340 Index. ISCOM, see Immunostimulating complex Iscomatrix, see Immunostimulating complexmatrix

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1 Index 337 Index A A-B-A nonionic block copolymer adjuvant, see CRL-1005 Adjuvant, see also specific adjuvants advantages, 8, 9 classes, 4, 5 clinical trials, Center for Biologics Evaluation and Research guidelines, 16, 17 criteria for selection, 15 Food and Drug Administration regulations for early trials, 15, 16 framework, 17 comparative trialsanimal studies, 17, 18human studies, 18, 19 cytotoxic T lymphocyte priming, 197 definition, 2 design approaches, 211, 212 formulations, 3 ideal adjuvant characteristics, 12, 13, 30 mechanisms of action, 6 8 modulators of activity, 9 rational development, impediments, aluminum adjuvants, suboptimal use, 13, 14 animal model limitations, 14 immunoassay utilization, 14, 15 limited adjuvanticity, 13 reasons for interest, 1, 2, 273 safety, see Safety, adjuvants Aluminum adjuvants, adsorption of antigen, assays, 75, 76 factors affecting, 66, 67, 80, 81 advantages and limitations, 66 alum-precipitated vaccines, nomenclature, 65 preparation, aluminum hydroxide adjuvant preparation, adsorption of antigens, in situ adsorption, 70 overview, 69, 70 preformed gel adsorption, 71 materials, 67, 68 Aluminum adjuvants (cont.), aluminum hydroxide adjuvant preparation (cont.), aluminum phosphate adjuvant preparation, adsorption of antigens, in situ adsorption, 72 overview, 71, 72 preformed gel adsorption, 72, 73 materials, 68 potassium alum as starting material, 73 animal experiments, antibody responses, dose, 81, 82 mechanism of action, antigen-presenting cell targeting, 83 depot formation, 82, 83 immune system activation, 83, 84 physiochemical characterization, 74, 75 potency of types, 84 quantification of adjuvants, 68, 76, 77 storage, 73, 82 suboptimal use, 13, 14 C Carrier, adjuvant activity effects, 44, 46 definition, 3 Cholera toxin (CT), mechanism, adjuvant activity, 328 toxin, 327, 328 transcutaneous immunization adjuvant, humoral response dose sensitivity, 320, 321 immune responses, antibodies, Langerhans cell activation, 316, 317 overview, 315, 316 structure, 316 Chromium-51 release assay, CTL activity assay, 329, 331, 332 Cochleate delivery vehicles, adjuvant applications, 186 advantages, 182, 185 From: Methods in Molecular Medicine, Vol. 42: Vaccine Adjuvants: Preparation Methods and Research Protocols Edited by: D. T. O Hagan Humana Press Inc., Totowa, NJ 337

2 338 Index Cochleate delivery vehicles (cont.), comparison with liposomes, 181 DNA cochleates, encochleation, 194 overview, 186 quantification of cochleate-associated DNA, 191, 192 endotoxin contamination, 193 membrane fusion, 187, 189 preparation, encochleation methods, DC dialysis, 189, 190, 193 LC dialysis, 189, 193 pelleting and resuspension, 191 trapping, 190, 191 materials, 187, 192, 193 overview, 181, 182 protein cochleates, cross-linking, 194 immunogenicity of peptides, 186 influenza vaccines in mice, membrane proteins, 193, 194 quantification of cochleate-associated proteins, 192 summary of vaccine studies, 183 structure, 181 CpG, see DNA adjuvants CRL-1005, advantages as adjuvant, 121, 122 antigen, effects on particle size, 123 interactions, 123 protein assay for dosing, 125, 132, 133 cloud point, factors affecting, 124 copolymer assay to determine dosing, 125, 132 dosing and applications, formulation, antigen mixing, 126, 134 copolymer solution preparation, 125, 126, 133, 134 materials, 124, 125 overview, 125 particle size determination, 125, 133 physical properties, safety, structure, 121, 122 CT, see Cholera toxin CTL, see Cytotoxic T lymphocyte Cytotoxic T lymphocyte (CTL), activity assay, heat-labile enterotoxin