Experimental infection and protection against ... - TI Pharma

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Long-term protection against malaria after experimental sporozoite inoculation 209 but without overt clinical thrombotic microangiopathy or bleeding complications. In addition we report incidental decreases of von Willebrand cleaving protease, possibly as a result of increased consumption of the protease [30]. This is consistent with previous data concerning von Willebrand factor activation in experimental malaria [13]. The clinical relevance of these findings and their relation with the cardiac event is as yet unclear. Our relatively simple immunisation protocol represents a blueprint for induction of sustained anti-malarial immunity, providing a novel tool for exploring mechanisms of immunity and highlighting new research priorities. Precedence must be given to basic understanding of mechanisms of protection in this study and those factors which inhibit protection in naturally-exposed populations. Furthermore, strain specificity can be investigated with the use of heterologous challenge infections and in field studies. Given the efficacy of our immunisation protocol, however, equal emphasis on a pragmatic parallel approach to develop an implementable whole-organism-based vaccine is justified. In conclusion, the irrefutable evidence that long-term immunity against malaria is possible holds a promise for an urgently needed malaria vaccine. Acknowledgements This trial was financed by a grant from the Dioraphte foundation. ACT is funded by the European Malaria Vaccine Development Association, MBBM was supported by an European Union FP6 Network of Excellence (BioMalPar) fellowship, KNM was funded by a Mozaiek grant from the Netherlands Organisation for Scientific Research. We thank the trial volunteers and the staff from the Clinical Research Centre Nijmegen who made this study possible. We thank the following individuals for their assistance during the trial: Laura Pelser, Jolanda Klaassen, Astrid Pouwelsen, Jacqueline Kuhnen for the mosquito infection and dissection work, Wendy Arts, Nanny Huiberts, Chantal Siebes, Marlou Kooreman, Paul Daemen and Ella Driessen for reading many thick smears. We would also like to acknowledge the contributions of Alexander Rennings for his help with monitoring volunteer safety and the cardiologists Gheorghe Pop and Marc Brouwer for their dedication to the cardiac monitoring of the trial volunteers. We acknowledge the work of Richard Huijbens for the
210 Chapter 10 cytokine measurements by Luminex. We would like to thank Rob Woestenenk for use and support of the flowcytometer. Funding This trial was funded by the Dioraphte foundation.
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Experimental infection and protecti
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Experimental infection and protecti
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Contents Contents 5 Chapter 1 - Int
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Introduction 9 Malaria Malaria is o
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Introduction 11 Preclinical Clinica
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Introduction 13 pipeline of clinica
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Introduction 15 The division of ant
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Introduction 17 Figure 4. Populatio
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Introduction 19 candidates. Initial
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Introduction 21 - to identify param
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Introduction 23 20. Nussenzweig RS,
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Introduction 25 50. Ouedraogo AL, R
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Introduction 27 RTS,S/AS02 in malar
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Chapter 2 Safety and Immunogenicity
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Safety and Immunogenicity of a Reco
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Chapter 3 Humoral immune responses
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Humoral immune responses to a singl
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Chapter 4 82 Abstract The functiona
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84 Chapter 4 Figure 1. Schematic re
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86 Chapter 4 Concentration (mg/ml,
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88 Chapter 4 Figure 4: Correlation
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90 Chapter 4 positively correlated
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92 Chapter 4 Acknowledgements The a
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94 Chapter 4 determinant of subsequ
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Chapter 5 Comparison of clinical an
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Comparison of clinical and parasito
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Chapter 6 Efficacy of pre-erythrocy
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Efficacy of pre-erythrocytic and bl
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Chapter 7 NF135.C10: a new Plasmodi
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NF135.C10: a new Plasmodium falcipa
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Chapter 8 Induction of malaria in v
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Induction of malaria in volunteers
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Page 160 and 161: Induction of malaria in volunteers
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
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Page 193 and 194: 192 Chapter 9 medium A (Caltag Labo
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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.
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Page 205 and 206: 204 Chapter 10 Figure 4. Number of
Page 207 and 208: 206 Chapter 10 temperature (Pearson
Page 209: 208 Chapter 10 immune modulating ef
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 230 and 231: General Discussion 229 to induce pr
Page 232 and 233: General Discussion 231 Conclusions
Page 234 and 235: General Discussion 233 References 1
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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
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Page 247 and 248: 246 Chapter 12 Controlled human mal
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Page 255 and 256: 254 Chapter 12 Roestenberg M, Teirl
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