Experimental infection and protection against ... - TI Pharma

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Chapter 9 Protection against a Malaria Challenge by Sporozoite Inoculation Meta Roestenberg 1 *, Matthew McCall 1 *, Joost Hopman 1 , Jorien Wiersma 1 , Adrian J.F. Luty 1 , Geert Jan van Gemert 1 , Marga van de Vegte-Bolmer 1 , Ben van Schaijk 1 , Karina Teelen 1 , Theo Arens 1 , Lopke Spaarman 1 , Quirijn de Mast 2 , Will Roeffen 1 , Georges Snounou 3 , Laurent Rénia 4 , Andre van der Ven 2 , Cornelus C. Hermsen 1 , Robert Sauerwein 1 *These authors contributed equally 1 Department of Medical Microbiology Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands 2 Department of General Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands 3 Department of Parasitology, INSERM Unité 511, Hôpital Pitié– Salpêtrière, and the Université Pierre et Marie Curie, Paris, France 4 Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Technology and Research, Biopolis, Singapore [L.R.). N Engl J Med 2009; 361:468-77.
174 Chapter 9 Abstract An effective vaccine for malaria is urgently needed. Naturally acquired immunity to malaria develops slowly, and induction of protection in humans can be achieved artificially by the inoculation of radiation-attenuated sporozoites by means of more than 1000 infective mosquito bites. We exposed 15 healthy volunteers — with 10 assigned to a vaccine group and 5 assigned to a control group — to bites of mosquitoes once a month for 3 months while they were receiving a prophylactic regimen of chloroquine. The vaccine group was exposed to mosquitoes that were infected with Plasmodium falciparum, and the control group was exposed to mosquitoes that were not infected with the malaria parasite. One month after the discontinuation of chloroquine, protection was assessed by homologous challenge with five mosquitoes infected with P. falciparum. We assessed humoral and cellular responses before vaccination and before the challenge to investigate correlates of protection. All 10 subjects in the vaccine group were protected against a malaria challenge with the infected mosquitoes. In contrast, patent parasitemia (i.e., parasites found in the blood on microscopic examination) developed in all five control subjects. Adverse events were mainly reported by vaccinees after the first immunization and by control subjects after the challenge; no serious adverse events occurred. In this model, we identified the induction of parasite-specific pluripotent effector memory T cells producing interferon-γ tumour necrosis factor α, and interleukin-2 as a promising immunologic marker of protection. In conclusion, protection against a homologous malaria challenge can be induced by the inoculation of intact sporozoites.
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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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Page 193 and 194: 192 Chapter 9 medium A (Caltag Labo
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Page 199 and 200: 198 Chapter 10 procedures described
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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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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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