Poster Presentation The 47th Lorne Conference on Protein Structure and Function 2022

Targeting the circumsporozoite protein of Plasmodium falciparum (#215)

Joe A Kaczmarski 1 2 , Henry J Sutton 3 , Lauren Abraham 3 , Xin Gao 3 , Hayley A McNamara 3 , Deepyan Chatterjee 3 , Colin J Jackson 1 2 , Ian A Cockburn 3
  1. ARC Centre of Excellence in Synthetic Biology, Research School of Biology, Australian National University, Canberra, ACT, Australia
  2. ARC Centre of Excellence for Innovations in Peptide and Protein Science , Research School of Chemistry, Australian National University, Canberra, ACT, Australia
  3. John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia

The most advanced malaria vaccine, RTS,S/AS01, aims to induce antibodies that target the central repeat region of the Plasmodium falciparum circumsporozoite protein (PfCSPrep.), an immunodominant antigen that covers the surface of the sporozoite-stage parasite. However, evidence suggests that PfCSPrep. may have evolved to act as an immune decoy to direct the immune response away from more protective epitopes on PfCSP or other Plasmodium proteins. Indeed, vaccination with RTS,S/AS01 confers sub-optimal protection, with overall efficacy below 40 % in clinical trials. A better molecular understanding of how antibodies and B-cell receptors recognise PfCSPrep. and the mechanisms that drive or constrain the development of a protective immune response is essential for guiding the design of more effective malaria vaccines based on PfCSP. Using X-ray crystallography, computational modelling and isothermal titration calorimetry, we have previously shown that up to six copies of the murine monoclonal antibody, mAb 2A10, bind the central repeats of PfCSP to form a high-avidity complex, and that shortening of the central repeat region can help direct the immune response to more protective epitopes on PfCSP. Here, we look more closely at the factors that determine the fate of B-cells targeting PfCSPrep. during the process of affinity maturation. Combining single cell RNA-sequencing and surface plasmon resonance experiments, we track the development of the immune response following PfCSP exposure in mice that carry the germline precursor of mAb 2A10 and highlight the connection between IgG-PfCSP affinity and B-cell fate. We discuss how structural characteristics of PfCSP may promote sub-optimal immune responses, and explore implications for the design of next-generation antimalarial vaccines and prophylaxis treatments.

  1. Fisher CR, Sutton HJ, Kaczmarski JA, McNamara HA, Clifton B, Mitchell J, Cai Y, Dups JN, D'Arcy NJ, Singh M, Chuah A, Peat TS, Jackson CJ, Cockburn IA. T-dependent B cell responses to Plasmodium induce antibodies that form a high-avidity multivalent complex with the circumsporozoite protein. PLoS Pathog. 2017 Jul 31;13(7):e1006469. doi: 10.1371/journal.ppat.1006469. PMID: 28759640; PMCID: PMC5552345.
  2. Chatterjee D, Lewis FJ, Sutton HJ, Kaczmarski JA, Gao X, Cai Y, McNamara HA, Jackson CJ, Cockburn IA. Avid binding by B cells to the Plasmodium circumsporozoite protein repeat suppresses responses to protective subdominant epitopes. Cell Rep. 2021 Apr 13;35(2):108996. doi: 10.1016/j.celrep.2021.108996. PMID: 33852850; PMCID: PMC8052187.