Experimental infection and protection against ... - TI Pharma

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Efficacy of pre-erythrocytic and blood-stage malaria vaccines can be assessed in small sporozoite challenge trials in human volunteers The decreasing malaria incidence in several endemic areas [12] has increased the size and costs of Phase IIb malaria vaccine field trials. Sporozoite challenges can be used for preliminary efficacy selection of candidates. Efficacy goals set by the Malaria Vaccine Roadmap and the target product profile of RTS,S, the only candidate currently in phase III clinical development, dictate a protective efficacy of more than 80% against clinical disease [13] and a 50% reduction of clinical attacks due to Pf respectively [14]. So called all-or-nothing vaccines or very effective “leaky” vaccines will induce full protection and can thus easily be tested by controlled infection. However, in addition to these promising vaccines, vaccine developers may be interested in less efficacious vaccines when combining antigens. Such approach is currently followed, for example, for the malaria vaccine ME-TRAP [15]. We show that in these vaccines, Q-PCR may be useful to improve the power of sporozoite challenge trials to detect 80-90% parasite inhibition. These biological effects correspond with clinical protection in a smaller proportion of subjects. We show that the sensitivity of sporozoite challenge trials is limited by variation in vaccine effect, inter-individual variation in parasite development and the limited time window during which blood-stage parasitemia can be assessed. Inter-individual variation is the most important determinant. Three factors may account for this variation: the parasite inoculum size, parasite fitness and human (innate) immune factors. Standardizations of these points would likely decrease variance. For this purpose, clinical trials testing the needle administration of a predefined number of viable sporozoites are currently planned (NCT01086917). As an alternative, challenge trials using low numbers of erythrocytic stage parasites are conducted, allowing for a longer time window of follow-up [16]. Careful analyses of Q-PCR data from several of such trials are needed to quantify their benefit. We performed calculations using simplified methodology based on crude empirical data, taking into account a limited number of variables. The power of sporozoite challenge trials may be higher if inhibiting effects transcend parasite developmental stage when antigens are shared or combined between stages, or when inter-individual variation is limited. More complicated statistical models, such as previously described by Hermsen et al. [6] and Bejon et al. [17], take into account more variables and may subsequently generate data with higher precision and power, but also require more assumptions and may be less reliable. 125
126 Chapter 6 The community is in urgent need of criteria for selection of vaccine candidates that warrant clinical efficacy trials in the field. Knowing that sporozoite challenge trials can not only evaluate pre-erythrocytic vaccines, but can also confidently assess asexual erythrocytic malaria vaccine candidates is an assuring consummation to the malaria vaccine development community. Acknowledgements We acknowledge the support of the team from the Clinical Centre for Malaria Studies and the volunteers participating in the challenge trials. We would like to thank Teun Bousema for his critical review of the manuscript.
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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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Page 76 and 77: 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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Page 152 and 153: Chapter 8 Induction of malaria in v
Page 154 and 155: Induction of malaria in volunteers
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Page 175 and 176: 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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