Mechanism of action.
Nanocrystalline particles of inulin, a natural plant-derived polysaccharide consisting of a linear chain of fructose molecules
capped by a single glucose, are the active constituent of Advax. A relatively hydrophobic backbone structure gives inulin
unique physicochemical properties: it can be crystallized into a number of different isoforms.100 Specific isoforms of inulin have the unique ability to enhance antigen-specific humoral and cellular immune responses without
reactogenicity.101–103 Another advantage of Advax is that inulin can be prepared in exceptionally pure form, free of endotoxin or other contaminants,
is heat stable with an extremely long shelf-life, and has had no safety issues over many decades of human use in intravenous
injections for renal function testing (British Pharmacopoeia). Inulin is not metabolized in humans but is excreted unchanged in the urine as fructose and a small quantity of glucose.
Advax's excellent safety and tolerability make it well suited to inclusion in childhood as well as adult vaccines.
Limitations of Advax.
Currently, one of the main obstacles facing Advax is the presumption within the vaccine community that adjuvant potency is
proportionate to inflammation and reactogenicity.104–110 This dogma has arisen from uncritical acceptance of the "danger" hypothesis, which suggests that immunogenicity is linked
to activation of the innate immune system. Advax gives good humoral and cell mediated immune responses in the absence of inflammation100–103,111–114 or reactogenicity, thereby refuting the idea that "danger" signals are essential to eliciting potent adaptive immune responses.
This paper highlights that the major differences between current adjuvants is not their efficacy, but their reactogenicity
and safety. Increased reactogenicity reflects either an adjuvant's intrinsic tissue irritant effect, e.g., for MF59 and other
oil emulsions or QS21, or its ability to induce inflammatory cytokines, e.g., LPS or MPL (through TLR activation). While alum
has a modest tissue irritant effect, it does not directly induce inflammatory cytokine production, thereby explaining its
Advax polysaccharide adjuvant has no local tissue irritant effects and does not induce cytokine production in vitro, explaining its almost complete lack of reactogenicity, which is unique among the known adjuvants. Adjuvant potency must be
balanced against potential to do harm. Microbial cell components and TLR agonists including MDP, LPS, trehalosedimycolate,
and beta glucan, and also oils such as pristane and squalene, are potent inducers of inflammatory arthritis in arthritis-prone
animal strains. Since rheumatoid arthritis affects 1% of the population, there is significant risk of exacerbating or inducing
such autoimmune syndromes in humans. Similarly, TLR agonists such as CpG have been shown to induce and exacerbate EAE and
lupus. The ability of TLR agonists to break immune tolerance, potentially leading to autoimmunity in susceptible individuals,
may preclude their inclusion in prophylactic vaccines, particularly for children.
Similarly, the severe reactogenicity of compounds such as QS21 and oil emulsions preclude their inclusion in prophylactic
vaccines. They may have restricted use in applications such as vaccine treatment of life-threatening conditions such as cancer
and HIV. Although alum is the current gold standard and has a favorable reactogenicity profile compared to other adjuvants,
major long-term safety issues continue to cloud its future, with concerns including MMF and vaccine allergy.
Liposome technology is highly promising and appears to offer significant advantages, providing reactogenicity is not excessive
and sufficient immunogenicity is obtained. Currently, Advax is the only adjuvant that is non-reactogenic and without safety
concerns in pre-clinical and clinical trials. This profile makes it ideal for inclusion in prophylactic vaccines, including
those intended for use in children where maximum safety and tolerability are paramount.
This article demonstrates the relative under-development of the science of adjuvants, compared with the rapidly advancing
knowledge of vaccine antigens. It is extraordinary that the exact mechanism of action remains unknown for many adjuvants,
including alum, the oldest known vaccine adjuvant. Given the increasing importance of adjuvants to modern vaccines, national
and international funding agencies urgently need to institute policies to address this imbalance and provide major new support
for adjuvant basic science and clinical development.