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Vaccine Safety Conference: Evaluating the Science January 3-9 2010 Tryall Club West Indies Jamaica

Vaccine Safety Conference: Evaluating the Science January 3-9 2010 Tryall Club West Indies Jamaica
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A Mechanism of Toxicity of Aluminium-based Adjuvants?

Consumer Summary | by Chris Exley

Christopher Exley PhD, The Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire ST5 5BG, UK. Email: c.exley@chem.keele.ac.uk

Here in a case is made for a role for aluminium (Al) in adverse-effects related to vaccination. In essence a general mechanism of vaccine-induced injury related to human exposure to Al. The ubiquitous nature of Al both as a constituent of the Earth’s crust and in everyday life is highlighted against the lack of essentiality of this metal for any living form including humans. Indeed some mention is made of the known toxicity of Al including Al-related disease in humans. It is recognised that Al has been used as an adjuvant in vaccines for almost a century and, regardless of its potency in this application, it is acknowledged that we still do not understand the mechanism whereby Al acts as an adjuvant. Possible mechanisms related to the known biological activity are discussed and the question is raised if such same mechanisms might explain adverse reactions to Al adjuvants in vaccinations. Indeed the wider question is asked if Al anywhere in the body and not just that administered as an adjuvant could also produce similar biological reactivity. Many examples are given as to how humans are exposed to Al in their everyday lives and how this will result in a body burden of Al. We will all accumulate Al in our bodies with time and how much we accumulate and where it is accumulated could have significant consequences for any reaction to vaccination. The suggestion is made that significant body stores of Al, those which may approach or exceed a critical threshold, may become biologically active following an event such as single or multiple vaccinations including (or not) Al adjuvants. Significant changes in the biological activity of body stores of Al could result in symptoms of known Al intoxication in humans many of which share much in common with those suffering from vaccine-related disorders. Does vaccination remind the body of previous and ongoing exposures to Al causing the body to react to current and future body stores of this non-essential and largely inimical metal? If such a suggestion is in the future demonstrated by experiment then these effects could be easily minimized by including a silicon-rich mineral water in the diet. Silicon is the natural antagonist to Al and we have demonstrated its efficacy in removing Al from the body. If Al is involved directly or indirectly in vaccine-related disease then such effects should be countered by silicon-rich mineral water therapy. This is an eminently testable hypothesis.

Slide Summary | by Chris Exley

Slide 1

A Mechanism of Toxicity of Aluminium-based Adjuvants?

Slide 2

One purpose of this presentation is to outline a possible mechanism whereby exposure to Al not only in adjuvants in vaccination but also in our everyday lives might predispose us to possible vaccine-related disease.

Slide 3

I am a biologist by first degree and my research goal is to understand the myriad ways that Al impacts upon life and life processes.

Slide 4

The biogeochemical cycle of Al describes why it is important to research the biological activity of Al (Exley, 2003). Though non-essential, the arrival of the ‘Aluminium Age’ at the end of the 19th Century, heralded an era of biological availability for Al. The question is how will living things respond to a burgeoning exposure to biologically-reactive Al?

Slide 5

Darwin’s ‘natural selection’ is as appropriate to the evolution of biochemistry as it is to the evolution of species.

Slide 6

This ‘Darwin-like’ biochemical tree of life asserts that it is only very recently that Al has played an active role in biochemical evolution (Exley, 2009). Could it be that present evidence of Al playing an active role in such includes a number of chronic diseases of unknown aetiology?

Slide 7

So what does Al have to do with vaccination? Clearly Jenner and all after him have provided a possible solution to many human diseases. However, what happens when the mechanism of action of such a solution is only incompletely understood?

Slide 8

Probably 80% of all vaccinations given to all ages use an Al-based adjuvant without the mechanism of action of such adjuvants being understood and the safety of such products ever being tested (Exley et al., 2010).

Slide 9

Breaking down the individual components which consititute the potential adjuvant activity of Al demonstrates the potential complexity beginning with the biological chemistry at the site of injection.

Slide 10

Here the potentially wide number of cell types which could respond to adjuvant activity are recognised in their generic groups.

Slide 11

There are numerous ways in which a cell can then be influenced by adjuvant activity including both extracellular and intracellular signalling mechanisms.

Slide 12

There are similarly both direct and indirect ways that adjuvant activity actually stimulates immunity. In this paper I contend that a lack of appreciation of the bioinorganic chemistry of Al means that we are far from identifying the mechanism of action and potential toxicity of Al-based adjuvants (Exley et al., 2010).

Slide 13

So what are the potential mechanisms of action of Al-based adjuvants?

