Experimental infection and protection against ... - TI Pharma

More documents

Recommendations

Info

General Discussion 229 to induce protection when co-administered with live sporozoites in a mouse model [111]. Interestingly, both drugs also exhibit immunoregulatory properties [112-114]. Alternatively, the passive transfer of antibodies directed against blood-stage antigens could also prevent clinical disease and modulate the immune response [115]. As an alternative to radiation, several other methods of attenuation, mainly in rodent models, have been developed. Treatment of sporozoites with the DNA alkylating agent centanamycin, a compound that particularly attenuates malaria parasites because it exploits the AT-richness of the parasite genome, impairs the infection of hepatocytes by sporozoites and arrests liver stage parasite development. Mice inoculated with centanamycin-treated sporozoites failed to produce blood stage infections and were protected against subsequent challenge with wild-type sporozoites [116]. Moreover, cross-species protection could be induced and parasite-specific antibodies and IFN-gamma-producing CD8(+) T cells were induced that were not significantly different from radiationattenuated sporozoites [116]. In fact, CPS immunisation also implies chemical attenuation, albeit in vivo. CPS as currently presented is not a widely implementable vaccine strategy, but one could envision the co-administration of a drug with a needle administered live vaccine product for a selected group of subjects. However, safety requirements for such in vivo attenuated product will likely be very stringent, e.g. full attenuation must be independent from compliance and pharmacokinetics of the drug. Moreover, in vivo attenuation precludes the ability to carry out viability checks before the vaccine is administered, necessitating extensive postvaccination follow-up. In addition to the random genetic attenuation induced by radiation or chemicals, targeted attenuation of sporozoites can be achieved by inactivation of specific genes by molecular techniques. The main advantage of Genetically Attenuated Parasites [GAP) over radiation and chemically attenuated parasites is the fact that a homogeneous parasite population with a defined phenotype is obtained. The recent availability of complete Plasmodium genome sequences permits the development of live-attenuated parasites by more precise and defined genetic manipulations [117]. Based on their expression profile and phenotype, approximately seven genes have been selected for attenuation and knock-out strains created primarily in rodent malaria parasites P. berghei and P. yoelii (p52, p36, uis3, uis4, fabb/f, fabz, sap1 [118-126]). Immunisation of mice with GAP
230 Chapter 11 results in protective immune responses that are similar to those induced by irradiated sporozoites [127, 128]. To ensure safety of the GAP vaccine, the liver arrest of a genetically attenuated parasite vaccine needs to be complete and irreversible [129]. Occasional breakthrough infections in GAP lacking genes uis4 and p52, emphasize that multiple genes will have to be removed in order to achieve complete arrest [119, 120]. Recently studies, however, show that also parasites lacking expression of both P52 and P36 are capable of developing through the liver stage into blood stage infections in vitro and in mouse models [130]. This raises concerns about the number of genes that need to be attenuated to ensure safety of a whole-sporozoite vaccine. The potency of a GAP, on the contrary, depends on development of the attenuated parasites into the late liver stage, engendering higher levels of T-cell responses and cross-stage and cross–species protection [124]. Whether or not safety and potency requirements can both be adequately met in one multiply-attenuated whole parasite product will have to be investigated. In addition, the GAP vaccines also require precautions with respect to the introduction of attenuated parasites into the environment, most likely necessitating the removal of foreign DNA sequences from the parasite clones [131]. Regardless of the method of attenuation, a live attenuated sporozoite vaccine will have to meet stringent safety regulations, as accidental parasite multiplication may induce a potentially fatal disease particularly if the vaccine is to be used in immunologically vulnerable populations: HIV-infected subjects or malnourished infants. An assay that could be reliably and repeatedly used to check the potency of sporozoites for vaccination would be an important asset. Such a potency assay could also potentially address the issue of translating the dose of mosquito-delivered inoculation into a needle-delivered vaccines. The only currently available potency assay is the in vitro hepatocyte invasion assay. This assay relies on the in vitro invasion of Pf sporozoites in the hepatoma cell line HepG2, the human transformed hepatocyte cell line HC04 or primary human hepatocytes, all of which are unfortunately limited by very low infection efficiencies (
