Kalvodova L.,Infectious Disease Research Institute
Biochemical and Biophysical Research Communications | Year: 2010
Oil-in-water emulsions are used as vaccine adjuvants, but the mechanism of action remains unknown. In this paper we used phagocytes (monocytes, macrophages, dendritic cells) and non-phagocytic cells (fibroblasts, skeletal muscle cells) to study internalization of emulsions in vitro, and to characterize the influence of emulsion uptake on cellular metabolism of neutral lipids. We found that all tested cell types endocytose the emulsion droplets, and that the uptake leads to an acute accumulation of neutral lipids in the form of cytoplasmic lipid droplets. The accumulated lipids comprise not only the delivered squalene, but also cholesteryl esters, triacylglycerols, fatty acids, and diacylglycerols. Lipid metabolism and innate immunity are closely linked, and accumulation of lipids in non-adipose tissues is known to induce inflammatory conditions. We propose that one aspect of o/w emulsion adjuvanticity could depend on their ability to rapidly change lipid metabolism of the target cells. © 2010.
Alving C.R.,U.S. Army |
Peachman K.K.,U.S. Army |
Rao M.,U.S. Army |
Reed S.G.,Infectious Disease Research Institute
Current Opinion in Immunology | Year: 2012
Rational selection of individual adjuvants can often be made on the basis of innate molecular interactions of the foreign molecules with pattern recognition receptors such as Toll-like receptors. For example, monophosphoryl lipid A, a family of endotoxic TLR4 agonist molecules from bacteria, has recently been formulated with liposomes, oil emulsions, or aluminum salts for several vaccines. Combinations of antigens and adjuvants with particulate lipid or oil components may reveal unique properties of immune potency or efficacy, but these can sometimes be exhibited differently in rodents when compared to nonhuman primates or humans. New adjuvants, formulations, microinjection devices, and skin delivery techniques for transcutaneous immunization demonstrate that adjuvant systems can include combinations of strategies and delivery mechanisms for uniquely formulated antigens and adjuvants. © 2012 .
Ireton G.C.,Infectious Disease Research Institute
Sub-Cellular Biochemistry | Year: 2010
Natural derivatives and synthetic analogues of lipopolysaccharide are potent stimulators of the mammalian immune system. Retained adjuvant activity with reduced toxicity was obtained by the development of monophosphoryl lipid A (MPL®), which is approved for use in several vaccine products. Ongoing research and development of synthetic TLR4 agonists may offer increased purity and biological activity with reduced cost. Extensive research has elucidated the mechanism of action of TLR4 agonists and structure-function relationships. Moreover, the formulation of TLR4 agonists has been shown to significantly affect the type and magnitude of elicited immune response. TLR4 agonists comprise a promising class of adjuvants for safe and effective vaccines. © Springer Science+Business Media B.V. 2010.
Infectious Disease Research Institute | Date: 2014-03-21
Compounds, particularly, glucopyranosyl lipid adjuvant (GLA) compounds, having the following structure (I) are provided: or a pharmaceutically acceptable salt thereof, wherein L
Infectious Disease Research Institute | Date: 2015-09-09
Compositions and methods, including vaccines and pharmaceutical compositions for inducing or enhancing an immune response are disclosed based on the discovery of useful immunological adjuvant properties in a synthetic, glucopyranosyl lipid adjuvant (GLA) that is provided in substantially homogeneous form. Chemically defined, synthetic GLA offers a consistent vaccine component from lot to lot without the fluctuations in contaminants or activity that compromise natural-product adjuvants. Also provided are vaccines and pharmaceutical compositions that include GLA and one or more of an antigen, a Toll-like receptor (TLR) agonist, a co-adjuvant and a carrier such as a pharmaceutical carrier.