Structure of transmission-blocking malaria vaccine candidate Pfs48/45

How can we stop transmission of the malaria parasite?

The malaria parasite is transmitted to an unfortunate person through the bite of an infected mosquito, which in turn has fed on the blood of another infected person. The journey from the mosquito gut to its salivary glands requires a series of complex developmental changes in the parasite and if we can stop these events, we can prevent transmission of the disease.

Pfs48/45 is a protein found on the surface of the developmental form of the parasite taken up into the mosquito gut. Previous studies have shown that if the blood meal of a mosquito contains antibodies which target Pfs48/45, then these can block development of the parasite and can prevent the mosquito from being able to transmit malaria. This makes Pfs48/45 a prime candidate as a transmission blocking component of a malaria vaccine, and clinical trials will be taking place in 2022 in which Pfs48/45 is tested in human volunteers.

In this study, we teamed up with Sumi Biswas’ group to determine the structure of Pfs48/45 and to assess how it is recognised by transmission-blocking antibodies. This project was started by Frank Lennartz and completed by Kuang-Ting Ko, who used a combination of protein crystallography, guided by an AlphaFold2 model, to determine the structure of the intact Pfs48/45 domain. They show it to form a disc, which is likely to lie approximately parallel to the membrane surface, and show how it is recognised by five different antibodies.

Previous vaccine studies have used one of the three modules of Pfs48/45, the C-terminal domain, as a vaccine immunogen, as this module contains the epitope for the most effective known transmission-blocking antibody, 85RF45.1. However, the structure of Pfs48/45 shows that all three of its domains are exposed to the immune system. Therefore David Mekhaiel assessed the efficacy of antibodies targeting regions of Pfs48/45 other than the C-terminal domain, showing that these are also highly effective at blocking transmission.

This study provided the first detailed structural insight into the complete Pfs48/45 ectodomain and will be used to guide design of future transmission-blocking vaccines which correctly present the most effective epitopes to our immune systems.

Ko, K, Lennartz, F., Mekhaiel, D., Guloglu, B., Marini, A., Deuker, D.J., Long, C.A., Jore, M.M., Miura, M., Biswas, S. and Higgins, M.K. (2022) Structure of the malaria vaccine candidate Pfs48/45 and its recognition by transmission blocking antibodies. Nature Communications 13 5603