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Woolley, StephenDerek (2021) Utilising volunteer infection studies in the characterisation of anaemia in early malaria, Thesis (Doctoral), Liverpool School of Tropical Medicine.
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S Woolley - Final Version - MD Thesis.pdf - Accepted Version Download (7MB) | Preview |
Abstract
The rapid emergence and spread of antimalarial resistance, especially artemisinin resistance in Plasmodium falciparum, has led to the use of volunteer infection studies (VIS) in the drug development pipeline. This thesis aims to characterise malaria-associated anaemia using the data from an induced blood stage model (IBSM trial), pooled analysis of existing haematology data and the investigation of the iron-infection axis. Investigation of the iron-infection axis has not been conducted previously in VIS studies.
First, the haematology and parasite dataset were expanded with the execution of two IBSM VIS, one using a new bioreactor manufactured malaria cell bank (MCB) and the other a historical MCB. The clinical studies identified that both MCB were safe to use in malaria-naïve, healthy participants, and that the parasite growth and clearance profiles of the new biomanufactured MCB were comparable to the existing P. falciparum MCB used.
Secondly, the haematology and parasite data from 315 participants inoculated with either P. falciparum (n=269) or P. vivax (n=46) were interrogated in a pooled analysis. The effects of age, sex, drug and parasitaemia and recrudescence were evaluated against the fractional fall in haemoglobin, haemoglobin nadir and the reticulocyte response. The fractional fall in haemoglobin, attributable to malaria was ~4% in P. falciparum and ~5% in P. vivax after correction for phlebotomy; the contribution of parasitised erythrocytes to the malaria attributable losses was less than 1% in both species.
Lastly, malaria has recently been described as a cause of iron deficiency, which is a significant public health threat in malaria endemic regions. An exploratory study to characterise the markers of iron metabolism in early malaria was conducted in retrospective samples from previous IBSM VIS. The iron-axis was characterised in P. vivax and artemisinin-resistant K13 strain of P. falciparum, as well as fully drug-sensitive P. falciparum. Those inoculated with P. falciparum had depletion of their body iron stores, with a ~23% reduction in their log ferritin/soluble transferrin receptor index. Reduced baseline iron stores were associated with a reduced reticulocyte response (r=0.39, p=0.015) in those inoculated with P. falciparum.
Finally, in those inoculated with P. falciparum, increased iron stores were associated with increased post-treatment liver transaminases (ALT-r=0.54, p<0.001; AST-r=0.31, p=0.047).
These studies have characterised malaria-attributable malaria in experimental and low-level malaria and have extended the existing information on iron-axis in early P. falciparum infection, as well a possible mechanism for elevations in liver transaminases in malaria VIS.
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