Experimental infection and protection against ... - TI Pharma

More documents

Recommendations

Info

Comparison of clinical and parasitological data from experimental human malaria challenge trials malarial treatment with 48 hours delay after parasites were detected by microscopy. The RUNMC II cohort includes volunteers from 2004 onwards, when more stringent cardiovascular inclusion criteria (based on SCORE cardiovascular risk [11]) were adapted following a case of myocardial infarction in a malarianegative volunteer [7] and an increased threshold for microscopic parasite detection was implemented. RUNMC II includes 12 volunteers who participated in a candidate malaria vaccine trial, but were not protected (Nieman et al. manuscript in preparation). All other volunteers were unimmunized In Oxford, 65 infectivity control volunteers participated in 14 studies [12-18]. All included subjects were healthy, male and female, malaria-naïve volunteers between the ages of 18 and 50 years (Table 1). Malaria naiveté was confirmed by medical and travel history. Volunteers from the RUNMC cohorts were also confirmed negative for antibodies against blood-stage Pf by ELISA [19]. Volunteers were excluded in case of known allergies to anti-malarials, pregnancy, systemic disease or chronic use of medication. Volunteers were screened by a physician based on medical history, physical examination, complete blood count, liver and renal function tests, pregnancy test and serological testing for HIV, hepatitis B and C. Volunteers provided written informed consent and all studies were approved by either the RUNMC Committee on Research involving Human Subjects or Central Committee on Research involving Human Subjects (CMO 0004-0090, 0011-0262, 2001/203, 2002/170, 2004/129, 2006/207, NL14715.000.06, NL24193.091.09) or the Oxfordshire Research Ethics Committee or the UK Gene Therapy Advisory Committee (C01.111, C02.069, C02.152, C02.153, C02.266, C02.268, C02.293, C02.305, CL03.100, C03.088, 04/Q1604/93, 06/Q1604/55, 05/Q1604/69, GTAC 160-02). Infection procedures. Anopheles stephensi mosquitoes were infected with the NF54 strain of Pf (RUNMC) or 3D7, a clone originally derived from NF54, (Oxford) following previously described procedures [20]. Both strains are chloroquine sensitive (data not shown). Fixed numbers of mosquitoes were allowed to bite volunteers during five (Oxford) or ten (RUNMC) minutes. Fully blood-engorged mosquitoes were confirmed positive for salivary gland sporozoites by dissection (a threshold of >10 sporozoites/gland was used in all centres). If necessary, feeding sessions were repeated until exactly the predefined number of infected mosquitoes were 101
102 Chapter 5 fully engorged, i.e. five mosquitoes, except for the RUNMC I cohort, where volunteers were exposed to the bites of four to seven mosquitoes (Table 1). Monitoring took place twice (Oxford) or thrice daily (RUNMC) using microscopy of Giemsa-stained blood smears starting on day five at RUNMC or on the afternoon of day six at Oxford. Volunteers were treated with a standard therapeutic regimen of chloroquine, arthemether/lumefantrine or atovaquone/proguanil as soon as microscopy confirmed the presence of parasites or by the discretion of the physician. Trial volunteers were followed on an outpatient basis and lived in the vicinity of the hospital. An active tracking policy using mobile phones and/or home visits was operational at both institutions during the monitoring period. Adverse events were recorded at every visit. Investigators evaluated the potential relation of adverse events with trial procedures. All probable or possible related events were included in the analysis, with exception of the five volunteers for whom anti-malarial treatment was delayed by 48 hours. The USMMVP report included adverse events from day seven after challenge [6]. Severity of symptoms in RUNMC II and the USMMVP report were assessed according to standard guidelines (http://www.fda.gov/BiologicsBloodVaccines/GuidanceCom plianceRegulatoryInformation/Guidances/Vaccines/ucm074775.htm). Mild symptoms (grade 1) did not interfere with daily activities, moderate symptoms (grade 2) interfered with daily activities, severe symptoms (grade 3) prevented daily activity. Symptom severity was not consistently assessed in the other cohorts, with exception of fever, which was graded mild when 37.5 to 37.9°C, moderate when 38 to 38.9°C and severe when ≥39°C in all cohorts. All centres recorded oral temperatures, which were measured at least once daily, either by volunteers themselves or by the attending physician at the