Experimental infection and protection against ... - TI Pharma

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Induction of malaria in volunteers by intradermal injection of cryopreserved Plasmodium falciparum sporozoites Introduction Malaria caused by Plasmodium falciparum [Pf] causes approximately one million deaths and 250 million clinical cases annually [1-2]. Implementation of insecticide impregnated bednets, residual insecticide spraying, and combinations of antimalarial drugs, has reduced malaria associated morbidity and mortality in many areas [1]. Questions related to sustainability of this effort, however, have led to a recent delineation of requirements for new tools [3]. A safe, long-acting anti-malarial drug and a highly effective malaria vaccine would be powerful tools for control and elimination of Pf malaria. Progress has been facilitated by the capacity to infect volunteers under controlled conditions in order to test new vaccines and drugs. Volunteers are infected by exposure to laboratory-reared Anopheles spp. mosquitoes transmitting Pf sporozoites (SPZ) [4], which was first introduced for treatment of neurosyphilis in the 1920s [5]. The development of drugs such as chloroquine [6], primaquine [7], and atovaquone [8] were facilitated by these controlled human malaria infections. The ability to culture Pf gametocytes [9-10] enhanced the capacity to produce infected mosquitoes for controlled human malaria infection (CHMI) studies. Although potentially serious or even lethal, Pf malaria can be radically cured at the earliest stages of blood infection when risks of complications are virtually absent. CHMIs are restricted to a few specialized centres that can produce PfSPZ-infected mosquitoes, where more than 1,300 volunteers have been safely infected by the bite of PfSPZ-infected mosquitoes since 1986, primarily for clinical trials of malaria vaccines [4, 11-15], but also for trials of drugs [8] and diagnostic tests [16], and studying human immune responses to Pf [17]. In addition to the use of CHMIs for testing vaccines and drugs, controlled infections can also be used to immunize against malaria. For example, immunization with radiation-attenuated PfSPZ by bites of mosquitoes protects > 90% of volunteers [18-20]. And recently 100% protection against CHMI was achieved by immunization of volunteers with PfSPZ by mosquito bites while taking chloroquine [21-22]. These highly protective immunization strategies have not been translated into an implementable vaccine, because they require inoculation of SPZ by mosquito bites. Inoculation of SPZ by injection would be a more feasible method and was performed through the early 1950s. The SPZ preparations used, however, were 153
154 Chapter 8 contaminated with bacteria and rates of infection with frozen and thawed SPZ were highly variable [23-26]. A contemporary approach to production of SPZ for vaccination requires generating aseptic SPZ-infected mosquitoes, purifying SPZ from mosquito tissues, vialing, preserving, and administering the SPZ by needle and syringe. Sanaria has met these requirements to produce an attenuated (irradiated) PfSPZ vaccine [27-28] and infectious (non-irradiated) aseptic, purified, vialed, cryopreserved PfSPZ (PfSPZ Challenge). Here we report infection of volunteers with PfSPZ Challenge administered intradermally (ID) by needle and syringe. Methods Study population and study design This open label, Phase 1 clinical trial was performed at Radboud University Nijmegen Medical Centre, the Netherlands, from October 2010 to July 2011. Volunteers aged 18-35 years were screened for eligibility by assessing medical history, physical examination, haematological, biochemical, urine toxicology, and pregnancy tests, and malaria, HIV, hepatitis B and hepatitis C serology. The main exclusion criteria were pregnancy, residence in a malaria endemic area within the previous six months, positive Pf serology, symptoms, physical signs or laboratory test results suggestive of systemic disorders, and history of drug or alcohol abuse interfering with normal social function. All volunteers gave written informed consent. Eighteen healthy malaria-naïve volunteers were recruited for this trial. Groups of six volunteers were injected ID with 2,500, 10,000, or 25,000 PfSPZ Challenge. The sample size of six per group had a power of 75% to show a difference between 2 of 6 volunteers infected in the 2,500 PfSPZ group and 6/6 volunteers infected in the 25,000 PfSPZ group. Dose escalation was done at a minimum interval of 3.5 weeks. The trial was performed in accordance with Good Clinical Practice and an Investigational New Drug application filed with the U.S. Food and Drug Administration, and approved by the Central Committee for Research Involving Human Subjects of The Netherlands (CCMO NL31858.091.10). Clinicaltrials.gov identifier: NCT 01086917.
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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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Comparison of clinical and parasito
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Page 177 and 178: 176 Chapter 9 Figure 1. Study desig
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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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