effect. No photosensitivity data for the two ingredients were available.

Conclusions
On the basis of the available information presented in this report, The Expert Panel concluded that both Squalane and Squalene are safe as cosmetic ingredients in the present practice of use and concentration.

Second Report of the Cosmetic Ingredient Review Expert Panel Journal of the American College of Toxicology (Special issue) Volume 1 Number 2 1982 Pgs. 37-56

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

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by: SusanC @ Mon Oct 15, 2007 at 16:22:45 PM CDT

this same reference

from the American College of Toxicology, is also quoted in the IOM report 2002
The Anthrax Vaccine: Is It Safe? Does It Work? as the ONLY reference on the safety of squalene.  Check it out here

Final Report. 1982. Final report on the safety assessment of squalane and squalene. Journal of the American College of Toxicology 1(2):37-56.

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

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by: SusanC @ Mon Oct 15, 2007 at 16:30:10 PM CDT

[ Parent ]

also check out this paper

published in 1999 in Methods, a respectable journal, Squalene and Squalane Emulsions as Adjuvants.  The author is Anthony C. Allison, SurroMed Corporation, 1060 East Meadow Circle, Palo Alto, California 94303

When you look up #7 in the reference section, here's what you see.

And then of course, this paper is cited by other researchers, 27 of them according to scopus (from the link, look to the right of the page).

Who was it who said, if a lie is told enough times, it becomes the truth?


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

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by: SusanC @ Mon Oct 15, 2007 at 21:20:46 PM CDT

[ Parent ]

this can easily become a systematic pattern

like the 5 lupus cases in military personnel.  Publish them as post-vaccination lupus, don't mention that they are military, nor whether the military gives the same commercial vaccines as what the general public gets, and the 'case' for post-vaccination lupus becomes established.

Instead of post-adjuvant lupus.....maybe?


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

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by: SusanC @ Mon Oct 15, 2007 at 21:28:22 PM CDT

[ Parent ]

safety of squalene/MF59 as adjuvant

Susan, thank you for writing this diary.

I am trying to read it all and keep up, but frankly I am getting confused. 

The text you cite above (Compendium of Vaccine Adjuvants) seems to be saying that MF59 is safe.  "Minor reactogenicity upon intramuscular injection of humans in combination with HSV or HIV antigens."

That sounds OK, doesn't it?

But I don't see any studies or anything listed backing that up -- are there supposed to be any?

Then for squalene itself (they do say squalene by itself isn't an adjuvant, only MF59 is the adjuvant, do I have that right?) the text says "May be harmful"... and that the one reference for that is from a cosmetics study.

OK, well, that doesn't sound like a lot of information to me on squalene OR MF59, not for a "Compendium".  But -- I looked at this compendium, and can't find a date, or get a sense of how authoritative this text is supposed to be, or anything like that.  Is it recent, do you know?  The latest dates I saw in the references seemed to be 1995 so could it be that the Compendium was published 10 or so years ago?  Maybe that could account for why there doesn't seem to be any studies listed?

Also, a different question:

I did read through the GAO report that came out in 1999 --

Appendix V, page 23 shows a list of NIH investigational new drug studies using adjuvants with squalene. I think there were 23 studies listed from 1991 to 1997.  There were over 1,000 human subjects. 

I assume that a big part of these studies was to investigate the safety of the MF59 adjuvant.  I would really like to see if any of these studies have specifically looked for autoimmune disorder symptoms on people, say two years after the drug was tested on them.  Do you (or anyone here) know where I could find the results of these studies? 

Sorry if these questions seem out of place here.  I am just trying to get a grip on what this adjuvant is and how well researched it is, in terms of safety -- especially long-term (over the course of a year or two, not just the first 2 weeks.)

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

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by: Average Concerned Mom @ Mon Oct 15, 2007 at 21:24:59 PM CDT

[ Parent ]

last question first

How well researched is this?  I'd say very well researched indeed.  Just for example, go to PubMed, here and just do a plain search for "squalene".  It gives you 2431 articles. 

The text you cite above (Compendium of Vaccine Adjuvants) seems to be saying that MF59 is safe.  "Minor reactogenicity upon intramuscular injection of humans in combination with HSV or HIV antigens."

Localized reactions at the injection site is a known and undisputed adverse reaction.  It is noted everywhere, so I don't have a quarrel with that, if there is no reference for it.  The problem that I have is in misrepresenting the systemic safety issues, the most blatant example is the one that I just put up, in the 1999 study by Allison.  BUT the problem is, it's never just one study.  Scientists do not have time to re-invent the wheel.  So if one study has somehow passed through the peer-review process, ie that misrepresentation not being picked up by editors, it becomes possible for everyone else to cite it as the gospel truth.

As I said, the same thing happened with the post-vax lupus paper.

On the 23 studies and 1000 humans.  Well, I can't say about those, cos I have no way of knowing which ones they were, but no, generally, I haven't seen any that specifically looked for autoimmune conditions.  Here's the problem: autoimmune disorders often have non-specific, delayed, and generalized symptoms, so unless you are specifically looking out for associations, you may not find them. 

Plus, the idea that such adjuvant oils can cause autoimmune conditions is/was really known only to the small group of researchers working on this, and many would mostly be working with animals.  Those who deal with human subjects, or clinicians, would not know about this effect at all.

Think about it this way: before the adjuvants (or any substance for that matter) were ever used in humans, scientists didn't know what problems there might be.  Animal models can tell us a lot, but the thing is, if the next lot of people who come along to investigate adjuvants are doing it for commercial reasons, ie with a vested interest in making the product succeed, then it becomes easy to "not find" vague non-specific symptoms.

Consider this: like I said at the very beginning of part I, a large volume of literature on adjuvant oils and autoimmune conditions in animal studies has been available for years, and yet the few studies on MF59 prior to and immediately after the licensing of Fluad did not mention any of that at all!


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

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by: SusanC @ Mon Oct 15, 2007 at 21:51:32 PM CDT

[ Parent ]

finding deceptions as I speak!

or at least misrepresentation.  I found this only just now.

