How do naturally occurring antibodies recognise the malaria vaccine candidate PfRH5?

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The PfRH5 protein is essential for the most-deadly malaria parasite, Plasmodium falciparum, to invade human red blood cells and to replicate. PfRH5 is therefore the leading blood-stage malaria vaccine candidate currently in development. Understanding how human antibodies bind to PfRH5 will be important to guide the design of vaccine immunogens which induce the most protective immune response.

Our previous work structurally characterised the most parasite growth-neutralising antibodies generated when human volunteers are vaccinated with PfRH5, revealing that antibodies which bind to two key epitopes regions are the most effective. But what about antibodies which are induced in people in malaria endemic regions when they suffer from malaria? We have now teamed up with Joshua Tan’s team to see where the most effective infection-induced antibodies bind on PfRH5.

Lawrence Wang and Andrew Cooper, working with Josh, isolated a large panel of PfRH5-binding antibodies from Malian volunteers who had previous experienced natural malaria infection. They also cloned a panel of antibodies from volunteers in Oxford who had not experienced malaria infection but had been vaccinated with PfRH5. In both cases, they identified effective parasite-neutralising antibodies, albeit finding these to be much less common in those who experienced natural infection than those vaccinated.

Brendan Farrell then joined the project to structurally characterise the most important antibodies. He showed that the two most effective antibodies generated by natural infection bind to the same sites on PfRH5 as the most effective antibodies induced by vaccination. He also structurally characterised a neutralising vaccine-induced antibody, R5.008 previously isolated by Dan Alanine, revealing for the first time this third neutralising epitope. 

This study has various important consequences for vaccine design. First, it reveals that the three epitopes for neutralising antibodies span around the full ‘top-half’ of PfRH5. This comprehensive analysis of PfRH5-tageting antibodies has shown us the antigenic landscape which we must include when designing vaccine immunogens.

Secondly, it shows that neutralising antibodies that target PfRH5 are much less likely to be induced by natural infection than by vaccination. In a way, this is also good news, as natural infection does not induce sterile protection against future malaria infection. Perhaps PfRH5 vaccination might?

The final piece of good news is that, while different in their prevalence, neutralising antibodies induced by natural infection and vaccination are very similar in their sequence and epitopes. It is therefore possible that people who have been vaccinated with PfRH5 and are then infected with the parasite, might have their vaccine-induced antibodies boosted by parasite infection. If true, this might increase the length of time over which PfRH5 vaccines retain their effects.

Wang, L.T.*, Cooper, A.*, Farrell, B.*, Miura, K., Diouf, A., Muller-Sienerth, N., Crosnier, C., Purser, L., Maciuszek, M., Barret, J.R., McHugh, K., Tucker, C., Li, S., Doumbo, S., Doumtabe, D., Pyo, C.-P., Nielsen, C.M., Silk, S.E., Kayentao, K., Ongoiba, A., Nguyen, D.C., Lee, F.E., Minassian, A.M., Geraghty, D.E., Traore, B., Seder, R.A., Crompton, P.D., Wright, G., Draper, S.J., Long, C., Higgins, M.K. and Tan, J. (2023) Natural malaria infection elicits rare but potent neutralizing antibodies to the blood-stage antigen RH5. BioRXIV doi.org/10.1101/2023.10.04.560669 (* contributed equally)