clinical site. RUNMC also recorded auricular temperatures at the clinical site up to three times daily. Serious adverse events (grade 4) were defined according to International Conference of Harmonization Good Clinical Practice Guidelines. Clinical haematological laboratory data were available on a daily basis from day five post-challenge until three days after anti-malaria treatment for RUNMC cohorts. Biochemical parameters in RUNMC cohorts were assessed once, at three days after anti-malarial treatment. Clinical laboratory parameters in Oxford were not routinely recorded during challenge in any trials. For the USMMVP cohort, clinical laboratory parameters were reported at days 10-12 after challenge.
Page 2 and 3:
Experimental infection and protecti
Page 4 and 5:
Experimental infection and protecti
Page 6:
Contents Contents 5 Chapter 1 - Int
Page 10 and 11:
Introduction 9 Malaria Malaria is o
Page 12 and 13:
Introduction 11 Preclinical Clinica
Page 14 and 15:
Introduction 13 pipeline of clinica
Page 16 and 17:
Introduction 15 The division of ant
Page 18 and 19:
Introduction 17 Figure 4. Populatio
Page 20 and 21:
Introduction 19 candidates. Initial
Page 22 and 23:
Introduction 21 - to identify param
Page 24 and 25:
Introduction 23 20. Nussenzweig RS,
Page 26 and 27:
Introduction 25 50. Ouedraogo AL, R
Page 28:
Introduction 27 RTS,S/AS02 in malar
Page 32 and 33:
Chapter 2 Safety and Immunogenicity
Page 34 and 35:
Safety and Immunogenicity of a Reco
Page 36 and 37:
Page 38 and 39:
Page 40 and 41:
Page 42 and 43:
Page 44 and 45:
Page 46 and 47:
Page 48 and 49:
Page 50 and 51:
Page 52 and 53: Safety and Immunogenicity of a Reco
Page 58 and 59: Chapter 3 Humoral immune responses
Page 60 and 61: Humoral immune responses to a singl
Page 80: Humoral immune responses to a singl
Page 83 and 84: Chapter 4 82 Abstract The functiona
Page 85 and 86: 84 Chapter 4 Figure 1. Schematic re
Page 87 and 88: 86 Chapter 4 Concentration (mg/ml,
Page 89 and 90: 88 Chapter 4 Figure 4: Correlation
Page 91 and 92: 90 Chapter 4 positively correlated
Page 93 and 94: 92 Chapter 4 Acknowledgements The a
Page 95 and 96: 94 Chapter 4 determinant of subsequ
Page 98 and 99: Chapter 5 Comparison of clinical an
Page 100 and 101: Comparison of clinical and parasito
Page 118 and 119: Chapter 6 Efficacy of pre-erythrocy
Page 120 and 121: Efficacy of pre-erythrocytic and bl
Page 130 and 131: Chapter 7 NF135.C10: a new Plasmodi
Page 132 and 133: NF135.C10: a new Plasmodium falcipa
Page 152 and 153:
Chapter 8 Induction of malaria in v
Page 154 and 155:
Induction of malaria in volunteers
Page 156 and 157:
Page 158 and 159:
Page 160 and 161:
Page 162 and 163:
Page 164 and 165:
Page 166 and 167:
Page 168 and 169:
Page 170 and 171:
Page 172:
Section 3 Whole parasite inoculatio
Page 175 and 176:
174 Chapter 9 Abstract An effective
Page 177 and 178:
176 Chapter 9 Figure 1. Study desig
Page 179 and 180:
178 Chapter 9 followed by five iden
Page 181 and 182:
180 Chapter 9 Figure 2. Parasitemia
Page 183 and 184:
182 Chapter 9 Test Day I-1 Day C-1
Page 185 and 186:
184 Chapter 9 strain P. falciparum-
Page 187 and 188:
186 Chapter 9 protective role in ot
Page 189 and 190:
188 Chapter 9 References 1. Greenwo
Page 191 and 192:
190 Chapter 9 27. Orjih AU. Acute m
Page 193 and 194:
192 Chapter 9 medium A (Caltag Labo
Page 195 and 196:
194 Chapter 10 Abstract Induction o
Page 197 and 198:
196 Chapter 10 Pre-erythrocytic sta
Page 199 and 200:
198 Chapter 10 procedures described
Page 201 and 202:
200 Chapter 10 by hand-dissection.
Page 203 and 204:
202 Chapter 10 Figure 3. Mean numbe
Page 205 and 206:
204 Chapter 10 Figure 4. Number of
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
Page 216 and 217:
Chapter 11 General Discussion
Page 218 and 219:
General Discussion 217 occurrence o
Page 220 and 221:
General Discussion 219 mediating th
Page 222 and 223:
General Discussion 221 AMA1 express
Page 224 and 225:
General Discussion 223 troponins ca
Page 226 and 227:
General Discussion 225 and between
Page 228 and 229:
General Discussion 227 immunologica
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
Page 236 and 237:
General Discussion 235 polymorphonu
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
Page 244:
Chapter 12 Summary Samenvatting Lis
Page 247 and 248:
246 Chapter 12 Controlled human mal
Page 250 and 251:
Summary, Samenvatting, List of publ
Page 252:
Page 255 and 256:
254 Chapter 12 Roestenberg M, Teirl
Page 258 and 259:
Page 260 and 261:
Page 262:
show all

Experimental infection and protection against ... - TI Pharma

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?