Experimental infection and protection against ... - TI Pharma

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Introduction 19 candidates. Initially developed as a therapy for neurosyphilis in the 1920’s [67], controlled malaria infections were established in their present form in the 1980s, when techniques to culture parasites and obtain laboratory-reared infectious mosquitoes were available [68-70]. In controlled infection trials, human (malaria-naïve) volunteers are deliberately exposed to bites of a predefined number of infectious mosquitoes. Subjects are subsequently followed, mostly on an out-patient basis, for clinical and parasitological endpoints. As soon as parasites are detected in the circulation by microscopy, volunteers are treated with anti-malarials for obvious safety reasons. As such, parasitemia is generally kept below 0.0004% (~10-20 Pf/µl) and severe malaria does not occur [71-73]. By comparing the proportion of infected subjects between vaccine and control groups, preliminary efficacy data can be obtained. If clinical protection is not achieved, the pre-patent period may be used as a surrogate marker preceding clinical protection. The recent development of molecular techniques for the detection and quantification of parasites [74] has further refined the parasitological endpoints to include a detailed analysis of kinetics of blood stage parasite growth. In addition, statistical models have become available to analyse these data [75, 76]. Such analysis may be helpful to identify the mechanism of immunity induced by the vaccine candidate [77, 78]. Controlled malaria infection studies have halted the development of candidate vaccines LSA1 and PfCS102 [31, 79], whereas a ~30-50% protection induced by the vaccine candidate RTS,S in an initial controlled infection study was translated into a similar protectivity against clinical malaria in the field [27, 80-83]. Controlled malaria infection trials are thought particularly suitable for evaluation of pre-erythrocytic malaria vaccine candidates, since they employ the natural route of infection (mosquito bite) and allow full pre-erythrocytic stage development. For asexual erythrocytic stage vaccines, the use of controlled malaria infections is controversial, because only low levels of blood stage parasitemia are induced until the trial is interrupted by treatment [12]. Vaccines would thus have to exert significant inhibition in a very small time window. Because controlled human malaria infection trials require the combined technical ability to rear Pf infected mosquitoes and the clinical facility to closely monitor healthy human volunteers, such trials are currently routinely carried out in only five institutions worldwide: the US Military Malaria Vaccine Program; the University of Maryland, USA; the Radboud University Nijmegen Medical Centre,
20 Chapter 1 The Netherlands; The University of Oxford, UK; and, more recently, Seattle Biomed, USA [84]. Thesis outline The current thesis aims at exploring the induction of protection against Plasmodium falciparum malaria in humans with specific attention for three research questions: What is the safety and immunogenicity of malaria vaccine candidate Apical Membrane Antigen 1 (AMA1) in humans? Apical Membrane Antigen 1 is a promising vaccine candidate. It has been produced as a recombinant protein, covering amino acids 25-545, in Pichia pastoris and has shown to be immunogenic with satisfactory pharmacotoxicology in animal models. As with most asexual erythrocytic stage antigens, AMA1 is highly polymorphic and relies on the induction of antibodies for conveying protection. We will address the following objectives in its first phase of clinical development: - to determine the safety profile of PfAMA1 FVO (25-545) when administered to humans in two different doses with three different adjuvants (Chapter 2) - to determine the quantity and quality of antibodies induced by PfAMA1 FVO (25-545) in humans (Chapter 2,3,4) How can we optimize controlled human malaria infections in order to maximize safety and scientific information? Controlled human malaria infections (CHMI) are currently used to assess preliminary efficacy of pre-erythrocytic vaccine candidates in a limited number of institutions worldwide. Because controlled infections seem an efficient tool for investigating malaria immunology and candidate vaccine efficacy, we will investigate how to optimize its protocol. We will explore the comparability and power of the current model with the following specific objectives: - to identify parameters influencing the comparability of CHMI safety and parasitological outcome in different institutions (Chapter 5)
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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 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
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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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