How do naturally occurring antibodies recognise the malaria vaccine candidate PfRH5?
Brendan Farrell from the Higgins group, working with colleagues at the National Institute of Health, has played a major role in a new study which examines how naturally occurring human antibodies prevent malaria parasites from invading our blood cells.
The PfRH5 protein is essential for the most-deadly malaria parasite, Plasmodium falciparum, to get inside 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 help us to make the best possible PfRH5-based vaccine.
The figure shows PfRH5 (yellow) bound to two different human monoclonal antibodies induced by natural malaria infection
Previous studies from members of the Higgins lab 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 most effective. But what about antibodies which are induced in people in malaria endemic regions when they suffer from malaria?
Lawrence Wang and Andrew Cooper, working with Josh Tan at NIH, 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 who had been vaccinated with PfRH5. In both cases, they identified effective parasite-neutralising antibodies, albeit finding them to be much less common in those who experienced natural infection than those vaccinated.
Brendan Farrell then joined the project to understand how the most effective antibodies bind to PfRH5. He showed that the two most growth-inhibitory antibodies generated by natural infection bind to the same sites on PfRH5 as the most effective antibodies induced by vaccination. Indeed, antibodies induced by malaria infection in Malian adults looked remarkably similar to antibodies induced by vaccination of volunteers in Oxford.
This study has various important consequences for vaccine design. First, it reveals that the epitopes for all 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. The Higgins lab are now applying to this insight to make the best possible PfRH5-based vaccine immunogen.
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. Cell https://doi.org/10.1016/j.cell.2024.06.037 (* contributed equally)
Matt Higgins
24th July 2024
