[the whole theory is flawed from how vaccines affect
the immune system to adjuvants and everything else in between
and the below is certainly convoluted---Sheri]
Doubts raised over vaccine
10 June 2008
Two recent studies examining how aluminium adjuvants boost the effectiveness of
vaccines may be flawed because they did not use either of the two compounds
commercially licensed for the purpose, Chemistry World has learned.
Aluminium hydroxide (in the form of crystalline aluminium oxyhydroxide , AlOOH)
and aluminium phosphate (amorphous aluminium hydroxyphosphate, Al(OH)x(PO4)y)
are both licensed for use as adjuvants. These aluminium salts - generically
dubbed 'alum' by doctors - have been used for decades to stimulate the immune
response to the antigen in vaccines. But precisely how they help the body to
produce more antibodies has remained a mystery.
Two teams of researchers recently claimed to have found the answer. A study led
by Richard Flavell of the Yale University School of Medicine, and published
online by Nature in May, suggested that alum activates the Nalp3
inflammasome, a receptor that prompts white blood cells to produce antibodies.
 Two months earlier, work by the group of Bart Lambrecht at the Erasmus
University Medical Centre in Rotterdam, Netherlands, together with colleagues at
the University of Ghent, had shown that alum triggered the release of uric acid
in mice. Uric acid is also known to boost the production of antibodies.
However, both groups' experiments used Imject Alum, sold by Pierce Biotechnology
of Rockford, Illinois, a division of Thermo Fisher. Imject is a roughly equal
mixture of amorphous aluminium hydroxycarbonate and crystalline magnesium
hydroxide which is known to be an effective adjuvant in mice, but is not used in
vaccines for humans.
According to Chris Exley, who has studied the biological effects of aluminium
for over 20 years, the mix of compounds in Imject more closely resembles the
antacid Maalox than commercial adjuvants.
'This significant mistake in both of these high profile publications has serious
implications for the interpretation of the results,' says Exley, a reader in
bioinorganic chemistry at Keele University, UK. 'While there is no dispute that
Imject Alum has "adjuvant-like" properties, it will not behave like commercially
available aluminium adjuvants and as such should not really be used to explain
how adjuvants work.'
He points out that Imject, unlike licensed adjuvants, contains magnesium.
Secondly, the aluminium in Imject is likely to be more soluble than in
commercial adjuvants - in Maalox, these Al3+ ions help to buffer pH
changes, contributing to its antacid properties. Both the presence of Mg2+
and the higher concentration of Al3+ in Imject may have affected the
results of the two studies, Exley suggests.
Adjuvant or antacid?
Both groups have responded to the criticism by agreeing that they will
repeat their experiments with a commercially licensed form of alum. 'We should
certainly also test a commercially licensed form of alum, and are planning those
experiments,' says Lambrecht.
However, neither group thinks that the magnesium ions are producing the effects
they observed because they tested aluminium hydroxide containing no magnesium,
and got similar results.
'Imject is the most widely used form of alum adjuvant in the mouse,' explains
Lambrecht. 'We have the same results using aluminium hydroxide, but published
the whole story with Imject.'
Flavell also rejects the idea that the higher solubility of aluminium in Imject
is playing a role. 'We actually did experiments to assess the role of soluble
aluminium and found no stimulation,' he says. 'We will however look at the
licensed adjuvant for completeness.'
Stephanie Eisenbarth, the postdoctoral fellow in Flavell's lab who was first
author on the Nature paper, says that the chemistry of alum may not be
critical to its vaccine boosting properties anyway. 'There's a whole class of
compounds, including uric acid crystals, asbestos and silica, that activate an
immune response through Nalp3 and may also work as adjuvants. It could be the
physical nature of how these crystals interact with cells that is key to
stimulating the immune response.'
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1 S C Eisenbarth Et al, Nature, 2008, DOI: 10.1038/nature06939
2 M Kool et al, J. Exp. Med., 2008, DOI: 10.1084/jem.20071087
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