Page 2 and 3:
Experimental infection and protecti
Page 4 and 5:
Experimental infection and protecti
Page 6:
Contents Contents 5 Chapter 1 - Int
Page 10 and 11:
Introduction 9 Malaria Malaria is o
Page 12 and 13:
Introduction 11 Preclinical Clinica
Page 14 and 15:
Introduction 13 pipeline of clinica
Page 16 and 17:
Introduction 15 The division of ant
Page 18 and 19:
Introduction 17 Figure 4. Populatio
Page 20 and 21:
Introduction 19 candidates. Initial
Page 22 and 23:
Introduction 21 - to identify param
Page 24 and 25:
Introduction 23 20. Nussenzweig RS,
Page 26 and 27:
Introduction 25 50. Ouedraogo AL, R
Page 28:
Introduction 27 RTS,S/AS02 in malar
Page 32 and 33:
Chapter 2 Safety and Immunogenicity
Page 34 and 35:
Safety and Immunogenicity of a Reco
Page 36 and 37:
Page 38 and 39:
Page 40 and 41:
Page 42 and 43:
Page 44 and 45:
Page 46 and 47:
Page 48 and 49:
Page 50 and 51:
Page 52 and 53:
Page 54 and 55:
Page 56 and 57:
Page 58 and 59:
Chapter 3 Humoral immune responses
Page 60 and 61:
Humoral immune responses to a singl
Page 62 and 63:
Page 64 and 65:
Page 66 and 67:
Page 68 and 69:
Page 70 and 71:
Page 72 and 73:
Page 74 and 75:
Page 76 and 77:
Page 78 and 79:
Page 80:
Page 83 and 84:
Chapter 4 82 Abstract The functiona
Page 85 and 86:
84 Chapter 4 Figure 1. Schematic re
Page 87 and 88:
86 Chapter 4 Concentration (mg/ml,
Page 89 and 90:
88 Chapter 4 Figure 4: Correlation
Page 91 and 92:
90 Chapter 4 positively correlated
Page 93 and 94:
92 Chapter 4 Acknowledgements The a
Page 95 and 96:
94 Chapter 4 determinant of subsequ
Page 98 and 99:
Chapter 5 Comparison of clinical an
Page 100 and 101:
Comparison of clinical and parasito
Page 102 and 103:
Page 104 and 105:
Page 106 and 107:
Page 108 and 109:
Page 110 and 111:
Page 112 and 113:
Page 114 and 115:
Page 116 and 117:
Page 118 and 119:
Chapter 6 Efficacy of pre-erythrocy
Page 120 and 121:
Efficacy of pre-erythrocytic and bl
Page 122 and 123:
Page 124 and 125:
Page 126 and 127:
Page 128 and 129:
Page 130 and 131:
Chapter 7 NF135.C10: a new Plasmodi
Page 132 and 133:
NF135.C10: a new Plasmodium falcipa
Page 134 and 135:
Page 136 and 137:
Page 138 and 139:
Page 140 and 141:
Page 142 and 143:
Page 144 and 145:
Page 146 and 147:
Page 148 and 149:
Page 150 and 151:
Page 152 and 153:
Chapter 8 Induction of malaria in v
Page 154 and 155:
Induction of malaria in volunteers
Page 156 and 157:
Page 158 and 159:
Page 160 and 161:
Page 162 and 163:
Page 164 and 165:
Page 166 and 167:
Page 168 and 169:
Page 170 and 171:
Page 172:
Section 3 Whole parasite inoculatio
Page 175 and 176:
174 Chapter 9 Abstract An effective
Page 177 and 178:
176 Chapter 9 Figure 1. Study desig
Page 179 and 180: 178 Chapter 9 followed by five iden
Page 181 and 182: 180 Chapter 9 Figure 2. Parasitemia
Page 183 and 184: 182 Chapter 9 Test Day I-1 Day C-1
Page 185 and 186: 184 Chapter 9 strain P. falciparum-
Page 187 and 188: 186 Chapter 9 protective role in ot
Page 189 and 190: 188 Chapter 9 References 1. Greenwo
Page 191 and 192: 190 Chapter 9 27. Orjih AU. Acute m
Page 193 and 194: 192 Chapter 9 medium A (Caltag Labo
Page 195 and 196: 194 Chapter 10 Abstract Induction o
Page 197 and 198: 196 Chapter 10 Pre-erythrocytic sta
Page 199 and 200: 198 Chapter 10 procedures described
Page 201 and 202: 200 Chapter 10 by hand-dissection.
Page 203 and 204: 202 Chapter 10 Figure 3. Mean numbe
Page 205 and 206: 204 Chapter 10 Figure 4. Number of
Page 207 and 208: 206 Chapter 10 temperature (Pearson
Page 209 and 210: 208 Chapter 10 immune modulating ef
Page 211 and 212: 210 Chapter 10 cytokine measurement
Page 213 and 214: 212 Chapter 10 14. Hermsen CC, Telg
Page 216 and 217: Chapter 11 General Discussion
Page 218 and 219: General Discussion 217 occurrence o
Page 220 and 221: General Discussion 219 mediating th
Page 222 and 223: General Discussion 221 AMA1 express
Page 224 and 225: General Discussion 223 troponins ca
Page 226 and 227: General Discussion 225 and between
Page 228 and 229: General Discussion 227 immunologica
Page 232 and 233: General Discussion 231 Conclusions
Page 234 and 235: General Discussion 233 References 1
Page 236 and 237: General Discussion 235 polymorphonu
Page 238 and 239: General Discussion 237 57. Church L
Page 240 and 241: General Discussion 239 85. Beier JC
Page 242 and 243: General Discussion 241 118. Mueller
Page 244: Chapter 12 Summary Samenvatting Lis
Page 247 and 248: 246 Chapter 12 Controlled human mal
Page 250 and 251: Summary, Samenvatting, List of publ
Page 252: Summary, Samenvatting, List of publ
Page 255 and 256: 254 Chapter 12 Roestenberg M, Teirl
Page 262: Summary, Samenvatting, List of publ
show all

Experimental infection and protection against ... - TI Pharma

Create successful ePaper yourself

Delete template?

Save as template?