This paper is literally hot off the press, from the Oct 07 issue of Expert Review of Vaccines, O'Hagan, MF59 is a safe and potent vaccine adjuvant that enhances protection against influenza virus infection

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]

The reference quoted for that remark is this paper The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine., with the following from the abstract:

Data from a clinical database of over 10000 elderly subjects immunised with this adjuvanted vaccine (Fluad, Chiron Vaccines, Siena, Italy) demonstrate that, although common postimmunisation reactions are more frequent in recipients of the adjuvanted vaccine, this vaccine is well tolerated, also after re-immunisation in subsequent influenza seasons.

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

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by: SusanC @ Mon Oct 15, 2007 at 22:32:15 PM CDT

[ Parent ]

see, after a while

you begin to doubt that you are not looking at isolated incidents.

Check out this page again, http://home.att.net/... for what the good old Dr Carl Alving said or did not say to the GAO at various points of their attempts to get some answers out of him.  The same Alving who co-authored the Compendium above.  And, just in case anyone is wondering, this is from a report compiled by a Congressman for a Congressional committee.


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

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by: SusanC @ Mon Oct 15, 2007 at 22:46:46 PM CDT

[ Parent ]

here's a breakthrough

trying to track down this paper, the cosmetic ingredient review that was/is being used as reference for safety of MF59 in publications from such august institutions as the IOM (see this comment) and the NIH.

The paper was cited as being published in the 'Journal of the American College of Toxicology'.  Well, the American College of Toxicology no longer publishes their journal in that name, but under International Journal of Toxicology.  

http://www.actox.org/Journal/J...

International Journal of Toxicology (ISSN 1091-5818), formerly the  Journal of the American College of Toxicology, is published bimonthly by Informa Healthcare, 4th Floor, 27 Mortimer Street, London W1T 3JF, UK. Subscription is included with membership in the American College of Toxicology.

And...drum rolls please... here's the paper

http://www.informaworld.com/sm...
Final Report on the Safety Assessment of Squalane and Squalene
DOI: 10.3109/10915818209013146
Publication Frequency: 6 issues per year
Published in: International Journal of Toxicology, Volume 1, Issue 2 1982 , pages 37 - 56

Abstract
Squalane and Squalene have been identified as natural components of human sebum. Both ingredients are used in a variety of cosmetics at concentrations ranging from ?0.1 to gt50%.

Animal studies indicate Squalene is slowly absorbed through the skin, while both compounds are poorly absorbed from the gastrointestinal tract. The acute animal toxicity of these ingredients by all routes is low. Both compounds are nonirritants to rabbit skin and eye at 100% concentration. Formulations containing Squalene indicate it is not a significant human skin irritant or sensitizer. Limited contact sensitization tests indicate Squalene is not a significant contact allergen or irritant.

It is concluded that both Squalane and Squalene are safe as cosmetic ingredients in the present practices of use and concentration.

You can pay $35 to get the paper, if you want...  Note that even the page numbers are the same as the one cited by the IOM report, The Anthrax Vaccine: Is It Safe? Does It Work?.  

This link takes you to page 98 from the IOM report, published by the National Academies Press, showing the reference: http://www.nap.edu/openbook.ph...

Or here's a screenshot of that page

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

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by: SusanC @ Tue May 20, 2008 at 16:05:50 PM CDT

[ Parent ]

By "breakthrough" do you mean that you found it, not that it convinces you?

It is concluded that both Squalane and Squalene are safe as cosmetic ingredients in the present practices of use and concentration.

So it was tested on rabbit's skin and eyes, not an injection either subcutaneously or intramuscularly, not to mention not being mixed with a vaccine.  I guess this means that claims of safety are based on nothing.   :-P

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

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by: Jane @ Tue May 20, 2008 at 18:51:21 PM CDT

[ Parent ]

remember that

in toxicology nothing can ever be proven safe. There's always something else that hasn't been checked. Things can only be shown not to cause harm (and even there, only regarding that which has been tested).  

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by: DemFromCT @ Tue May 20, 2008 at 19:05:44 PM CDT

[ Parent ]

that I found it

I have now paid for a copy of it.  

I guess this means that claims of safety are based on nothing.   :-P

Well, I wouldn't say nothing, cos they must have other studies that we don't know about.  Not citing them doesn't mean they don't exist, just a little baffling, that's all.

But this particular issue is different.  Using a review of squalene as a cosmetic ingredient for topical use (ie spread on our skin not injected into your body) as evidence of safety for a vaccine adjuvant is really out there, you know.  Particularly since it ended up in an IOM report and a compendium for researchers written by some NIH experts.

There is of course the chance that I'm mistaken, that the reference WAS to a different study in a journal by the American College of Toxicology (although their website said they only publish one journal) which happens to have the same name, year, volume, and page numbers.

Think that might be it?


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

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by: SusanC @ Tue May 20, 2008 at 19:10:28 PM CDT

[ Parent ]

recommendations?

Susan,
Is there an adjuvant that you feel might be a good one for use in influenza vaccines?
(Thank you for all that you have put together here.  I am typing minutes for a meeting and it is astonishing how much time putting together even simple stuff can take.)

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by: Olymom @ Mon Oct 15, 2007 at 22:14:55 PM CDT

sorry, I don't.

I don't know enough about adjuvants nor about vaccines to make recommendations.  All I'm doing is a bit of due diligence, to check whether the science is being misrepresented.


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

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by: SusanC @ Mon Oct 15, 2007 at 22:19:07 PM CDT

[ Parent ]

Adjuvant research

Researchers are looking at the use of special adjuvants that stimulate the body's innate immune system (which is different from antibody immunity--also called humoral immunity--and cellular immunity.)

The innate immune system developed over millions of years of evolution and targets certain chemical patterns found on harmful viruses and bacteria. It mounts a response within hours, rather than the days to weeks it may take to mount an antibody response. I don't believe there are any such adjuvants in any licensed vaccines yet (for flu or other diseases), but some vaccines are getting close to clinical trials.