response, calculations, 333, 334 chromium release assay, 329, 331, 332 Cytotoxic T lymphocyte (CTL) (cont.), activity assay, heat-labile enterotoxin (cont.), materials, 328, 329 spleen preparation for bulk culture stimulation, 330, 331, 333 splenocyte stimulation, 328, 329 MF59 response, 224 priming, 197 virus-like particle response, 199 Cytotoxicity assay, adjuvant safety testing in monolayers, 32, 36 D DNA adjuvants, clinical applications, CpG immunostimulation, 299 cytokine induction, assays, overview, 299, 303 DNase digestion, 306, 309 endotoxin assay, 305, 306, 309 mechanisms of action, 300 phosphorothioate oligonucleotides, 299, 300, 303 plasmid manipulations, 305, 306, 309 safety, 303, 304 thymidine incorporation assay, 305, 308, 310 vectors, 300, 301 DNA vaccine, cochleate delivery vehicles, encochleation, 194 overview, 186 quantification of cochleate-associated DNA, 191, 192 immunopotentiating reconstituted influenza virosome, antisense L-myc oligonucleotides, mumps vaccine in mice, 164, 172, 173 preparation, 163, 164 liposome, entrapment, cationic lipids for DNA entrapment, 147 coentrapment with cytokines, 147 hydration, 141 materials, 140 microfluidization, 144, 145 monitoring, 142, 143 salt addition, 142 size of vesicles, 144 solutions, 140 sonication, 141 time requirements, 146 genetic immunization, 138, 139 Droplet test, mineral oil adjuvants, 57 59

3 Index 339 E ELISA, see Enzyme-linked immunosorbent assay Emulsion, manufacturing considerations, 230, 231 theory, 229, 230 Enzyme-linked immunosorbent assay (ELISA), cytokine assays, F FDA, see Food and Drug Administration Food and Drug Administration (FDA), Center for Biologics Evaluation and Research guidelines, 16, 17 regulations for early adjuvant trials, 15, 16 Food protein allergy, adjuvant safety testing, 32, 40, 41 Freund s adjuvants, complete vs incomplete adjuvants, 50, 51 historical background, mineral oil adjuvants, droplet test, emulsifier, characteristics, 53, 59 metabolic degradation, 55, 56 emulsion preparation, 57, 58 injection in animals, 60 mechanism of action, 53, 54 mineral oil, characterization, 59, 60 metabolic degradation, 55 types, 52, 53 Trypan blue test, modern formulations, 45, 49, 50 overview, 49, 50 reaction profile, 56, 57 side effects, 50 G GM-CSF, see Granulocyte-macrophage colony stimulating factor Granulocyte-macrophage colony stimulating factor (GM-CSF), adjuvant use, rationale, , 289 functions, 283, 284 receptor, 285 structure, 285 H Heat-labile enterotoxin (LT), cytotoxic T lymphocyte activity assay, calculations, 333, 334 chromium release assay, 329, 331, 332 materials, 328, 329 spleen preparation for bulk culture stimulation, 330, 331, 333 splenocyte stimulation, 328, 329 Heat-labile enterotoxin (LT) (cont.), immunization of mice, intramuscular, 330 intranasal, 330 intraperitoneal, 329, 330 schedule, 330 mechanisms, adjuvant activity, 328 toxin, 327, 328 mutants for toxicity reduction, 327, 328 transcutaneous immunization adjuvant, 316, 317, 322 Hemolysis test, adjuvant safety, 31, 33, 34 Hepatitis A, immunopotentiating reconstituted influenza virosome vaccine, clinical evaluation, 165, 166 preparation, 161, 162 I IL-2, see Interleukin-2 IL-12, see Interleukin-12 Immune response, adjuvant assay, dose of adjuvant, 43 injection, 42, 43 standard adjuvants, 41, 42, 45 standard antigens, 42 Immunostimulating complex (ISCOM), characterization, quality control, 251, 252 composition, 240 immune response, 240, 241 materials, antigen, 242, 243 cross-linking reagents, 245 detergents, 243, 244 equipment, 245, 246 lipids, 243 materials, 244 Quillaja saponin, 243 preparation, antigen lipidation, 250, 251 guidelines for mixing, 247, 252, 253 hydrophobic interactions, 246, 247 structure, 239 Immunostimulating complex-matrix (Iscomatrix), applications, 241, 242 comparison with ISCOM, 241 conjugation to preformed ISCOM-matrix, , 253 immune response, 242 preparation, 246 structure, 241

