Experimental infection and protection against ... - TI Pharma

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General Discussion 223 troponins can also be found in marathon runners [70], providing evidence for minimal cardiac damage that may not be clinically relevant. D-dimers and LDH have also been proposed as markers for ischemia, based on the hypothesis that endothelial cell activation and increased turnover of coagulation would lead to thrombotic events. Again, although highly sensitive, these markers lack specificity for clinically relevant cardiac damage. Highly elevated d-dimers, particularly after initiation of antimalarial-treatment, have been found in several CHMI volunteers since the initiation of monitoring without re-occurrence of cardiac damage. The correlation of d-dimers with peak temperature suggests that d-dimers are a bystander in inflammation rather than a predictor of cardiac damage (Chapter 10). In conclusion, the lack of knowledge on the aetiology of the cardiac event makes the identification of a “risk correlate” for cardiac damage, and the subsequent identification of volunteers at risk difficult, if not impossible. The continuous monitoring of volunteers for the occurrence of cardiac damage, by means of regular measurement of highly-sensitive troponins thus seems reasonable in order to detect any cardiac event in an early stage. Moreover, the occurrence of the cardiac event has, once again, stressed the importance of close and committed monitoring by the study physicians in order to detect any events in an early stage and prevent escalation. However, the apparently infrequent occurrence of serious adverse events in the large group of volunteers exposed to controlled infections so far and the wealth of data on clinical cases lacking evidence for cardiac damage, may be somewhat reassuring. In addition to the clinical manifestations, participation in a controlled malaria infection trial has a major impact on the daily life of volunteers. This is particularly due to the intense follow-up with blood sampling several times daily. Volunteers’ perception of their participation in such a trial depends mainly on whether they have realistic expectations of trial procedures and the severity of symptoms, indicating the importance of providing accurate and sufficient information to volunteers before the onset of the trial. As is true for any type of clinical research, risks must be minimized and scientific benefits maximized. We believe that the benefits of Phase IIa trials outweigh the potential risks in well-designed studies and will be essential to the development of an effective malaria vaccine, provided that all safeguards are in place for the safety of volunteers [71]. Differences between natural and controlled experimental infections signify the importance of validating the results of Phase IIa challenge trials with data from
224 Chapter 11 Phase IIb field trials in malaria-endemic areas. Only four candidate vaccines have been assessed by both types of trial, allowing a comparison of the protective outcomes. The best studied candidate vaccine, RTS,S, which is currently in Phase III trials, has repeatedly demonstrated a protective efficacy of ~30–50% in Phase IIa trials with sterile protection as the study end point [41, 72, 73]. Interestingly, a similar ~30–50% efficacy of RTS,S was found in Phase IIb trials in the field using time to first clinical malaria episode as the primary study end point [74, 75]. A similar association between the results of Phase IIa and Phase IIb trials was found when testing long-term protection in adults [74, 75]. A second preerythrocytic stage candidate vaccine, ME-TRAP (a multi-epitope string fused to thrombospondin-related adhesion protein), delivered by a DNA prime and attenuated poxvirus boost, induced complete protection in only a few volunteers (three out of 74) in Phase IIa trials, and no protection was found in adult Phase IIb field studies in the Gambia [76, 77]. Artificial blood-stage challenge has been used in a Phase II trial after immunization with Combination B, a combination of merozoite surface protein 1 (MSP1), MSP2 and ring-infected erythrocyte surface antigen (RESA) in 17 volunteers, which resulted in no decrease in parasite growth rates [78]; this is in line with results from a Phase IIb trial of Combination B conducted in Papua New Guinea [79]. Finally, the vaccine candidate AMA1 (3D7 strain) did not show protection in a controlled infection trial [26] and parasitological outcome in an efficacy trial was also non-significant [16]. These limited data indicate that results obtained in controlled malaria infection trials are generally in line with results in the field, but more comparisons are required before definite conclusions can be drawn. The extrapolation of results from controlled infections to the field may also be limited by several potential differences between controlled human malaria infections and naturally acquired infections. One important difference is the delivery of parasites. In an experimental situation the parasite load is delivered almost instantly by five infected mosquitoes. Such a high parasite burden has been considered unnatural and might be an overly stringent test for the protective capacity of the vaccine-induced immune response [80]. However, although the frequency of infectious mosquito bites is generally less than this in malaria-endemic areas, intense transmission can occur. A person may be subjected to 35–96 mosquito bites per night, and in certain areas approximately 10% of mosquitoes are infected with Pf [81]. Second, controlled malaria infections are carried out using one parasite strain only, whereas it is well known that Pf field strains are genetically diverse within
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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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NF135.C10: a new Plasmodium falcipa
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Chapter 8 Induction of malaria in v
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Induction of malaria in volunteers
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Section 3 Whole parasite inoculatio
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Page 199 and 200: 198 Chapter 10 procedures described
Page 201 and 202: 200 Chapter 10 by hand-dissection.
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Page 207 and 208: 206 Chapter 10 temperature (Pearson
Page 209 and 210: 208 Chapter 10 immune modulating ef
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 230 and 231: General Discussion 229 to induce pr
Page 232 and 233: General Discussion 231 Conclusions
Page 234 and 235: General Discussion 233 References 1
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Page 238 and 239: General Discussion 237 57. Church L
Page 240 and 241: General Discussion 239 85. Beier JC
Page 242 and 243: General Discussion 241 118. Mueller
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