Kent R. Myers

Monophosphoryl Lipid A as an Adjuvant

The increasing threat to the human population posed by new or resurgent infectious diseases, coupled with an alarming rise in the incidence of antibiotic-resistant microbes, has created a tremendous need for new vaccines. A critical element in the development of these new vaccines is the ability, via adjuvants, to potentiate and focus the immune response to the vaccine in beneficial ways so that optimal protection can be achieved. One promising candidate adjuvant in this regard is MPL® immunostimulant, a monophosphoryl lipid A preparation derived from the lipopolysaccharide (LPS) of Salmonella minnesota R595. MPL® is being considered as an adjuvant for a number of human vaccines, and experience to date has shown that it is safe, well tolerated, and able to provide a heightened immune response to coadministered antigens. In this chapter, various topics related to the preparation, formulation, and use of MPL® as an adjuvant will be discussed. In addition, our current knowledge of the mechanisms of action of MPL® will be reviewed.

Modulation of Humoral and Cell-Mediated Immune Responses by a Structurally Established Nontoxic Lipid A

In 1954 Westphal and his associates reported on the isolation of a moiety of bacterial endotoxin which they liberated by means of hydrolysis in dilute acetic or hydrochloric acid solutions (25). The water soluble phase of the hydrolysis reaction contained a haptenic polysaccharide which no longer retained the ability to stimulate physiological responses characteristic of the starting material (3,4). On the other hand, the hydrolysis products extractable with organic solvents did retain some of the endotoxic properties of the original substance, leading Westphal and coworkers to postulate that the “endotoxic” activities of LPS were attributable to a lipidic component, which they designated lipid A (5).

Monophosphoryl Lipid A and Synthetic Lipid A Mimetics As TLR4-Based Adjuvants and Immunomodulators

MPL adjuvant, a monophosphoryl lipid A (MLA) derivative of the lipopolysaccharide (LPS) from Salmonella minnesota R595, and RC-529, a synthetic lipid A mimetic, are promising adjuvant candidates for a number of human vaccines and have been shown to be safe, well-tolerated, and to effectively enhance immune responses to co-administered vaccine antigens. Preliminary evidence suggests that, like LPS, MLA and RC-529 activate cells via the pattern recognition receptor, Toll-like receptor 4 (TLR4).