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Protection against a Malaria Challenge by Sporozoite Inoculation 181 No parasites were seen in the thick blood-smears of any of the 10 vera following each of the three immunization sessions under CQ prophylaxis, but after the first immunization a brief sub-microscopic parasitemic episode was detected in all vera (Figure 2a). This was not unexpected, since CQ has no effect against either sporozoites, liver-stage parasites, or the early ring forms of the first generation of blood-stage parasites caused by merozoites released from mature hepatic schizonts [11]. Following each of the subsequent two immunizations, a progressively reduced incidence and burden of sub-microscopic parasitemia was seen. In line with these findings, all vera reported solicited or unsolicited adverse events at least once during the immunization phase. When excluding local itching after the mosquito bites, adverse events were most commonly reported after the first immunization (9/10 volunteers), with headache being the most frequent (7/10) (Table 1). Only few adverse events occurred subsequently (0/10 and 2/10 volunteers after the second and third immunization respectively). Severe adverse events were reported by three vera: two experienced fever above 39°C after the first immunization, one reported severe malaise after the last immunization. Following challenge with homologous NF54 strain of P. falciparum, asexual blood-stage parasites were detected in thick blood smears of all 5 control volunteers between days 7 and 10.6 post-exposure (mean pre-patent period 9.2 days). Real-time PCR analyses revealed the expected cyclical multiplication of blood-stage parasites (Figure 2b). Clinical course and kinetics of parasite multiplication were identical to those in previous studies involving naïve volunteers [23,24], with all controls reporting severe events, in particular fever above 39°C and malaise (Table 1). In marked contrast, there was no evidence of blood-stage parasites in any of the vera at any time during the post-challenge follow-up period till day 20, either by repeated microscopy of thick blood smears or by real-time PCR analyses (Figure 2b). Interestingly, 9/10 vera did report mild to moderate events in the week following challenge. No serious adverse events occurred during any part of the trial and all 15 volunteers completed follow-up according to protocol. Mean peak chloroquine and desbutyl-chloroquine levels measured 24 hours after administration were 76 µg/l (range 58-104 µg/l) and 13 µg/l (5-33 µg/l) respectively and did not differ between control and vera. The day before challenge plasma levels had dropped to 8 µg/l (range
182 Chapter 9 Test Day I-1 Day C-1 Vaccine group (N=10) Control group (N=5) Vaccine group (N=10) Control group (N=5) No. of Median No. of Antibody Median No. of Antibody Median Antibody No. of Median Antibody Subjects Titre Subjects Titre Subjects Titre Subjects Titre AU AU AU AU CSP 0
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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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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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Page 154 and 155: Induction of malaria in volunteers
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Page 177 and 178: 176 Chapter 9 Figure 1. Study desig
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Page 193 and 194: 192 Chapter 9 medium A (Caltag Labo
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Page 197 and 198: 196 Chapter 10 Pre-erythrocytic sta
Page 199 and 200: 198 Chapter 10 procedures described
Page 201 and 202: 200 Chapter 10 by hand-dissection.
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Page 205 and 206: 204 Chapter 10 Figure 4. Number of
Page 207 and 208: 206 Chapter 10 temperature (Pearson
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Page 211 and 212: 210 Chapter 10 cytokine measurement
Page 213 and 214: 212 Chapter 10 14. Hermsen CC, Telg
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Page 218 and 219: General Discussion 217 occurrence o
Page 220 and 221: General Discussion 219 mediating th
Page 222 and 223: General Discussion 221 AMA1 express
Page 224 and 225: General Discussion 223 troponins ca
Page 226 and 227: General Discussion 225 and between
Page 228 and 229: General Discussion 227 immunologica
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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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