Understanding the human antibody response to RH5 vaccination

How do human antibodies that target RH5 prevent erythrocyte invasion during malaria? 

The RH5 protein from the deadly malaria parasite, Plasmodium falciparum, is a promising target for vaccines to prevent malaria, due to its essential role when the parasite invades human red blood cells. Block RH5 and we can prevent the symptoms of malaria, as well as stopping the parasite from being transmitted.

Vaccination of a group of volunteers in Oxford, during assessment of the safety of an RH5-based vaccine, provided Simon Draper’s group with the opportunity to see which antibodies are produced when a human volunteer is vaccinated with RH5. Dan Alanine took blood samples and used them to identify a set of RH5-reactive antibodies.

These antibodies were sorted into groups, which bound to different regions of RH5. Some were directly inhibitory of erythrocyte invasion by the parasite, and Dan worked with us to determine their target epitopes. This information will guide the development of a future generation of RH5-based vaccines, designed to specifically induce the most protective antibody responses.

A final class of antibodies displayed unusual behaviour. While these failed to prevent erythrocyte invasion by themselves, mixing them with inhibitory antibodies made those inhibitory antibodies more potent. The structure of one of these potentiating antibodies did not clarify its mode of action. However, Paul Gilson at the Burnet Institute revealed that it slowed the process of erythrocyte invasion by nearly four-fold, giving inhibitory antibodies longer to act.

The malaria parasite only takes around 20 seconds to get inside an erythrocyte and this study shows the value of slowing it down.

 Alanine, D.G.W, Quinkert, D., Kumarasingha, R., Mehmood, S., Donnellan, F.R., Minkah, N.K., Dadonaite, B., Diouf, A., Galaway, F., Silk, S.E., Jamwal, A., Marshall, J.M., Miura, K., Foquet, L., Elias, S.C., Labbé, G.M., Douglas, A.D^., Jin, J., Payne, R.O., Illingworth, J., Pattinson, D.J., Pulido-Gomez, D., Williams, B.G., de Jongh, W.A., Wright, G.J., Kappe, S.H.I., Robinson, C.V., Long, C.A., Crabb, B.S., Gilson, P.R., Higgins, M.K.* and Draper, S.J.*. (2019) Human antibodies that slow erythrocyte invasion potentiate malaria-neutralizing antibodies. Cell 178 216-228 (* joint corresponding)