Experimental infection and protection against ... - TI Pharma

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Humoral immune responses to a single allele PfAMA1 vaccine in healthy malarianaïve adults. Growth Inhibition (%) 80 60 40 20 0 −20 FCR3 400 800 1600 3200 6400 12800 25600 51200 102400 3D7 400 800 1600 3200 6400 12800 25600 51200 AMA1 IgG (AU/mL) 102400 400 800 1600 3200 6400 12800 25600 51200 102400 Figure 8. Relation between AMA1-specific IgG titre and GIA titre for the homologous (FCR3) and two heterologous strains (3D7 and HB3). The GIA value for the designated strain measured at 10 mg /mL total IgG is depicted on the yaxis and the corresponding Elisa titre to the corresponding AMA1 allele is depicted on the x-axis. Estimated IC50 values are indicated by dashed lines. Symbols represent treatment groups: white circles = Alhydrogel 10 µg, black circles = Alhydrogel 50 µg, white squares = Montanide ISA 720 10 µg, black squares = Montanide ISA 720 10 µg, white diamonds = AS02 10 µg and black diamonds = AS02 50 µg, where the 10 or 50 µg refers to the AMA1 dose. GIA titres determined on the 3D7 laboratory strain at 10 mg/ml IgG were lower than those to the FCR3 strain at the same total IgG concentration and no significant differences were observed between the treatment groups (p=0.095, ANOVA). Interestingly, GIA titres on the 3D7 strain at 10 mg/ml were similar to GIA titres to the homologous FCR3 strain at 5 mg/ml total IgG (Figure 7). GIA titres on the 3D7 laboratory strain at 5 mg/ml IgG were low; only 2 out of 47 subjects had GIA titres higher than 20% (Figure 7). GIA titres determined on the HB3 laboratory strain at 10 mg /ml IgG were lower than to the FCR3 strain and similar to the titres observed for the 3D7 strain. Significant treatment group differences were observed (p=0.004, ANOVA). GIA titres in the AS02 10 µg group were significantly higher than in the Alhydrogel 10 µg group (24.6 %-points, 95% CI 3.4 to 45.8%, p = 0.014, Tukey HSD) and GIA titres in the AS02 10 µg group tended to be higher as compared to the Alhydrogel 50 µg group (20.5%-points, 95% CI -0.2 to 41.3%, p = 0.053, Tukey HB3 71
72 Chapter 3 GIA (%) 80 60 40 20 0 −20 80 60 40 20 0 −20 Alhydrogel 10 Alhydrogel 50 10 FCR3 5 FCR3 ISA 720 10 ISA 720 50 AS02 10 AS02 50 Alhydrogel 10 Alhydrogel 50 10 3D7 5 3D7 ISA 720 10 ISA 720 50 Treatment AS02 10 AS02 50 Alhydrogel 10 Alhydrogel 50 10 HB3 5 HB3 . Figure 7. GIA to 3 laboratory strains (FCR3, homologous and 3D7 and HB3, heterologous) at 10 and 5 mg /ml total IgG obtained at day 84. Top row: GIA at 10 mg /ml and bottom row GIA at 5 mg /ml IgG. Boxes indicate median and quartile ranges. Treatment groups are indicated by Adjuvant name and AMA1 dose, respectively ISA 720 10 ISA 720 50 AS02 10 AS02 50
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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
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 58 and 59: Chapter 3 Humoral immune responses
Page 60 and 61: Humoral immune responses to a singl
Page 80: Humoral immune responses to a singl
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 118 and 119: 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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Section 3 Whole parasite inoculatio
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174 Chapter 9 Abstract An effective
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176 Chapter 9 Figure 1. Study desig
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178 Chapter 9 followed by five iden
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180 Chapter 9 Figure 2. Parasitemia
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182 Chapter 9 Test Day I-1 Day C-1
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184 Chapter 9 strain P. falciparum-
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186 Chapter 9 protective role in ot
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188 Chapter 9 References 1. Greenwo
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190 Chapter 9 27. Orjih AU. Acute m
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192 Chapter 9 medium A (Caltag Labo
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194 Chapter 10 Abstract Induction o
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196 Chapter 10 Pre-erythrocytic sta
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198 Chapter 10 procedures described
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200 Chapter 10 by hand-dissection.
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202 Chapter 10 Figure 3. Mean numbe
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204 Chapter 10 Figure 4. Number of
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206 Chapter 10 temperature (Pearson
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208 Chapter 10 immune modulating ef
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210 Chapter 10 cytokine measurement
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212 Chapter 10 14. Hermsen CC, Telg
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Chapter 11 General Discussion
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General Discussion 217 occurrence o
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General Discussion 219 mediating th
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General Discussion 221 AMA1 express
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General Discussion 223 troponins ca
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General Discussion 225 and between
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General Discussion 227 immunologica
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General Discussion 229 to induce pr
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General Discussion 231 Conclusions
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General Discussion 233 References 1
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General Discussion 235 polymorphonu
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General Discussion 237 57. Church L
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General Discussion 239 85. Beier JC
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General Discussion 241 118. Mueller
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Chapter 12 Summary Samenvatting Lis
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246 Chapter 12 Controlled human mal
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Summary, Samenvatting, List of publ
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254 Chapter 12 Roestenberg M, Teirl
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