An interesting research article was published recently reporting the use of an innate-immune-system-stimulating adjuvant in conjunction with a regular human flu vaccine, inoculated intranasally in mice (http://www.journals....)

The ordinary annual flu vaccine (inactivated, not live vaccine) was inoculated in mice intranasally with a special adjuvant (proprietary name "Ampligen,") and helped protect the mice from fatal illness when challenged with various H5N1 viruses from 1997, 2004 and 2005. Injecting the vaccine subcutaneously with the same adjuvant was not effective.

If you want to learn more about the innate immune system you might want to look for the January 2005 Scientific American article "Immunity's Early-Warning System."  Or you can buy the whole issue online for $7.95 at http://www.sciam.com...  , which also includes a good article on the 1918 flu virus, written by Jeffrey Taubenberger and others.

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by: big critter @ Tue Oct 16, 2007 at 22:51:57 PM CDT

[ Parent ]

the problem could be

that instead of stimulating only the innate immune system as scientists postulate, what if these molecules are perfectly capable of stimulating the much more specific adaptive immune system as well?

With the adaptive response, the body begins to react specifically towards the 'foreign' substance introduced, in this case the adjuvant, eg by producing antibodies .  If the adjuvant is very similar in structure to molecules that are naturally occurring in our bodies, which is exactly the case with MF59 (remember how they said it's natural and we all have it?) you may well end up with an overstimulated and unregulated response against your own body, ergo autoimmune disease!

The problem as far as I understand, and I wish someone can show me where I'm wrong, is that all these studies on adjuvanted vaccines make the assumption that the adjuvant is not an active substance.  One of the earliest patients that came to the Tulane group was a patient who took part in an NIH vaccine trial where he was given a placebo, and that placebo was MF59!

(btw. A placebo is supposed to be an inert substance, something that will absolutely do nothing to your body, such as saline solution or vitamin pill, in order to remove or counter the psychological effects of being in a study.  Using MF59 as placebo would have caused them to completely miss the side effects due to that adjuvant itself, cos BOTH groups would be getting it.)

I was flabbergasted to learn that, until I did hours and hours of searches and found one paper after another that did exactly that, compare an adjuvanted vaccine against the adjuvant.  Like this one or this one

See, I'm not a researcher, and this is all speculation.  But I'd really like to know what makes them (the big shot learned scientists) think that our bodies are not going to react towards the adjuvant molecules themselves?


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

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by: SusanC @ Wed Oct 17, 2007 at 00:06:12 AM CDT

[ Parent ]

btw using MF59 as placebo

is one way to drastically reduce the reported side effects of your vaccine.  Because in the results, you can honestly say there is no significantly increased adverse reactions compared to placebo. 

Most people, clinicians or scientists or laymen, including myself for all the years of my educated life until my encounter of 'MF59 science', would assume that the researchers have taken due care and made sure that the placebo IS actually a pharmacologically and immunologically inert substance.

I don't know how this all got started, but at some point it became the accepted protocol in vaccine research to accept adjuvants as placebos.  After which no one questions the practice any more.

Which is why we need to do some more detective work, to discover how that line was crossed and what if any evidence exists to support such an assumption. 

See, it's like building a skyscraper.  If there was something wrong with the foundation, it takes a heck of a lot of effort to look for the origin of the problem after the building is finished.

And there is a lot less incentive on all sides to go to so much trouble.  Too many people have too much to lose...

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

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by: SusanC @ Wed Oct 17, 2007 at 07:43:13 AM CDT

[ Parent ]

on the subject of using experimental vaccines

on military personnel, here's a sobering study from way back, a follow-up study on 18,000 army recruits vaccinated with an influenza vaccine adjuvanted with incomplete Freund's adjuvant.

Beebe et al, Long-term mortality follow-up of Army recruits who received adjuvant influenza virus vaccine in 1951-1953. Am J Epidemiol. 1972 Apr;95(4):337-46.

ABSTRACT: Although studies sponsored by the Commission on Influenza, Armed Forces Epidemiological Board have shown that the effectiveness of influenza virus vaccine can be greatly increased by emulsification in light mineral oil, concern as to the safety of oil-adjuvant preparations has prevented their acceptance for routine use pending definitive long-term testing of both emulsifying agent (Arlacel A) and mineral oil (Drakeol) in experimental animals. In a previous 10-year follow-up study based on Salt's 1951-1953 randomized trials of the adjuvant influenza virus vaccine at Ft. Dix, there was no suggestion of a mortality effect attributable to the adjuvant. In the present study the mortality follow-up has been extended through April 1969, 16 to 18 years after vaccination. The vaccine groups have been compared with respect to all diagnoses listed on the death certificates, autopsy protocols, and terminal hospital records. The findings are essentially negative with respect to malignant neoplasms, allergic diseases, and collagen diseases. In addition, there is no evidence that men known to have had the cystlike reaction at the site of the inoculation, or thought to have had allergic reactions mediated by the adjuvant vaccine, have experienced a higher mortality risk.

This study is instructive for many reasons, although the results look benign on the surface:

1. This was carried out before the age of informed consent.  But the mind-boggling thing is the fact that they injected 18,000 people in their prime with substances that were still "pending definitive long-term testing"!

2. The second thing is the number of government agencies involved:
   

   From the Follow-up Agency, Division of Medical Sciences, National Academy of Sciences-National Research Council, and the American Cancer Society. One of a program of medical follow-up studies organized by the NAS-NRC at the request of the Veterans Administration, the Department of Defense, and the Public Health Service, this study was conducted in collaboration with the Commission on Influeza of the Armed Forces Epidemiological board and was supported by Contract DADA17-C-8147 with the U.S. Army Medical Research and Development Command, Washington, D. C. 

   Seems to me everyone had a hand in the game...

3. One thing to note is this only compares mortality data.  Assuming that most recruits were in their late teens or early twenties at the time of vaccination, 16-18 years later, they would still be in their prime.  Chronic illnesses would not show up in this comparison.