Slide 14

While it has been suggested that endocytosis of Al adjuvant could lead to disruption of the internalised endosome the mechanism whereby such might take place is not likely to be similar to that of uric acid crystals or silica (Marrack et al., 2009). While there is clearly the potential for cytotoxicity of Al-based adjuvant both at and far from the injection site the mechanism of cell death remains to be elucidated.

Slide 15

The adjuvant activity of Al may not actually require cell death.

Slide 16

There are a number of recent studies which implicate reactive oxygen and nitrogen species (ROS / RNS) in adjuvant activity. Since Al is a powerful pro-oxidant (Exley, 2004) and most vaccine preparations are contaminated with significant amounts of iron then Al adjuvants are likely to significantly stimulate the signalling and biological activities of these species in immunopotentiation.

Slide 17

ATP is the most important extracellular signalling molecule in the body and we are beginning to understand its role in the immune response, having both stimulatory and inhibitory effects (Di Virgilio et al., 2009). Since Al is known to potentiate the signalling activity of ATP (Korchazhkina et al., 1998) it is likely that Al adjuvants also contribute towards such mechanisms.

Slide 18

Perhaps most unusual are the recent observations that Al salts can ‘sensitise’ the body to the presence of other substances which might not normally elicit any response (Palli-Schöll et al., 2010). Effectively this suggests that the persistence of Al in any particular environment could sensitise the immune system to other usually non-immune-reactive susbstances co-localised with the Al.

Slide 19

The observation that Al can be both adjuvant and antigen appears to have been ignored (Levy et al., 1998). The possibility that Al added as an adjuvant as well as other sources and sinks of Al could induce the formation of antibodies against itself is intriguing and such would definitely contribute towards the mode of action of Al adjuvants.

Slide 20

We recently suggested that in one individual a higher than usual body burden of Al contributed towards vaccine-related injuries (Exley et al., 2009).

Slide 21

This suggestion that the body burden of Al might contribute towards vaccine-related disease asks the question if Al, not just when administered as an adjuvant, but when present throughout the body could also act as an adjuvant?

Slide 22

How do we define the body burden of Al?

Slide 23

The body burden of Al is simply the balance between our exposure to Al and its excretion from the body. So how are we exposed (Exley, 2009)?

Slide 24

We are exposed to Al in water (and drinks), primarily through its absorption across the gut (Yokel et al., 2001), but other potential sites of exposure would include the lung, the nose and the skin.

Slide 25

Al is a major contaminant of food (Saiyed & Yokel, 2005) It is also a known contaminant of parenteral solutions.

Slide 26

It is perhaps less well known that tobacco and cannabis are significant sources of biologically available Al (Exley et al., 2006). For example, when you smoke a cigarette you excrete Al in your urine.

Slide 27

Recreational drugs including heroin and cocaine can also be significant routes of exposure to Al (Exley et al., 2007).

Slide 28

It is becoming of increasing interest that the skin is not a complete barrier to Al. For example, it has been shown that Al applied as an antiperspirant does cross the skin and enter the systemic circulation, albeit in relatively small amounts (Flarend et al., 2001). Aerosol antiperspirants could result in the uptake of Al into the body through the lung and, worryingly, directly to the brain via the nose and olfactory system.

Slide 29

Medicines both include Al as active ingredients and are also ‘contaminated’ by significant amounts of Al (Reinke et al., 2003).

Slide 30

It was recently demonstrated that sunscreens and sunblocks may contain significant amounts of Al such that one might apply up to 5 g of Al onto the skin surface during an average day on the beach. Little is known about the biological availability of Al in such products but it has to be asked if they could contribute towards the high rate of melanoma found in populations using large amounts of sunscreens/sunblocks regularly (Nicholson & Exley, 2007)?

Slide 31

Worryingly we are still exposing the most vulnerable members of society, pre and post-term infants, to very high levels of Al in infant formulas (Burrell & Exley, 2010).

Slide 32

When we consider the myriad ways in which we are exposed to Al in our everyday lives it must be a concern that in addition we are also exposing ourselves to Al in vaccines. We know that this Al both elicits a strong immune response and is transported away from the injection site to the other organs and tissues of the body (Flarend et al., 1997).

Slide 33

Thus living in ‘The Aluminium Age’ means that a body burden of Al is inevitable for all of us.

Slide 34

There will be differences between individuals both in the overall size of the Al body burden and in where in the body the majority of the Al is found. These differences could have profound effects upon the potential toxicity of Al and even on how our body responds to an Al adjuvant in one or more vaccines (Exley, 2009).

