Structure guided design of a transmission-blocking malaria vaccine targeting Pfs48/45 Malaria is one of the most devastating infectious diseases to affect humankind. It kills around half a million people, mostly young children in Africa. It also places a huge disease burden on large parts of the world, leading to hundreds of millions of serious infections. As well as directly causing suffering and death, this limits the development of large parts of the globe, reducing productivity and maintaining inequality.  Malaria is caused by a tiny, single celled parasite, known as Plasmodium. An individual contracts malaria when bitten by an infected mosquito. The parasites are injected into the blood stream as the mosquito feeds. These first develop and divide within the liver without causing disease. They next emerge from the liver and infect red blood cells, replicating and increasing in number and driving the symptoms of malaria. At the same time, a fraction of the parasites within the blood take a different developmental route, adopting a form known as the gametocytes. When a mosquito takes a blood meal from an infected person, they are likely to ingest some of these gametocytes. Within the midgut of the mosquito these develop into male and female gametes, and fuse together. This completes the infection cycle and the parasites move to the salivary glands of the mosquito, ready to be injected into another human victim.  Development of a vaccine to prevent malaria has proved very challenging and it is likely that the vaccines of the future will simultaneously target multiple stages of the parasite life cycle, blocking both liver and blood cell entry. One component of such a vaccine is likely to target the gametes of the parasite and to stop them from fusing. This is known as a transmission-blocking vaccine component as it will prevent the development of the parasite within the mosquito and will therefore stop the disease from being passed from person to person through the action of this blood-sucking insect.   We study a molecule called Pfs48/45 that is found on the surface of the gametocytes and gametes of Plasmodium parasites. Pfs48/45 is essential for a male gamete to fuse with a female gamete and if the immune system of an animal is exposed to Pfs48/45, it produces molecules called antibodies that bind to Pfs48/45 and prevent gametes from fusing. This means that if we can include Pfs48/45 in a vaccine, it will trigger the human body to make antibodies that will prevent malaria from being transmitted to other people. This will reduce the prevalence of malaria in the community and will help to eradicate the disease.  Despite this promise, Pfs48/45 is a challenging molecule to produce in a functional form and in large quantities. In addition, if we are to make vaccines that simultaneously contain multiple components, it will be important for each component to be as small and focused as possible, to make it easier and cheaper for them to be produced and distributed. For this reason we aim to understand the structure and shape of Pfs48/45 and also to understand the location and the nature of the sites where the gamete-fusion-preventing antibodies bind. This information will allow us to use the latest computational tools to design novel molecules which contain just the regions of Pfs48/45 that are needed to bind to inhibitory antibodies.  We will then inject mice with these novel immunogens and study the antibodies that are produced in a mosquito-infection experiment. If mosquitoes are fed on human blood containing malaria parasites, gametes can fuse, leading to the formation of cysts in the gut wall of the mosquito. If gamete fusion is prevented, the cysts are no longer formed. We will therefore study the ability of the antibodies induced by our novel immunogens to prevent cyst formation revealing which of our designs is most effective at blocking gamete fusion and preventing transmission of the malaria parasite. These newly designed molecules will form part of the malaria vaccines of the future. The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world.