Abstract
Development of liposome-based formulations as vaccine adjuvants has been intimately associated with, and dependent on, and informed by, a fundamental understanding of biochemical and biophysical properties of liposomes themselves. The Walter Reed Army Institute of Research (WRAIR) has a fifty-year history of experience of basic research on liposomes; and development of liposomes as drug carriers; and development of liposomes as adjuvant formulations for vaccines. Uptake of liposomes by phagocytic cells in vitro has served as an excellent model for studying the intracellular trafficking patterns of liposomal antigen. Differential fluorescent labeling of proteins and liposomal lipids, together with the use of inhibitors, has enabled the visualization of physical locations of antigens, peptides, and lipids to elucidate mechanisms underlying the MHC class I and class II pathways in phagocytic APCs. Army Liposome Formulation (ALF) family of vaccine adjuvants, which have been developed and improved since 1986, and which range from nanosize to microsize, are currently being employed in phase 1 studies with different types of candidate vaccines.
Highlights
The concept of using vesicles constructed from purified lipids, known as liposomes, as models of cell membranes was introduced by (Bangham et al 1965)
In conjunction with the secondary stimulus consisting of costimulatory molecules, an antigen-specific cellular (Th1) or a humoral (Th2) response is induced along with the corresponding cytokines. Both anionic and cationic, induce mixed Th1/Th2 responses (Rao et al 1999a, 2002; Jafari et al 2018). Antigen processing through both the major histocompatibility complex (MHC) class I and class II pathways can account for the mixed Th1/Th2 responses induced by liposomes containing monophosphoryl lipid A (MPLA)-associated antigen
Since the peptide has to traverse through the Golgi complex before being transported to the cell surface, and because this is an important step in the intracellular trafficking pathway, localization of the peptide/ lipopeptide in the trans-Golgi can be visualized by the congruence of the overlaid fluorescence of the labeled protein and a vital stain for the Golgi apparatus, C6NBD-ceramide, that is specific to the trans-Golgi (Lipsky and Pagano 1985; Pagano et al 1989)
Summary
The concept of using vesicles constructed from purified lipids, known as liposomes, as models of cell membranes was introduced by (Bangham et al 1965). Various physical factors of liposomes, such as: surface charge (neutral, anionic, cationic); size (nano vs micro); phospholipid fatty acyl composition (saturated vs unsaturated); molar ratios of cholesterol and phospholipid in the lipid bilayer; number of lipid bilayer lamella (unilamellar, oligolamellar, or multilamellar vesicles); targeting molecules for attachment to immune cells; and the type, composition and number, if any, of attached adjuvant(s); have all been identified as factors related to the ease and cost of manufacture, and potential for unwanted toxicity Putting all of these variables together has generated a complex number of ingenious physical immunostimulant compositions (Wang et al 2019). Regardless of the structures of different types of liposomes, they are all foreign materials in the body, and each of the different liposome formulations faces the challenge of activation of innate immunity which has as its main goal the removal of the foreign particle
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