Abstract
Functional antibody responses to malaria transmission-blocking vaccines (TBVs) are assessed using the Standard Membrane Feeding Assay (SMFA). This assay quantifies percentage reduction of oocyst levels in mosquitoes fed gametocytes mixed with antisera/antibodies, referred to as transmission-reducing activity (TRA). As TBVs advance to large clinical trials, new scalable assays are needed to characterize vaccine responses. Here, we developed an epitope-specific competitive ELISA platform (P230Compete) for TBV candidate Pfs230D1, based on single-chain variable fragments (scFv) against epitopes recognized by human monoclonal antibodies with high TRA. We quantified functional epitope-specific antibody responses (F) in Phase 1 Pfs230D1-EPA/AS01 vaccine trial participants, using 171 serum samples collected at two post-vaccination timepoints. Five antibody features were examined by P230Compete including total IgG (reported as ELISA units, EUF), IgG subclasses (IgG1F, IgG3F, IgG4F), and bound complement factor C1q (C1qF). EUF and IgG1F demonstrated strong correlation and excellent prediction of TRA≥80% in logistic regression analysis (AUC of 0.81 for both assays post-dose 3, and 0.80 and 0.76 post-dose 4). Furthermore, combining EUF and IgG1F showed even better predictive performance at each timepoint. P230Compete offers a promising proxy assay to replace SMFA in late-stage Pfs230D1 trials.
Authors
Cristina A. Meehan, Matthew V. Cowles, Robert D. Morrison, Yuyan Yi, Jingwen Gu, Jen C.C. Hume, Mina P. Peyton, Issaka Sagara, Sara A. Healy, Jonathan P. Renn, Patrick E. Duffy
