New paper describes a novel mechanism for antibody synergy against a malaria vaccine candidate

In our latest study in collaboration with the Higgins lab, led by PhD student Rob Ragotte, we describe the detailed characterisation of a panel of monoclonal antibodies targeting CyRPA. This highly conserved protein is essential for invasion of Plasmodium falciparum into human red blood cells and is a prominent blood-stage malaria vaccine candidate.

We identified anti-CyRPA monoclonal antibodies that strongly inhibit P. falciparum growth in in vitro assays and used structural studies to show that these antibodies bind epitopes on a single face of CyRPA and that they do not block the interaction between CyRPA and RH5, another key vaccine candidate. Surprisingly, we discovered that pairs of non-competing inhibitory antibodies have strongly synergistic growth-inhibitory activity. Even more surprisingly, we found that synergising antibodies bind to neighbouring epitopes on CyRPA to form lateral, heterotypic interactions that lead to improved stability of their binding to CyRPA and increased growth inhibitory activity. While homotypic antibody-antibody interactions have been observed for multiple copies of a same antibody binding to identical epitopes on a repeating antigen, as far as we are aware this is the first report that demonstrates antibody synergy through direct heterotypic interactions. Nevertheless, we anticipate that this mechanism will be a feature of many immune response, particularly as we observed that the lateral interactions between synergising antibodies are mediated by CDR loops and might thus be expected to result from normal processes of antibody diversification and selection.

We now aim to use the insight gained in this study to guide the design of improved CyRPA-based vaccine immunogens, focusing the immune response to the most inhibitory epitopes and driving the production of potently inhibitory antibodies, including those that form synergistic interactions.

Full publication

Ragotte RJ, Pulido D, Lias AM, Quinkert D, Alanine DGW, Jamwal A, Davies H, Nacer A, Lowe ED, Grime GW, Illingworth JJ, Donat RF, Garman EF, Bowyer PW, Higgins MK, Draper SJ. Heterotypic interactions drive antibody synergy against a malaria vaccine candidate. Nat. Commun. 2022. https://doi.org/10.1038/s41467-022-28601-4.