Dengue pathogenesis in Viet Nam: an exploration of transmission blocking antibodies and the host response to dengue in pregnant women

Thesis

Dengue is the most prevalent arboviral disease that affects humans. Only a small proportion of patients develop severe disease and death is rare, but no specific therapeutics are available and there is only one licensed vaccine, which has limited efficacy and can only be administered to certain groups. The pathogenesis of dengue is also not fully understood. Studies on mAbs from dengue immune donors have provided insights into antibody-mediated protection and disease pathogenesis. Human mAbs neutralize DENVs propagated in highly-controlled cell-culture systems, but there is limited information on whether any of these mAbs neutralize DENVs in viremic blood from patients. I led the development of a ViBNA and characterized the potency of 12 human-derived mAbs (Chapter 2). I found five mAbs failed to neutralize DENV serotypes using the ViBNA, in contrast to the effects observed in cell-culture systems, highlighting the requirement for a more robust DENV neutralization assay. Seven mAbs neutralized at least one DENV serotype, and may have potential as therapeutic antiviral agents for dengue. In Chapter 3, I established 50% effective concentrations for three neutralizing mAbs, ranging from 0.013 μg/mL to 1.289 μg/mL, which could inform the dosing strategy for therapeutic trials of these mAbs. In Chapter 4 I examined both antibodies and other immune response components in pregnant and non-pregnant women with dengue, comparing a range of immunological and virological factors between these two groups. I found the percentage of CD8+ CD27- CD45RA- T cells, and the concentrations of eotaxin, monocyte chemoattractant protein, and macrophage-derived chemokine were lower in pregnant patients. These results contribute to the understanding of dengue pathogenesis in pregnant patients, and support further studies on immunological and virological aspects of dengue during pregnancy.

Authors: Vu, TT

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English