Experimental infection and protection against ... - TI Pharma

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Safety and Immunogenicity of a Recombinant Plasmodium falciparum AMA1 Malaria vaccine Adjuvanted with Alhydrogel TM, Montanide ISA 720 or AS02 Figure 3. Representative immunofluorescent microscopy picture, showing recognition of native antigen on merozoites by induced anti-AMA1 antibodies. Immunofluorescence picture of merozoites incubated with 40x diluted anti-AMA1 plasma from an immunized volunteer one month after final immunisation stained with Rabbit anti-human immunoglobulin FITC (A) and DAPI (B). Photo was taken at magnification 400x. Incubation with monoclonal antibody 4G2, a pan-specific anti- AMA1 antibody, confirmed the surface staining pattern (not shown). Humoral immune response Peak antibody titres were observed one month after the final immunisation. 100% of volunteers in the 10 and 50 µg AS02 and 50 µg Montanide groups showed a greater than four-fold increase in antibody titre over preimmunisation compared to 60% in the 10 µg Alhydrogel, 80% in the 50 µg Alhydrogel and 90% in the 10 µg Montanide groups (Figure 2). All vaccinees had reached IgG titres comparable to or higher than semi immune sera. Two and four months post final immunisation both AS02 groups and the Montanide 50 µg group showed the highest IgG titres but given the small sample sizes there was no power to detect statistical differences between groups. Antibody titres decreased further one year post immunisation, with the steepest decline being in the Montanide groups, to a level comparable with the reference Alhydrogel groups. One year post vaccination, titres in the 10 µg AS02 group were significantly higher as compared to the reference group (post hoc Bonferroni when compared with low dose Alhydrogel reference group p
46 Chapter 2 Figure 4. ELISPOT assay for IFNγ (A) and IL-5 (B) after stimulation with 6 µg PfAMA1. Peripheral Blood Mononuclear Cells from immunised volunteers 28 days after the second immunisation and 28 days after the third immunisation (day 56 and 84 respectively) were stimulated with 6 µg of PfAMA1 vaccine. Production of IFNγ and IL- 5 was measured by counting spots in ELISPOT plates. Box plots and whiskers show the range and the 25th, 50th and 75th percentile of spots per 2x10 5 cells. Circles represent outliers.
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 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
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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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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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