4 340 Index Immunopotentiating reconstituted influenza virosome (IRIV), advantages as adjuvant, 159 foreign antigens, mucosal immunization, 159 hemagglutinin immunopotentiation, immunogenicity, comparison with alum adjuvants, 167 malaria peptide vaccine, neuraminidase immunopotentiation, 158, 159 phospholipids in preparation, 155, 156 principle of virosomal vaccines, 153, 154 prospects, 164 safety, 165 structure, 155 vaccine production, DNA vaccines, antisense L-myc oligonucleotides, 170 mumps vaccine, 164, 172, 173 preparation, 163, 164 hepatitis A vaccine, clinical evaluation, 165, 166 preparation, 161, 162 influenza vaccine, clinical evaluation, 166, 167 preparation, 160, 161 materials for adjuvant, 159, 160 multicombined virosomal vaccines, clinical trials, 170 preparation, 163 Influenza virosome, see Immunopotentiating reconstituted influenza virosome Interleukin-2 (IL-2), adjuvant use, animal models, 287, 288 dose response, 287 modifications for use, 287, 289 Proleukin, characteristics, 289, 292 preparation and administration, 291 rationale, 284, 286, 287, 289 functions, 283, 284 immune response, 286, 287 receptor, 286 structure, 286 systemic response, 289 Interleukin-12 (IL-12), adjuvant use, rationale, 284, 285, 289 DNA adjuvant induction assay, functions, 283, 284 receptor, 284 structure, 284, 309, 310 IRIV, see Immunopotentiating reconstituted influenza virosome ISCOM, see Immunostimulating complex Iscomatrix, see Immunostimulating complexmatrix L Langerhans cell, cholera toxin activation, 316, 317 Limulus lysate assay, adjuvant safety testing, 31, 32, 35, 36, 44, 305, 306, 309 Liposome adjuvants, depot effect, 154 entrapment of antigens and DNA vaccines, cationic lipids for DNA entrapment, 147 coentrapment with cytokines, 147 hydration, 141 materials, 140 microfluidization, 144, 145 monitoring, 142, 143 salt addition, 142 size of vesicles, 144 solutions, 140 sonication, 141 time requirements, 146 entrapment of large partricles or bacteria, 145, 146 genetic immunization, 138, 139 historic background, phase transitions, 139 LT, see Heat-labile enterotoxin M MF59, adjuvant, alum adjuvant comparison, 222, 223 cytokine response, 223, 224 cytotoxic T lymphocyte response, 224 potency, 212 reactogenicity, 213 availability, 226 fate, in vivo, 226 MF59C.1 production, in process assays, 214 large-scale manufacturing process, 213, 214 materials, 213 pharmaceutical feasibility, 213 release assays, 216, 217 safety, stability assays, 217 vaccine formats, antigens, 217, 218 dual-vial formulations, 219, 222 single-container vaccines, 218, 219 summary of formulations, 220, 221

5 Index 341 Microparticle adjuvants, see Poly(lactidecoglycolide) adjuvants; Poly(methyl methacrylate) adjuvants Mineral oil adjuvant, Freund s incomplete adjuvant, droplet test, emulsifier, characteristics, 53, 59 metabolic degradation, 55, 56 emulsion preparation, 57, 58 injection in animals, 60 mechanism of action, 53, 54 mineral oil, characterization, 59, 60 metabolic degradation, 55 types, 52, 53 Trypan blue test, safety, 45, 46 MPL adjuvants, applications of formulations, aqueous dispersion, overview, 274 preparation, 275, 276, 278 emulsions, overview, 274, 275 preparation, 275, 276, 278 immune response, 273, 274 structure, 274 Mucosal immunity, overview, 179, 180 Mucosal vaccine adjuvants, overview, 3, 6 N Nanoparticle adjuvants, see Poly(methyl methacrylate) adjuvants Nonionic block copolymer adjuvant, see CRL P Poly(lactide-coglycolide) adjuvants, advantages, animal studies of immune response, 93, 94 antigen