4. Although the gross study results appear to suggest nothing untoward happened to those who got vaccinated with the adjuvanted vaccine, on closer look, something strange emerges.

   Although the ascertainment procedures were unbiased with respect to the survey groups, the autopsy percentage was found to be appreciably higher for the adjuvant vaccine (AV) group (48 per cent for AV vs. 36 per cent for C, with p < .01), and the effect of this unexpected and unexplained imbalance is aggravated by a differential in the percentage of autopsy protocols submitted in response to our requests (81 per cent for AV vs. 69 per cent for C, with p = .06).

   In other words, not only were those who got the adjuvanted vaccine more likely to have had an autopsy at death, for some unknown reason, their healthcare providers were also more eager to present the findings to the investigators.  I wonder why?

5. Then there is a small difference in the no of neoplasms (cancers)

   Among the groups of special interest here it is only for neoplasia that there is any suggestion (p = .06) that the AV and C survey groups are not homogeneous. An age-adjustment has almost no effect on this outcome, but division of the material into two four-year periods puts the discrepancy largely into the second, viz.:
   

6. Here is IMO the most worrying finding:

   There is a significant excess of deaths in the AV group coded to ICD #334, other and ill-defined vascular lesions of the central nervous system,.... There is no hint of such heterogeneity in the death certificate diagnoses, and ICD #334 is almost exclusively an autopsy diagnosis.

   This is significant for 2 reasons:
   

   1. ill-defined vascular lesions may be descriptive of what we would now call vasculitic lesions, ie lesions caused by inflammatory changes at the small vessels, which are characteristic of autoimmune responses.  Is there any similarity between that and the rats that were injected with the various oils in this study and developed 'allergic encephalomyelitis'?  I don't know.  But cognitive and neurological symptoms are certainly prominent in Gulf War veterans.

   2. The second important part is ICD #334 is almost exclusively an autopsy diagnosis..  Which means that such problems would not be diagnosed properly, and the veterans may well have been ill but with no proper diagnosis or treatment available.  Was that the reason why more autopsies were ordered when they died?  Or why their docs were more likely to send in their records for the researchers?  It's all speculation, but it's still sobering to consider these implications, IMO.

7. One final piece.  There was "a greater number of diagnoses coded to therapeutic misadventures and late complications of therapeutic procedures in the AV group."

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

   ---

by: SusanC @ Tue Oct 16, 2007 at 23:39:54 PM CDT

that new O'Hagan article

This is my first posting on this forum, so I hope I'm doing everything correctly!

First I'd like to thank Susan and everyone for their dedicated follow-up on this issue.

About that new O'Hagan article you just mentioned, Susan.  The link you provided doesn't show it, but the abstract at PubMed shows he works for Novartis Vaccines & Diagnostics in Siena, Italy.  Of course, that's the company that makes the MF59-adjuvanted FLUAD vaccine.

So in one instance he states that elderly and non-elderly were followed.  But later it says only elderly.  Some of us have asked several times, what condition were the elderly in?  Were they able to clearly communicate?  Did they already have arthritis or other debilitation that may have masked an adjuvant reaction?  Was there a clear reporting protocol set up for doctors to use?

Does the article indicate how long they were followed?  1 week?  3 weeks?  6 months?  At least one animal study showed the adjuvant reaction did not occur until some months post-injection (this was for a different but closely-related adjuvant called pristane).

---

by: beehiver @ Tue Oct 16, 2007 at 23:53:14 PM CDT

well, thanks for bringing that up

I have been looking at this for so long I have taken this completely for granted, and assumed everyone knows that!

You are right, they ALL work for vaccine companies.  If you look at these studies, you will be hard pressed to not find one that is authored by someone from Chiron, initially, and now Novartis.

I'm in the process of writing up part 3.  It is taking a lot of time to research, but I want to put together a coherent set of information that is also scientifically valid.  The issue of elderly and non-elderly subjects will be addressed.

O'Hagan is a big shot in the adjuvant world.  If you look up pubmed, O'hagan DT, it will show you the range of his research interests...


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

---

by: SusanC @ Wed Oct 17, 2007 at 00:11:05 AM CDT

[ Parent ]

short answer

Does the article indicate how long they were followed?  1 week?  3 weeks?  6 months?  At least one animal study showed the adjuvant reaction did not occur until some months post-injection (this was for a different but closely-related adjuvant called pristane).

I have looked at not less than 10 of these clinical trials, and they mostly only assessed the subject's reactions for the 7 days post-vaccination.

But, as I said, more details later.  Give me a day or two, there's just a ton of papers to read.  I haven't done anything else except research this for the past few days, just to give you an idea.


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

---

by: SusanC @ Wed Oct 17, 2007 at 00:13:57 AM CDT

[ Parent ]

thanks, and see if you can outsource some of your research

"Given enough eyeballs, all bugs are shallow".

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

---

by: lugon @ Wed Oct 17, 2007 at 03:27:53 AM CDT

[ Parent ]

also this

So in one instance he states that elderly and non-elderly were followed.  But later it says only elderly.  Some of us have asked several times, what condition were the elderly in?  Were they able to clearly communicate?  Did they already have arthritis or other debilitation that may have masked an adjuvant reaction?  Was there a clear reporting protocol set up for doctors to use?

I don't know what conditions they were in.  The papers didn't say, but there was at least one paper that said the mean age was 71.  And there are a bunch of studies that said the subjects were institutionalized elderly people, like this one, or this one, or this one, which begs a number of questions:

1. whether they were healthy and able to communicate
   
2. whether they were fully capable of making independent decisions such as seeking physician consultation, which was often a required condition for the adverse event to be considered (not necessarily recorded, just considered)
   
3. whether there may be any issues of coercion, for subjects to refrain from complaining about problems
   
4. whether their long term healthcare providers, ie the HCW in the institutions are too closely involved with the trials to report subsequent adverse events.
   
   
   All 'safety concerns' are hypothetical.  If not, they'd be called side effects...
   

