Experimental infection and protection against ... - TI Pharma

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Chapter 2 Safety and Immunogenicity of a Recombinant Plasmodium falciparum AMA1 Malaria vaccine Adjuvanted with Alhydrogel TM , Montanide ISA 720 or AS02. Meta Roestenberg* 1 , Ed Remarque 2 , Erik de Jonge 1 , Rob Hermsen 1 , Hildur Blythman 3 , Odile Leroy 3 , Egeruan Imoukhuede 3 , Soren Jepsen 3 , Opokua Ofori- Anyinam 4 , Bart Faber 2 , Clemens H. M. Kocken 2 , Miranda Arnold 2 , Vanessa Walraven 2 , Karina Teelen 1 , Will Roeffen 1 , Quirijn de Mast 1 , W. Ripley Ballou 4,5 , Joe Cohen 4 , Marie Claude Dubois 4 , Stéphane Ascarateil 6 , Andre van der Ven 1 , Alan Thomas 2 , Robert Sauerwein 1 1 Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 2 Biomedical Primate Research Centre, Rijswijk, The Netherlands 3 European Malaria Vaccine Initiative, Copenhagen, Denmark 4 GlaxoSmithKline Biologicals, Rixensart, Belgium 5 Present address: Bill and Melinda Gates Foundation, Seattle, USA 6 SEPPIC, Paris, France PLoS ONE 2008; 3:e3960
Chapter 2 32 Abstract Plasmodium falciparum Apical Membrane Antigen 1 (PfAMA1) is a candidate vaccine antigen expressed by merozoites and sporozoites. It plays a key role in red blood cell and hepatocyte invasion that can be blocked by antibodies. We assessed the safety and immunogenicity of recombinant PfAMA1 in a doseescalating, phase Ia trial. PfAMA1 FVO strain, produced in Pichia pastoris, was reconstituted at 10 µg and 50 µg doses with three different adjuvants, Alhydrogel, Montanide ISA720 and AS02 Adjuvant System. Six randomised groups of healthy male volunteers, 8-10 volunteers each, were scheduled to receive three immunisations at 4-week intervals. Safety and immunogenicity data were collected over one year. Transient pain was the predominant injection site reaction (80-100%). Induration occurred in the Montanide 50 µg group, resulting in a sterile abscess in two volunteers. Systemic adverse events occurred mainly in the AS02 groups lasting for 1-2 days. Erythema was observed in 22% of Montanide and 59% of AS02 group volunteers. After the second dose, six volunteers in the AS02 group and one in the Montanide group who reported grade 3 erythema (>50mm) were withdrawn as they met the stopping criteria. All adverse events resolved. There were no vaccine-related serious adverse events. Humoral responses were highest in the AS02 groups. Antibodies showed activity in an in vitro growth inhibition assay up to 80%. Upon stimulation with the vaccine, peripheral mononuclear cells from all groups proliferated and secreted IFNγ and IL-5 cytokines. In conclusion, all formulations showed distinct reactogenicity profiles. All formulations with PfAMA1 were immunogenic and induced functional antibodies.
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 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
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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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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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