Defining mechanisms of protective antibody responses induced by vaccines against blood-stage Plasmodium vivax malaria

Thesis

Plasmodium vivax is the most common cause of malaria outside of Africa and the most geographically widespread. An effective vaccine against P. vivax would greatly aid malaria eliminations efforts worldwide. The leading vaccine candidates against blood-stage infection target the interaction between P. vivax Duffy-binding protein (PvDBP) and Duffy antigen receptor for chemokines (DARC) on red blood cells, an essential interaction required for parasite invasion. A protein/adjuvant vaccine targeting region II of PvDBP (PvDBPII) partially inhibited parasite growth in controlled human malaria infection studies. The degree of parasite growth inhibition correlated with vaccine-induced antibody responses, but the underlying mechanisms are poorly defined. The aim of this Thesis was to isolate and characterise the human antibody response to PvDBPII vaccination. A panel of over 150 IgG monoclonal antibodies (mAbs) against PvDBPII were isolated from human vaccinees. The mAbs were grouped into five epitope binning communities, which showed distinct binding and functional characteristics. Two epitope communities contained mAbs that bind subdomain 2 of PvDBPII and some inhibited binding of PvDBPII to DARC. In contrast, mAbs from all five epitope communities showed parasite growth inhibition activity (GIA) in vitro, including three communities that bind subdomain 3 of PvDBPII. The most potent growth-inhibitory mAbs in the panel were strain-specific, but mostly strain-transcending mAbs were found in one community that binds in subdomain 3. Testing combinations of different mAbs for functional interactions showed that mAbs from different epitope communities were predominantly antagonistic in GIA. This information on the breadth and mechanism of function of human antibodies induced by PvDBPII will help inform the rational design of future PvDBPII-based vaccines. In addition, engineering of mAbs by fusion of a DARC peptide to the Fc region identified an engineered mAb that exceeded the potency of all wild-type anti-PvDBPII mAbs and could be a candidate for further clinical development.

Authors: Hou, MM

• DOI: 10.5287/ora-o0doqnjyb
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: monoclonal antibodies; malaria; vaccines; Plasmodium vivax; Duffy-binding protein
• Subjects: Monoclonal antibodies; Malaria vaccine