   ---

by: SusanC @ Wed Oct 17, 2007 at 00:25:12 AM CDT

[ Parent ]

MF59 adjuvant in children

Well, MF59 MUST be considered quite safe, and actually perfectly harmless, if this study in very young children was done.

http://www.pslgroup....

Novel Vaccine Protects Younger Children Against Influenza Better Than Conventional Vaccine: Presented at ICAAC

By Rossana Coriandoli

CHICAGO, IL -- September 18, 2007 -- A novel adjuvanted vaccine induces significantly higher immune responses in younger children than does the conventional split vaccine, researchers reported here at the 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).

(snip)

A total of 130 children received two doses of the subunit vaccine and 139 received two dose of the split vaccine. The investigators used an HI assay to evaluate immunogenicity before and after each dose; they recorded local and systemic reactions for 7 days post-dose and assessed other adverse reactions throughout the duration of the study.

(snip)

In the group of children aged 6 to 11 months, seroprotection rates for the B strain evaluated after two doses were 70% with the MF59 vaccine and 0 with the split vaccine (P <.001); in children aged 12 to 23 months seroprotection rates for the B strain were 87% and 23% in favor of the MF59 vaccine (P <.001).

(snip)

The researchers concluded that in this group of children aged 6 months to 3 years, the adjuvanted influenza vaccine MF59 induced a significantly higher immune response compared with the split vaccine for all three strains evaluated.

These findings are of particular relevance for younger infants aged 6 to 24 months and for the influenza B strain, in which the conventional vaccine has failed to show adequate immune responses, the researchers noted."

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

---

by: Average Concerned Mom @ Wed Oct 17, 2007 at 06:25:40 AM CDT

here's the problem with that kind of logic

Well, MF59 MUST be considered quite safe, and actually perfectly harmless, if this study in very young children was done.

In science (also in real life) nobody has the time nor the ability to verify all the information they are given.  They have to rely to some extent on the integrity of the people giving them the info, and on the effectiveness of the institution to police the system.

Problems arise when some people either through negligence or malice, put in incorrect or misleading information, as I have cited in the examples given.  This may be picked up eg by journal editors, and corrected.  Or it may be missed, through oversight, negligence, incompetence, laziness, or collusion.

Whatever the case, as endusers of the information, we are at the mercy of the system. 

It doesn't mean that we have to verify every fact before we can make choices about anything in our lives.  We will have no life if we do that for everything!  But it does mean developing the ability to know when you are dealing with verified truth or when you are taking someone's word for it.  It's called CAVEAT EMPTOR!


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

---

by: SusanC @ Wed Oct 17, 2007 at 07:04:28 AM CDT

[ Parent ]

Studies on young children have rigorous safeguards

Susan -- you know I am an elementary school teacher trained at-home mom.  And I know very little about clinical trials.

I AM interested in finding out what safety data there is about  MF59.  Especially for kids.

I found that study I posted.  OK, it MUST have been approved by an "ethics or safety" group as being QUITE safe.  NO ONE experiments on healthy, 6 month to 24 month old children unless they are absolutely sure that the substances they are using have been well tested with a long history of low risk, low side effects.

The study itself seemed to be focusing on the effectiveness of MF59 -- not at all on its long term safety.

So, there MUST be -- somewhere -- studies -- maybe just a few -- testing the long-term safety of MF59 esp. in children and showing few harmful effects.

Given the fact that MF59 has been shown in animal studies to produce auutoimmune problems, the long term studies on children would of course test for those symptoms.

It is simply crazy to believe that anyone would inject a drug into A 6 MONTH OLD CHILD (who was not desperately ill) without having those long-term studies to back them up.

I am going to keep looking for these long term safety studies, or the studies that show MF50 is "inert" enough to be used as a placebo, because I just know they are out there.

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

---

by: Average Concerned Mom @ Wed Oct 17, 2007 at 08:03:07 AM CDT

[ Parent ]

well good luck ;-)

It is simply crazy to believe that anyone would inject a drug into A 6 MONTH OLD CHILD (who was not desperately ill) without having those long-term studies to back them up.

I am going to keep looking for these long term safety studies, or the studies that show MF50 is "inert" enough to be used as a placebo, because I just know they are out there.

I'm looking for them too.

Tell you what though.  I'm not even looking for long term studies, say follow-up for 1 year or more, nor studies in young children, for MF59.  You know why?  Cos I haven't found even short term studies.  Nor animal studies. 

Like you said, they must be somewhere.  I just haven't found them.  I've traced the bibliography of authoritative articles like the O'Hagan paper above.  I'm still looking.

The only long-term study quoted by O'Hagan to demonstrate the safety of such oil adjuvants is one paper published on the 1951 trials.  Page W. Long-term follow-up of army recruits immunized with Freund's incomplete adjuvanted vaccine.  Vaccine Research 2, 141-149 (1993), which I can't find.  It's not even on pubmed.  I found an abstract of it, in a round-about way.

Abstract
The oncogenicity of Freund's incomplete adjuvant was explored by ascertaining the mortality experience of 18,000 men who had been immunized with a mineral oil?adjuvanted influenza vaccine during their military recruit training in 1951?1952, compared with 22,000 men given formalinized saline. The death experience was obtained from the records of the Veterans Administration. An earlier study, until May 1, 1969, 16 to 18 years postinjection, found no significant differences in cancer mortality in the two groups. This study, over 35 years since injection, found 13,545 survivors with known birth dates in the adjuvant vaccine (AV) group and 18,294 in the control (C) group. Between May 1, 1969 and December 31, 1987, 10.2% of the AV group and 10.8% of the C group had died; 2.2% of the AV group and 2.4% of the C group had died of cancer. Standard mortality ratios (SMRs) for the AV group were equal to or lower than those for the C group except for respiratory tract neoplasms and leukemias; the differences were not statistically significant. In contrast, mortality was elevated in the C group over the AV group in five disease categories; the difference was statistically significant in the category of cancer of the digestive tract (p = 0.01). Comparison of the death experience over the total period from January 1, 1952 to December 31, 1987 yielded similar results.

