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Induction of malaria in volunteers by intradermal injection of cryopreserved Plasmodium falciparum sporozoites Figure 3. Number of possibly, probably, or definitely related solicited and unsolicited adverse events reported over time in the 2,500 (black ), 10,000 (red ) and 25,000 PfSPZ Challenge dose (green ) groups. Results Parasitemia after injection of PfSPZ Challenge Thirty-six healthy, malaria-naïve volunteers were screened and eighteen were included. All volunteers completed follow-up (Figure S2). After ID injection of PfSPZ Challenge, 15 of the 18 volunteers developed a positive blood smear for Pf, five of six volunteers from each group (Table 1). The slide-negative volunteers in each group were presumptively treated with atovaquone/proguanil at 21 days post-infection. Blood slides were first positive 11 to 14.3 days after administration of PfSPZ Challenge. The geometric mean (GM) pre-patent period was similar for all groups i.e. 13.0, 12.7, and 13.0 days for the groups receiving 2,500, 10,000, and 25,000 PfSPZ Challenge, respectively (ANOVA p=0.92). The GM parasite densities by microscopy at the time of diagnosis were 12.4, 11.2, and 23.4 parasites/μL blood (ANOVA p=0.69 on log-transformed data) (Table 1). Quantitative PCRs (qPCRs) were first positive 9⋅0 to 12 days after challenge (Table 1). Volunteers in the 2,500, 10,000, and 25,000 PfSPZ Challenge groups had similar GM times to first detection of parasites by qPCR of 10.6, 10.3, and 9.9 days (ANOVA p=0.486) at a GM parasite density of 0.07, 0.2 and 0.2 parasites/μL blood (ANOVA p=0.24), respectively. The GM parasite densities by PCR at the time of thick smear diagnosis were 35, 5, and 132 parasites/μL (ANOVA p=0⋅23). Thick smear and qPCR were negative throughout the 21-day 159
160 Chapter 8 Adverse-event Number of volunteers 2,500 (n=6) 10,000 (n=6) 25,000 (n=6) Mean Duration ±SD (days) Number of volunteers Mean Duration ±SD (days) Number of volunteers Mean Duration ±SD (days) Abdominal pain 1 2.9 1 0.04 2 0.3±0.1 Arthralgia 0 N/A 0 N/A 0 N/A Chest pain 1 0.04 0 N/A 0 N/A Chills 1 2.0 2 0.3±0.2 2 0.9±0.6 Diarrhea 0 N/A 0 N/A 1 0.8 Fatigue 5 2.9±3.3 3 2.5±1.7 5 3.0±3.9 Fever 3 1.6±1.5 2 1.8±0.6 4 0.8±0.4 Headache 6 1.1±1.1 6 1.5±1.6 6 1.4±2.6 Malaise 2 2.2±2.4 5 1.8±1.4 1 0.7 Myalgia 2 3.7±3.2 2 1.3±0.5 2 0.8±0.1 Nausea 3 1.7±1.3 5 0.9±0.9 3 1.0±0.9 Vomiting 0 N/A 2 0.01±0.0 0 N/A Any 6 2.0±1.4 6 1.1±0.8 6 1.1±1.0 Grade 3 adverse event Fatigue 0 N/A 0 N/A 1 2.2 Fever 0 N/A 1 1.2 0 N/A Headache 2 3.0±0.4 0 N/A 0 N/A Malaise 1 4.8 0 N/A 1 0.1 Vomiting 0 N/A 2 0.01±0.0 0 N/A Any 2 3.9±0.2 3 0.6±0.0 2 1.2±0.0 Table 2. Numbers of volunteers reporting solicited adverse events possibly, probably, or definitely related to administration of PfSPZ Challenge, with mean duration of events N/A: not applicable follow-up for the three slide-negative volunteers. Parasite growth was cyclical, and was similar in all dose groups (Figure 2). Safety. All volunteers, including the three volunteers who did not develop parasitemia, reported solicited adverse events (AEs) considered possibly, probably, or definitely related to the trial procedures (clinical malaria) (Table 2). Headache was the most frequently reported AE, and occurred in all volunteers including the three who did not develop parasitemia. There were no significant differences among the groups in solicited AEs, which were most frequently reported between days 12 and 18 post-injection. The total number of solicited and unsolicited AEs reported over time is shown in Figure 3. Routine daily laboratory tests showed no clinically significant abnormalities before initiation of anti-malarial treatment. Three or four days after receiving the first dose of atovaquone/proguanil, four volunteers had thrombocyte levels in the range 78-95 × 10 9 /L, which was below the lower limit of normal (120 ×
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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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Page 177 and 178: 176 Chapter 9 Figure 1. Study desig
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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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