Experimental infection and protection against ... - TI Pharma

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A saturation of antibody avidity and concentration induced by malaria vaccine candidate Apical Membrane Antigen 1 thus establish an equilibrium depending on their competition for common resources, of which antigen is only one [17]. The availability of other resources, such as growth factors, interleukins and the presence of adhesion molecules may provide critical advantage preserving diversity and preventing dominance of one B-cell pool [18]. This is an interesting hypothesis, because it suggests that possible addition of resources to the antigen (such as cytokine adjuvants) would offer an opportunity to increase the specific B-cell population beyond the current maximum. Few sera did not reach the saturated level, particularly in the Alhydrogel® adjuvanted group. We hypothesize that the antibody response in these sera may not have undergone full maturation and have not (yet) reached a maximum fraction of bound antigen. Similarly, allergen-specific IgE from atopic children also lacked a negative relationship between concentration and avidity [19], whereas this was apparent for the more matured antibody responses in adults [16]. These data are particularly relevant for vaccine development, since the avidity of antibodies may determine susceptibility to diseases such as the Respiratory Syncytial virus or meningococcal disease [20-22]. For AMA1 antibodies, we found a relation between in vitro parasite growth inhibition and antibody concentration, but not avidity. Caution should be taken, however, when concluding that the functionality of AMA1 antibodies in vitro seems to be governed primarily by concentration of antibodies, as epitope functionality has not been taken into account in this study. Particularly PfAMA1 domain I and domain II antibodies are thought to harbour the major targets for inhibitory responses [7]. Moreover, the results of in vitro growth inhibition so far do not correlate with in vivo susceptibility [23]. In conclusion, our data illustrate an inverse relation between concentration and avidity, that becomes saturated at a maximum, constant capacity to bind antigen. Any increase in antibody concentration at this saturated level will be balanced by a decrease in antibody avidity. The appreciation of a saturated antibody response may be crucial for the future development of PfAMA1 vaccine, since it provides guidance to the search for more effective antigens, adjuvants or delivery platforms. 91
92 Chapter 4 Acknowledgements The authors wish to thank GlaxoSmithKline Biologicals, Rixensart, Belgium for supplying AS02A and SEPPIC, Paris, France for supplying Montanide ISA 720. Funding This work was supported by a grant from the European Malaria Vaccine Initiative.
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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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Page 42 and 43: Safety and Immunogenicity of a Reco
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Page 60 and 61: Humoral immune responses to a singl
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Page 87 and 88: 86 Chapter 4 Concentration (mg/ml,
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Page 98 and 99: Chapter 5 Comparison of clinical an
Page 100 and 101: Comparison of clinical and parasito
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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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