As you can see, this study only compared mortality, not morbidity, and only for cancers, and not other illnesses such as autoimmune disorders.


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

---

by: SusanC @ Wed Oct 17, 2007 at 08:37:48 AM CDT

[ Parent ]

again this is typical

they recorded local and systemic reactions for 7 days post-dose and assessed other adverse reactions throughout the duration of the study.

of such studies.  Unless we can read the published data AND be able to determine what and how exactly they assessed for these other adverse reactions, we can't be sure that the right amount of due diligence has been carried out.  Particularly for unusual adverse effects that are not typical of other vaccine reactions, such as autoimmune disorders.

Remember adjuvants is a whole new group of chemicals that we are injecting into people and almost no one has any clinical experience with them.  Apart from experimental data, there has not been widespread knowledge of what would in the early days of such research be called 'human adjuvant disease'.  Unless researchers are specifically looking out for them, and there IS some disincentive to look for trouble if you are paid by the vaccine company, then these problems will not be picked up.

Suppose then a child becomes ill after such vaccinations, and he is taken to see a GP.  Most doctors have no understanding of these issues at all, and is likely in most instances to fail to make the connection between the illness and the vaccination!

Like I said, we can't go round being paranoid all the time.  OTOH, if some entity, be it an institution or an industry, has demonstrated a great deal of lack of respect or care for other people's wellbeing, then personally I'm reluctant to take them on faith. 

We as parents are the ultimate guardians for our children's safety.  How far we want to surrender our


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

---

by: SusanC @ Wed Oct 17, 2007 at 07:17:44 AM CDT

[ Parent ]

this is the also why

we cannot just rely on clinical trial data to reassure us about safety.  We need all the preclinical stuff, the animal trials, as well.

The important thing is researchers can do a lot of stuff with animals than with humans, including doing thorough autopsies of animals tested under different conditions.  Animal lovers may find this distasteful but the reality is there are lots of different types of information that you can only find with animal trials.


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

---

by: SusanC @ Wed Oct 17, 2007 at 07:21:08 AM CDT

[ Parent ]

missing sentence ;-)

We as parents are the ultimate guardians for our children's safety.  How far we want to surrender our autonomy and our right to scrutinize tptb is a personal choice that each of us has to decide for ourselves.


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

---

by: SusanC @ Wed Oct 17, 2007 at 07:25:51 AM CDT

[ Parent ]

"mineral oil" definitions

But, as I said, more details later.  Give me a day or two, there's just a ton of papers to read.  I haven't done anything else except research this for the past few days, just to give you an idea.

Oh yes!  I spent two days straight over the past weekend looking at papers!  It's quite a project to sort through all of this.

When I was doing so, question arose in my mind exactly what adjuvant oil substances were been tested in what studies.  Some said "mineral oil", others said "squalene", "pristane", "IFA" (incomplete Freund's adjuvant), or "n-hexadecane".  It seemed impossible to compare apples with apples from one study to another!  It's not until this morning that I was able to sort this out.  Here are some basic definitions and relationships that are important to this discussion.  They are quite necessary to understanding what might be happening.

"Mineral oil" is a petroleum-derived hydrocarbon.  Refined versions of it, especially "white mineral oil" are used in pharmaceuticals (yes, in the IFA adjuvant) and cosmetics.

I had previously thought that squalene was mainly sourced from shark liver oil.  A closely related oil called pristane is also in shark liver oil.  There is likely not enough sustainable shark liver oil available to provide the quantities of squalene necessary for vaccine adjuvant production.  Thus, it's likely refined from white mineral oil.  White mineral probably can no longer be used in a widespread manner as an adjuvant, because it contains pristane, a much more dangerous oil component.  More info will be posted about that shortly.

Now when looking at the abstracts or full text of these studies, here is what you'll need to know - the proof of what components are in what substances.

at http://toxsci.oxford... :

Toxicological Sciences 78, 222-228 (2004)
Distinctive Patterns of Autoimmune Response Induced by Different Types of Mineral Oil
Yoshiki Kuroda, et al

snipped from the abstract:
Although mineral oils are generally considered nontoxic and have a long history of use in humans, the mineral oil Bayol F (incomplete Freund's adjuvant, IFA) and certain mineral oil components (squalene and n-hexadecane) induce lupus-related anti-nRNP/Sm or -Su autoantibodies in nonautoimmune mice...Hydrocarbons were analyzed by gas chromatography/mass spectrometry...Pristane and n-hexadecane were found in IFA.

Next reference:  when doing a google search using the term: mineral oil pristane component , this result came up, but the full article (Autoimmunity induced by adjuvant hydrocarbon oil components of vaccine by Kuroda, et al) is not accessible as free text.

Biomedecine & Pharmacotherapy : Autoimmunity induced by adjuvant ...Autoimmunity induced by adjuvant hydrocarbon oil components of vaccine ... Pristane is derived from mineral oil, a byproduct of petroleum distillation. ...
linkinghub.elsevier.com/retrieve/pii/S0753332204000642

We now have proof that mineral oil does contain the following components:  squalene, n-hexadecane, and pristane.  So now, when an author refers to a "mineral oil adjuvant", we know it will contains those components.

Here is MSDS information on U.S. Pharmaceutical grades of Drakeol mineral oil, from a company that sells it:

http://www.penreco.c...
or from
http://www.whoi.edu/...

Chemical Family: Petroleum Hydrocarbon
[snip]

11. TOXICOLOGICAL INFORMATION

No definitive information available on carcinogenicity, mutagenicity, target organs or developmental toxicity.

And from another MSDS sheet on Drakeol mineral oil (yup, they are not all the same!):

http://www.ptichem.c...

"Exposure to a large single dose, or repeated smaller doses of mineral oil by inhalation, aspiration or ingestion leading to aspiration can lead to lipid pneumonia or lipid granuloma. These are low-grade, chronic, localized tissue reactions which are not fatal. Shortness of breath and cough are the most common symptoms."

I will follow this up with some results from an animal study that may help answer a few more questions about route of administration.