Slide 35

Al works effectively as an adjuvant as the relatively large dose which is administered at the injection site exceeds an ‘activity’ threshold which then iniates a cascade of following reactions (Exley et al., 2009; Exley et al., 2010). This ‘threshold effect’ is also probably relevant to Al’s activity as an antigen (Levy et al., 1998). A pertinent question to ask would be whether this ‘threshold effect’ and the resulting cascade of biological reactions would also apply to other body stores of Al, for example, following stimulation by single or multiple Al-adjuvant containing vaccinations?

Slides 36-38

The brain is one organ where Al is known to accumulate (Exley & House, 2011) and there are numerous possible compartments for Al including the very long-lived neurones (Exley, 1999). What might be the consequence of these stores of Al being ‘activated’ by an Al challenge through, for example, a vaccination (Exley et al., 2009)?

Slide 39

The good news is that the majority of Al that enters the body by any route of exposure will eventually be excreted (Exley, 2009).

Slide 40 & 41

We have developed a non-invasive method whereby the excretion of Al from the body via the urine can be facilitated (Exley et al., 2006). Ongoing research with both healthy individuals and individuals with disease is showing that regular drinking of a silicon-rich mineral water is helping to reduce the body burden of Al. The next question which follows is whether a reduced body burden of Al will result in less Al-related disease including possible vaccine-related disease?

References Cited in Presentation

Burrell & Exley (2010) There is (still) too much aluminium in infant formulas. BMC Pediatrics 10:63 doi:10.1186/1471-2431-10-63.

Di Virgilio et al., (2009) Extracellular nucleotides as negative modulators of immunity. Current Opinion in Pharmacology 9,507–513

Exley (1999) A molecular mechanism of aluminium-induced Alzheimer's disease? Journal of Inorganic Biochemistry 76, 133-140.

Exley (2003) A biogeochemical cycle for aluminium ? Journal of Inorganic Biochemistry, 97, 1-7.

Exley (2004) The prooxidant activity of aluminium. Free Radical Biology and Medicine 36, 380-387.

Exley (2009) Darwin, natural selection and the biological essentiality of aluminium and silicon. Trends in Biochemical Sciences 34, 589-593.

Exley (2009) Aluminium and Medicine. In; Molecular and Supramolecular Bioinorganic Chemistry: Applications in Medical Sciences. (Ed. ALR Merce, J Felcman, MAL Recio), Nova Science Publishers Inc. New York, p 45-68.

Exley & House (2011) Aluminium in the human brain. Monatsh Chem (In press)

http://www.springerlink.com/content/9550512205128414/

Exley et al., (2006) Non-invasive therapy to reduce the body burden of aluminium in Alzheimer’s disease. Journal of Alzheimer’s Disease 10, 17-24.

Exley et al., (2006) Aluminium in tobacco and cannabis and smoking-related disease. American Journal of Medicine 119, 276.e9-276.ell.

Exley et al., (2007) Elevated urinary aluminium in current and past users of illicit heroin. Addiction Biology 12, 197-199.

Exley et al., (2009) A role for the body burden of aluminium in vaccine-associated macrophagic myofasciitis and chronic fatigue syndrome. Medical Hypotheses 72, 135-139.

Exley et al., (2010) The immunobiology of aluminium adjuvants: how do they really work? Trends in Immunology 31, 103-109.

Flarend et al., (1997). In vivo absorption of aluminium-containing vaccine adjuvants using Al-26. Vaccine 15, 1314-1318. Flarend et al., (2001). A preliminary study of the dermal absorption of aluminium from antiperspirants using aluminium-26. Food and Chemical Toxicology 39, 163­ 168.

Korchazhkina et al., (1998) Action of Al-ATP on the isolated working rat heart. Journal of Inorganic Biochemistry 69, 153-158.

Levy et al., (1998) Specificity of an anti-aluminium monoclonal antibody toward free and protein bound aluminium. Journal of Inorganic Biochemistry 69, 159-163.

Marrack, et al., (2009) Towards an understanding of the adjuvant action of aluminium. Nature Reviews Immunology 9, 267–293.

Nicholson & Exley (2007) Aluminium: A potential pro-oxidant in sunscreens /sunblocks? Free Radical Biology and Medicine 43, 1216-1217.

Palli-Schöll et al., (2010) Antacids and dietary supplements with an influence upon the gastric pH increase the risk for food sensitisation. Clinical & Experimental Allergy 40, 1091-1098.

Reinke et al., (2003). Aluminium in over-the-counter drugs -Risks outweigh benefits? Drug Safety 26, 1011-1025.

Saiyed and Yokel (2005) Aluminium content of some foods and food products in the USA, with aluminium food additives. Food Additives and Contaminants 22, 234-244.

Yokel et al., (2001). Aluminum bioavailability from drinking water is very low and is not appreciably influenced by stomach contents or water hardness. Toxicology 161, 93-101.