Lipid-coated micro- and nanoparticles as a biomimetic vaccine delivery platform
Massachusetts Institute of Technology. Department of Materials Science and Engineering.
Darrell J. Irvine.
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Biomaterials provide a unique opportunity to control the display, release, and in vivo trafficking of vaccine components. We have designed and characterized a system for vaccine delivery that uses a "lipid surfactants" approach to combine a degradable polymer core with a two-dimensionally fluid lipid bilayer shell. Using optical and electron microscopy, we characterized the distribution, lamellarity, nanostructure, and mobility of the lipid shell. Single, tightly apposed bilayers could be formed around either microparticles or nanoparticles, mimicking bacteria or viruses in size. Alternative nanostructures could be formed at different lipid concentrations and compositions, such as multilamellar lipid "onions" stacked against a polymer core, or lipid "flowers" with petal-like projections emanating from a polymer core. The lipid nanostructure was characterized during the process of emulsion and solvent evaporation, and during degradation by hydrolysis. Design of this carrier was guided foremost by the goal of properly displaying minimal peptide epitopes from the Membrane-Proximal External Region of HIV gp41 (MPER) and enhancing their immunogenicity. Display within a lipid context was needed to provide the chemical environment appropriate for neutralizing antibodies, such as 4E10, to bind efficiently. Multifunctional vaccines were created through a combination of multivalent display, delivery of helper stimuli, and insertion of lipophilic adjuvant molecules in the lipid shell. We further explored the ability of this system to potentiate humoral immune responses against recombinant protein vaccines, using ovalbumin as a model antigen. In studies of both cellular and humoral immune responses, we found that lipid-coated microparticles co-displaying protein and lipophilic adjuvant molecules could potentiate immune responses in vivo. Notably, we found that the dose-sparing capabilities of the particles reached a potency that is seldom reported: a single injection of 2 ng antigen co-displayed on particles with c-galactosylceramide elicited measurable titers, and a prime-boost regimen of 2.5 ng ovaparticles adjuvanted with monophosphoryl lipid A elicited high titers that were sustained for >150 days. No studies to our knowledge have reported dose sparing to this degree with titers sustained over time. The mechanism of this dose sparing effect is of great interest, and will be a subject of future work.
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Materials Science and Engineering, 2010.Vita. Cataloged from PDF version of thesis.Includes bibliographical references (pages 128-146).
DepartmentMassachusetts Institute of Technology. Department of Materials Science and Engineering.
Massachusetts Institute of Technology
Materials Science and Engineering.