Experimental infection and protection against ... - TI Pharma

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Long-term protection against malaria after experimental sporozoite inoculation 205 Figure 5. In vitro production of IFNγ (A,B) or both IFNγ and IL-2 (C-F) by T-cells (A-D) or CD45RO+ and CD62L- effector memory (EM) T cells (E,F) on the day before (re-)challenge, upon stimulation with sporozoites (PfSpz, panel A,C,E) or asexual stage parasites (PfRBC, panel B,D,F). Numbers of cytokine producing cells are depicted as percentage of total T cells (A-D) or EM T cells (E-F). Symbols indicate individual values from immunised (n=6) and control (n=5) volunteers; horizontal lines represent group medians. Fully protected immunised volunteers and control volunteers are indicated as circles, immunised volunteers with delayed patency are indicated as triangles. this time in two of five volunteers with d-dimer above 1,000 ng/ml (58% and 38% compared with 80% and 67% respectively in a resting state). Fragmentocytes were never detected. Peak d-dimer values correlated with peak
206 Chapter 10 temperature (Pearson R=0.83, p=0.02). Platelets decreased slightly below 120x10 9 /l in one volunteer (nadir 108x10 9 /l). Lactate dehydrogenase levels were never elevated above 1000 U/l. Highly sensitive troponin T was never abnormal (max 0.011 µg/l). None of the volunteers showed any bleeding or thrombotic complications. None of the protected volunteers showed an elevation of ddimers above detection level (250 ng/ml). Real-time quantitative PCR (Q-PCR) was performed on all collected samples retrospectively. Control volunteers showed cyclical parasite growth, identical to control volunteers in previous malaria challenge infection trials [9,14]. Asexual blood-stage parasites were never detected by Q-PCR (detection limit 20 parasites/ml) in any of the four protected volunteers during the entire 21 day follow-up period. The remaining two immunised volunteers with delayed patency by microscopy also showed delayed appearance of blood-stage parasitemia by Q-PCR (Figure 4). Specific anti-parasite antibody responses were detectable at 28 months postimmunisation in only one of six immunised volunteers, i.e. against the major circumsporozoite antigen (NANP6 repeats) and crude blood-stage antigens (data not shown). Antibodies with specificity for individual asexual blood stage antigens (AMA-1 and GLURP) were not detectable. Blood stage parasitemia was accompanied by increased plasma concentrations of systemic inflammatory markers, including IFNγ (median peak 69 pg/ml, IQR 51-135), IL-6 (median peak 9.2 pg/ml, IQR 6.4-14) and C-reactive protein (median peak 52 mg/l, IQR 26.5- 57.5) with no difference between controls and volunteers with delayed patency. None of the protected volunteers showed any increase in plasma concentrations of IFNγ, IL-6 or CRP (max 5 pg/ml, 7 pg/ml and 2.5 mg/l respectively). In vitro stimulation assays showed a sustained Pf-specific T cell IFNγ re-call response to both pre-erythrocytic (sporozoite) and blood-stage parasites that persisted over years in all six immunised individuals (Figure 5). These responses remained significantly higher than those of control volunteers (p
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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 175 and 176: 174 Chapter 9 Abstract An effective
Page 177 and 178: 176 Chapter 9 Figure 1. Study desig
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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
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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
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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 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
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
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Page 255 and 256: 254 Chapter 12 Roestenberg M, Teirl
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Summary, Samenvatting, List of publ
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