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NF135.C10: a new Plasmodium falciparum clone for controlled human malaria infections ANY ADVERSE EVENT NF135.C10(n=3) NF54(n=4) frequency Mean duration days (stdev) frequency Mean duration days (stdev) Smear negative(n=3) frequency Mean duration days (stdev) Abdominal pain Arthralgia Chills 2 0 (0.0) Fatigue 3 2.4 (1.9) 1 3.0 -- 2 13.5 (9.3) Fever 1 0.2 -- 2 0.7 (0.8) Headache 3 1.5 (2.4) 4 2.3 (2.0) 3 4.6 (3.8) Itching 4 3.1 (1.5) 2 5.2 (0.3) Malaise 4 2.5 (3.3) Myalgia 1 2.7 -- 3 1.3 (1.4) 2 2.7 (2.4) Nausea 1 0.1 -- 3 2 (2.0) 1 0.0 -- Vomiting 1 0.4 -- Any 3 1.3 (1.7) 4 2.2 (1.9) 3 5.7 (5.8) GRADE 3 ADVERSE EVENT Headache 1 4.6 -- Malaise 1 0.4 -- Vomiting 1 0.4 -- Any 1 1.8 (2.4) Table 2. Reported solicited adverse events that were considered possibly, probably, or definitely related to the trial procedures. Data is displayed as frequency per event (n) with mean duration in days (n (stdev)), separately for volunteers infected with NF135.C10 (first column) or NF54 (second column) or volunteers that did not became positive by thick smear and PCR (third column). using PCR and rifin microsatellite mapping showed distinct genetic differences between the two strains (Figure 1). Controlled human malaria infection Ten Dutch malaria-naive volunteers were exposed to bites of mosquitoes infected with either NF135.C10 (n=5) or NF54 (n=5). Daily follow-up until day 21 revealed positive thick smears in three out of five volunteers infected with NF135.C10 and four out of five volunteers infected with NF54 parasites. The remaining three smear-negative volunteers were presumptively treated 21 days post-infection (Figure 2A). All blood samples from these three smear negative volunteers were also negative for Pf as retrospectively assessed by qPCR. In Pf positive volunteers, kinetics of parasitemia of both strains were comparable to historical controls (n=48) infected with NF54 (grey area represents 95% CI, Figure 2B [26]). Patent 139
140 Chapter 7 parasitemia for NF135.C10 seemed to occur slightly earlier than for NF54 as measured by thick smear (median of 7.0 days after infection; range 7.0-9.0 versus median of 10.6; range 10.6-11; p=0.05; Mann-Whitney test) and qPCR (median day 7.0; range 6.3-7.0 versus median day 7.3; range 7.0-7.3; p=0.1 Mann-Whitney test, Figure 2B). Particularly the peak of the first cycle seemed higher for NF135.C10 (Geometric Mean (GM) 1.2; 95% CI 0.61-2.4 parasites/µL) than NF54 (GM 0.16; 95% CI 0.055-0.46; p=0.06 Mann-Whitney test). The GM of peak parasitemia was 11 parasites/µL (95% CI 1.8-73) and 30 parasites/µL (95% CI 7.7-120) (p=0.4) for the positive volunteers of the NF135.C10 and NF54 infected groups, respectively. PCR identity of both strains was confirmed by culture of smear-positive samples from several randomly selected infected volunteers. Safety All volunteers, including the smear-negative volunteers, reported solicited adverse events (AEs) that were considered possibly or probably related to the trial procedures (Table 2). All volunteers reported headache with a mean duration of 1.5 (NF135.C10) versus 2.3 (NF54) days and most volunteers experienced fatigue, myalgia and nausea. One volunteer infected with NF54 reported grade three adverse events (malaise, headache and vomiting). Duration and frequency of AEs were not different between NF135.C10 and NF54 infected volunteers in this limited number of volunteers. One infected volunteer of the NF135.C10 group showed a decreased platelet count of 146x10 9 /L at day 3 after treatment (cut-off 150x10 9 /L), which returned to normal values at routine check-up on day 28. D-dimers did not increase in any of the volunteers before thick smear positivity. As can be expected, four volunteers had increased d-dimers (range 632-1100 ng/mL) during treatment, that decreased to normal levels after treatment. Highly sensitive troponin T values were always below 0.05 µg/L. Cellular immune responses We next compared the induction of cellular recall immune responses between volunteers infected with NF135.C10 or NF54. In 24-hour in vitro stimulation assays, T-lymphocytes of volunteers successfully infected with either NF135.C10 or NF54 showed similarly increased IFNγ, TNF and IL-2 responses 35 days after infection (Figure 3A-C). Furthermore, cellular responses showed the same kinetics for both homologous (NF135.C10 infected/NF135.C10 stimulated, NF54 infected/NF54 stimulated)
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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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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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