Advax™, a novel microcrystalline polysaccharide particle engineered from delta inulin, provides robust adjuvant potency together with tolerability and safety

Abstract

There is an ongoing need for new adjuvants to facilitate development of vaccines against HIV, tuberculosis, malaria and cancer, amongst many others. Unfortunately, the most potent adjuvants are often associated with toxicity and safety issues. Inulin, a plant-derived polysaccharide, has no immunological activity in its native soluble form but when crystallized into a stable microcrystalline particulate from (delta inulin) acquires potent adjuvant activity. Delta inulin has been shown to enhance humoral and cellular immune responses against a broad range of co-administered viral, bacterial, parasitic and toxin antigens. Inulin normally crystallizes as large heterogeneous particles with a broad size distribution and variable solubility temperatures. To ensure reproducible delta inulin particles with a consistent size distribution and temperature of solubility, a current Good Manufacturing Practice (cGMP) process was designed to produce Advax™ adjuvant. In its cCMP form, Advax™ adjuvant has proved successful in human trials of vaccines against seasonal and pandemic influenza, hepatitis B and insect sting anaphylaxis, enhancing antibody and T-cell responses while being safe and well tolerated. Advax™ adjuvant represents a novel human adjuvant that enhances both humoral and cellular immunity. This review describes the discovery and development of Advax™ adjuvant and research into its unique mechanism of action.

Keywords: Adjuvant; Advax™; Delta inulin; Immunity; Vaccine.

Fig. 1

Structure of a single inulin polymer. This shows inulin comprises a variable-length chain of fructose rings terminated with a single glucose ring. In general, inulin polymers isolated from plant sources range in length from 3 to 100 fructose units.

Fig. 2

Microscopic structures of crystalline inulin particles. Transmission electron microscopy (TEM) reveals gamma inulin particles to have highly variable shape, size and structure (A), potentially explaining their large batch-to-batch variation in adjuvant activity. Initial delta inulin particles had better defined structure on TEM but still exhibited considerable size variation (B). Optimization and control of crystallization parameters allowed reproducible production of delta inulin particles of consistent size and shape (C) that subsequently formed the basis of Advax™ adjuvant. Freeze-fracture scanning EM of Advax™ particles suspended in water reveals their discoid shape and formation from lamellar sheets (D and E). Atomic force microscopy of Advax™ particles during their formation confirms their discoid character and also reveals fine filament precursors from which the final delta inulin particles are assembled (F).