---

Tried this: < /b >

---

by: Bronco Bill @ Wed Oct 17, 2007 at 12:16:15 PM CDT

[ Parent ]

Yeah baby!!

That worked!!  :-))

---

by: Bronco Bill @ Wed Oct 17, 2007 at 12:16:53 PM CDT

[ Parent ]

The cosmetic & mineral oil study

http://www.pubmedcen...  or
http://www.pubmedcen...

Common commercial cosmetic products induce arthritis in the DA rat.

This study tested some commercial cosmetic products on animals, that contain an adjuvantal mineral oil of some type or another.  A surprising result is that one medicinal-grade white mineral oil ("Kaydol") induced "a very aggressive arthritis" in 90% of the rats when administered as an intradermal injection; but there was no such reaction when it was fed orally.  It also induced it in rats genetically prone to arthritis (Dark Agouti or DA rats), but not in Lewis rats - which shows a genetic tendency in this matter.

Snips from the article text:

Two different mineral oils dassified as medicinal white oil for food, pharmaceutical,and cosmetic use, Medicway M 68 (Statoil, Stavanger, Norway) and Kaydol(Witco Corporation, Greenwich, CT), were also studied.

One of the medicinal mineral oils, Kaydol, which is permitted as a food additive and which exhibited arthritogenicity in DA rats when injected intradermally, was also investigated for its potential arthritogenicity after oral sound feeding to DA rats. However, no arthritic reaction was detected in these animals during an observation period of 7 months

There is consequently a need for wellperformed studies, which include genetic techniques for identification of subgroups of potentially arthritis-susceptible individuals, to study the possibility that some commercial cosmetic products may have a capacity to contribute to arthritis induction in humans in some individuals and in certain situations. In the meantime, further mechanistic and genetic studies in the experimental systems may be able to define the pathophysiological mechanisms of this remarkable capacity of both nonimmunogenic adjuvant oils and several commercial products containing such oils to induce a polyarthritis with many similarities to inflammatory joint disease in humans.

---

by: beehiver @ Wed Oct 17, 2007 at 10:32:02 AM CDT

Pristane / lupus / hemorrhagic pulmonary capillaritis

Pristane is one of the component oils in shark liver oil and mineral oil.  While it is (hopefully) not appearing in vaccine adjuvants, it is closely related to squalene, and induces similar reactions at the molecular level as squalene.  Here is an alarming result from a pristane study.  It is also hot off the press.  And it is out of Mayo Clininc in Rochester, MN.  In the abstract please also note the cytokines that were induced.  Not something we would want to see happening in tandem with H5N1 infection, that's for sure.

Rheumatology (Oxford). 2007 Sep;46(9):1405-10

Characterization of haemorrhagic pulmonary capillaritis: another manifestation of Pristane-induced lupus.

Chowdhary VR, Grande JP, Luthra HS, David CS.
Division of Rheumatology, Department of Medicine, Mayo Clinic College of Medicine, 200, 1st SW Rochester, MN 55905, USA.

OBJECTIVES: Pristane-induced lupus is a well-established model of murine lupus. Mice injected with Pristane develop lupus-specific autoantibodies and glomerulonephritis. A chance observation led us to identify and characterize haemorrhagic pulmonary capillaritis in Pristane-injected mice. METHODS: Eight-week-old C57Bl/10 (B10, H-2(b)) mice received a single intraperitoneal injection of 0.5 ml of Pristane. Control mice received phosphate-buffered saline (PBS) injection. Mice were bled at 2 weeks after Pristane injection and monthly thereafter for serology and for antinuclear antibody (ANA). To characterize pulmonary disease, bronchoalveolar lavage (BAL) was carried out for total and differential cell count. Cytokines levels were checked for IL-2, IL-4, TNF-alpha, IFN-gamma, IL-6 and IL-10. Lungs were examined by histopathology and electron microscopy. RESULTS: All mice injected with Pristane developed a pulmonary capillaritis with perivascular infiltration with macrophages, neutrophils, lymphocytes and eosinophils. In addition, alveoli showed macrophage and neutrophil infiltration. The degree of perivascular and alveolar inflammation was moderate to severe. BAL was inflammatory with cell composition of macrophages, neutrophils, lymphocyte and eosinophils. There was evidence of endothelial injury on electron microscopy but no evidence of immune complex deposition. IL-6 and IL-10 were increased in BAL but levels of TNF-alpha, IFN-gamma, IL-2 and IL-4 were not. Anti-neutrophil cytoplasm antibody (ANCA) was negative. Kidneys demonstrated an increase in mesangial matrix and cellularity compatible with WHO Class II lupus lesion. There were immune complexes and complement deposition in the kidney. There were oil granulomas in peritoneum, spleen and liver but no evidence of vasculitis in these organs was seen. CONCLUSION: The relative ease and high penetrability of lesion makes it an attractive model to study pulmonary vasculitis.

PMID: 17576695
_____________________

Comment:  Of all the studies I have read on this subject matter, this one alarmed me more than any.

---

by: beehiver @ Wed Oct 17, 2007 at 10:54:23 AM CDT

let me see if I can fix this

if this doesn't work, and if you can save the posts somewhere, I can delete them so you can post again, before other people start adding comments.  This information is very important, but all this bolded text makes it very hard to read! '



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

---

by: SusanC @ Wed Oct 17, 2007 at 11:04:42 AM CDT

[ Parent ]

looks like the rest of the thread is working now

do you want to re-post this below?  I can delete after you're all done.


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

---

by: SusanC @ Wed Oct 17, 2007 at 11:05:50 AM CDT

[ Parent ]

bolding

Thanks Susan, yes I will repost.  The highlighting of certain text really helps the reading process.

---

by: beehiver @ Wed Oct 17, 2007 at 11:12:47 AM CDT

[ Parent ]

it's ok, i just deleted the last one

I think it's best to just leave it.  thanks!!