integrity assessment, chromatography, 99 gel electrophoresis, 98, 99 immunoassay, 99 antigen loading level determination, 97 antigen release, in vitro, 98 microencapsulation of antigens, 94 97, 100, 101 microparticle size determination, 97 miscellaneous tests, 100 particle size effects, 91 Poly(lactide-coglycolide) adjuvants (cont.), polymer type selection, 94, 100 residual solvent content assay, 100, 101 scanning electron microscopy of microparticle surface, 98, 101 Poly(methyl methacrylate) adjuvants, advantages, 105, 106, 115 carriers, emulsion polymerization, chemical initiation, 108, 109, 111 gamma rays, 108, 110, 111 overview, 106, 107 fate in tissues, 106 immune response, 113, 114 monomer purification, 108 particle size, consistency, 113 determination, 109, 111 storage, 110, 111 surfactant effects, 112 vaccination, 112 vaccine preparation, adsorption of antigen, 110 incorporation of antigen, 110 overview, 109, 110 Poly oxyethylene, see CRL-1005 Poly oxypropylene, see CRL-1005 Q QS-21 antigen quantification, 267 applications, 264 degradation products, 268 formulation of vaccines, alum-adsorbed antigens, 267, 269 lyophilization, 269 slow release antigen delivery systems, 269 soluble antigens, 266, 267 immune response, nuclear magnetic resonance, 262, 264, 267, 268 physiochemical properties, 262 preparation, 264, 265 quantification, safety, 261 source, 259 stability dependence on ph, 268 sterilization, 265 storage, 264 structure, 262 R, S Release assay, see Chromium-51 release assay SAF, see Syntex adjuvant formulation

6 342 Index Safety, adjuvants, assays, cytotoxicity assay in monolayers, 32, 36 food protein allergy induction, 32, 40, 41 hemolysis test, 31, 33, 34 intracutaneous toxicity tests, single and repeated doses, 37, 38 Limulus lysate assay, 31, 32, 35, 36, 44 mouse weight-gain test, 40 rabbit pyrogenicity test, 31, 34, 35 systemic toxicity test, 32, concerns expressed at meetings, 29, 30 CRL-1005, DNA adjuvants, 303, 304 immunopotentiating reconstituted influenza virosome, 165 local reactions, 10, 11 manufacturer specifications, 44 MF59, mineral oil adjuvants, 45, 46 overview, 9, 10 QS-21, 261 risks, 10 systemic reactions, 11, 12 virus-like particles, 198 Splenocyte, immunostimulatory DNA response assay, Stratum corneum, effectiveness as barrier, 316, 317 Subunit vaccine, overview, 180 Syntex adjuvant formulation (SAF), components, 229, emulsion theory, 229, 230 formulation and manufacture, manufacturing considerations, 230, 231 stability, 235, 236 storage, 235, 236 Systemic toxicity test, adjuvant safety testing, 32, T TCI, see Transcutaneous immunization Transcutaneous immunization (TCI), advantages, 315, 321, 322 Transcutaneous immunization (TCI) (cont.), antigen size in skin penetration, 317 cholera toxin as adjuvant, cholera toxin as adjuvant, dose sensitivity of humoral response, 320, 321 immune responses, antibodies, Langerhans cell activation, 316, 317 overview, 315, 316 structure, 316 definition, 315 heat-labile enterotoxin as adjuvant, 316, 317, 322 mouse immunization, back, ear, 323, 324 materials, 322 Trypan blue, mineral oil adjuvant test, Ty-VLP, see Virus-like particle V, W Vehicle, definition, 3 Virosome, see Immunopotentiating reconstituted influenza virosome Virus, immune response and vaccination, Virus-like particle (VLP), antigens, 198 immune response assessment, 197, 198, 206 safety, 198 Ty-VLP generation, cell growth, 202, 204, 208 cytotoxic T lymphocyte response, 199 disruption of cells, 202, 204, 208 overview, plasmids, , 207 purification, 202, 204, 205, 208 scale-up purification, 205, 206 transformation of yeast, , 207 yeast strains, 200, 201 yield and purity assessment, 202, 205 VLP, see Virus-like particle Whole body adjuvant, examples, 3