Structure-guided design of an epitope-focused malaria vaccine

What will it take to design a vaccine that prevents malaria? The blood stage of the disease is an excellent place to intervene as the symptoms of malaria and its transmission through mosquitos both require the malaria-causing parasites to get inside our blood cells. If we can block blood cell invasion, we can prevent malaria.

The most promising blood stage malaria vaccine candidate is PfRH5. We have previously shown how PfRH5 binds to basigin and how this can be prevented by human growth-inhibitory antibodies. However, if people are vaccinated with PfRH5, then parasite growth is slowed, but the disease is not prevented. Can we do better?

In this study, we use rational structure-guided design to make and test a highly focused PfRH5-based vaccine. The most growth inhibitory human antibodies that target PfRH5 bind to a single epitope on one side of the PfRH5 molecule. What happens if we make a vaccine immunogen which only contains this epitope? Will this induce a high-quality response by causing our bodies to only make the most parasite growth-inhibitory antibodies?

To produce a highly effective single epitope immunogen, we needed to build a protein scaffold on which this epitope will fold correctly. We therefore grafted the region of PfRH5 which forms the epitope onto a helical bundle scaffold and redesigned the resultant molecule to adopt the correct fold. We produced this novel molecule, RH5-34EM and showed, using structural biology, that it adopts the correct fold and binds correctly to the target antibody.

We next tested this molecule in a well-established pre-clinical assay, in which we immunised rats and assessed the quality of the antibody responses that resulted. When compared with rats immunised with PfRH5, our new immunogen induced fewer PfRH5-specific antibodies. However, the antibodies induced by the new immunogen were far more potent at preventing parasites from invading blood cells, leading to a very high-quality antibody response.

Finally, we assessed what would happen if we immunised with the focused immunogen and PfRH5 in different orders. Most effective was when we started by immunising with the synthetic immunogen to induce an epitope-specific PfRH5 response, and then followed this with subsequence doses of PfRH5. This immunisation regimen outperformed PfRH5 alone and was also better than starting with doses of a broad PfRH5 vaccine and then using subsequent doses of a focused immunogen to narrow the antibody response.

Our single epitope vaccine is now available for clinical testing for use in future malaria vaccines and we hope that our findings will also provide useful insight to guide future rational vaccine design programs.

Harrison, T.E., Alam, N., Farrell, B., Quinkert, D., Lias, A.M., King, L.D., Draper, S.J., Campeotto, I. and Higgins, M.K. (2024) Rational structure-guided design of a blood stage malaria vaccine immunogen presenting a single epitope from PfRH5. https://doi.org/10.1101/2024.02.29.582763