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

---

by: SusanC @ Wed Oct 17, 2007 at 11:43:59 AM CDT

[ Parent ]

bolding, again

Susan, if you or the other moderators have html copies of this morning's posts and can get past the bolding problem, I authorize them to be reposted from one of you.  Thanks.  I need to get to work.

---

by: beehiver @ Wed Oct 17, 2007 at 11:49:49 AM CDT

[ Parent ]

it's fine now,

don't worry about it.  and thank you.


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

---

by: SusanC @ Wed Oct 17, 2007 at 12:04:08 PM CDT

[ Parent ]

Pristane - manufacturer's information

http://www.sigmaaldr...

Descriptions

Biochem/physiol Actions 
A hydrocarbon oil adjuvant widely used to induce tumorgenesis in mice and arthritis and lupus nephritis in rats.

http://www.sigmaaldr...

Pristane

Prod. No. P2870  Minimum 98%

Adjuvant for inducing human-type diseases in rodent models
and for antibody production

Pristane (2,6,10,14-Tetramethylpentadecane) is an isoprenoid alkane that was initially isolated from shark liver oil [1]. The availability of natural source pristane became limited due to the protection of several shark species. Sigma is now synthesizing pristane in our production facilities, making us one of the few companies to continue to provide this product for research.

Pristane is used to induce plasmacytomas in mice as a model of human multiple myeloma [2,3].

Pristane induces a disease similar to lupus nephratis in mice, making it useful for autoimmune studies [4-6].

Pristane induces arthritis in rats for the study of rheumatoid arthritis [7,8].

These models have been used to investigate the role of c-myc chromosomal translocation [9,10], the role of growth factors including interleukin-6 (IL-6) [11-14], TFN-a [13], interleukin-12 (IL-12) [15], and g-interferon (IFNg) [16-18] in disease state signaling pathways, and the connection of prostaglandins and chronic inflammation [13,19] to cancer, arthritis, and lupus.

Pristane is used to precondition the peritoneal cavity of mice, prior to the induction of ascites fluid with myeloma cells for production of monoclonal antibodies [20-24].

Sigma is pleased to make this important compound available to cancer researchers.

---

by: beehiver @ Wed Oct 17, 2007 at 11:01:20 AM CDT

CNS damage after squalene injection

The experimental squalene encephaloneuropathy in the rat. Exp Toxicol Pathol. 1999 Jan;51(1):75-80.

Gajkowska B, Smialek M, Ostrowski RP, Piotrowski P, Frontczak-Baniewicz M.

The Laboratory of the Ultrastructure of the Nervous System, Medical Research Center, Polish Academy of Sciences, Warsaw.

ABSTRACT:
Accumulation of squalene in the CNS is observed after administration of tellurium and squalene has been proposed to be a mediator of tellurium encephaloneuropathy. The aim of this study was to investigate the effects of squalene on the central and peripheral nervous systems in rat at the ultrastructural level. Squalene was administered at a dose of 20 g/kg body weight, once daily for 4 days, and the animals were sacrificed 7 days and 30 days after the initiation of the experiment. After 7 days a mild swelling of mitochondria and dilation of the Golgi complex cisterns in few neurons in the cerebral cortex and hippocampus were observed. The swelling of astrocytes and their processes was also seen. Some myelin sheaths in the cerebral white matter were disintegrated. In the peripheral nervous system (the sciatic nerve), a damage of the Schwann cells, a destruction of the myelin sheaths, and lipid-like deposits between myelin lamellae causing a secondary compression of axons were present. Squalene administration caused a stimulation of fibroblast to synthesize collagen and an activation of macrophages in the perineurium. After 30 days, the lipid-like material was present in some neurons as well as in the myelin sheaths in the central nervous system. Endothelial cells were hypertrophic and a few demonstrated features of apoptosis. Endothelial cell hypertrophy caused a narrowing of vessel lumen associated with an aggregation of blood morphological elements. Disturbances in myelination and swelling of astrocytic processes persisted in the central nervous system. In the peripheral nervous system, lipid-like deposits were localized in some fibroblasts and extracellularly between the collagen fibers in the perineurium. In conclusion, our electron microscopic studies indicate that squalene produces characteristic pathological changes both in the central and peripheral nervous systems. However, these alterations differ in some aspects (changes in endothelia, accumulation of lipid-like material) from the known features of tellurium encephaloneuropathy.


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

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by: SusanC @ Wed Oct 17, 2007 at 12:45:26 PM CDT

one important point about all these studies

for me, is that there is ample evidence from animal data that squalene or MF59 is NOT a pharmacologically inactive substance.  I don't understand the logic of using this as a placebo in vaccine trials, for example.


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

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by: SusanC @ Wed Oct 17, 2007 at 13:02:43 PM CDT

[ Parent ]

some of the dilemmas for the vaccine industry

are captured in the abstract of this review.

  Edelman R, Tacket CO., Adjuvants. Int Rev Immunol. 1990;7(1):51-66.

Department of Medicine, University of Maryland School of Medicine, Baltimore 21201.

In summary, HIV vaccine studies described have generally not been designed to measure the effect of the adjuvant or to make comparisons between adjuvants. In only one study was a head-to-head comparison made between HIV antigen alone and antigen formulated with different adjuvants. We hope that future experiments with HIV/SIV vaccine candidates will be designed to determine the relative potency and safety of different adjuvants. Unfortunately, such experiments tend to be tedious and expensive. The design of these studies will need to address a number of variables which influence the response to the vaccine, including route and schedule of immunization, genotype and species of the vaccinated subject, and intrinsic characteristics of the antigen. In addition, the immunologic endpoints should include measurement of both B and T cell function. The carrier/adjuvant/antigen formulation should be hand-tailored and then standardized so that it is manufactured reproducibly without producing different biological effects between lots, and the vaccine formulation should be stable on storage and shipping. Finally, we obviously need to identify and test the protective antigen or antigens. The best adjuvant will never correct the choice of the wrong epitope.

PMID: 2132879 [PubMed - indexed for MEDLINE]

 


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

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by: SusanC @ Wed Oct 17, 2007 at 13:06:55 PM CDT