13.1 n&v113 MH

have been made to develop a vaccine against malaria, but the task is not easy. So far, one of the best prospects has been to use irradiated sporozoites — the form in which the malaria parasite is injected by the mosquito — which have proved highly protective. But such vaccines have gone no further, in part because of practical difficulties, in part because of safety concerns. Writing on page 164 of this issue, Mueller et al. describe an alternative approach — one using genetically weakened sporozoites. A malarial infection begins when the sporozoite stage of the parasite (a Plasmodium species) halts in the host’s liver. There, inside a liver cell (hepatocyte), the parasite transforms into the stage that will infect red blood cells (erythrocytes) and cause the symptoms, complications and fatality associated with malaria. This pre-erythrocytic phase of infection, which lasts for only a few days and is clinically silent, is a particularly attractive target for anti-parasite vaccination strategies (Fig. 1). Only a few (10–30) sporozoites are delivered during a mosquito bite and, crucially, the parasite stages that develop in the liver can be targets of protective immunity. This was first demonstrated in 1941, when Mulligan et al., using an avian Plasmodium system, found that immunization with irradiated sporozoites could prime the immune system to target normal sporozoites, thus preventing erythrocyte infection. Since then, irradiated sporozoites have proved to be potent vaccines in all Plasmodium systems. In an experimental set-up, for instance, irradiated sporozoites of P. falciparum — the species most deadly to humans — can generate robust, strain-transcendent, and lasting protection (for at least 10 months) in more than 90% of human recipients. Unfortunately, such a vaccine remains experimental because thousands of mosquito bites are required to deliver the protective dose of irradiated sporozoites; meanwhile, simple injections of sporozoites raise practical difficulties. Moreover, there is a concern that such sporozoites might retain some infectivity and cause breakthrough erythrocyte infection if under-irradiated, or fail to induce protection if over-irradiated. Studies of irradiated sporozoites have, however, continued to inform research into the immune response to the parasite. Much of what is known about the protective responses to irradiated sporozoites has come from studies using P. berghei and P. yoelii, species that infect rodents. In these systems, both the T cells that target intra-hepatocytic stages, and antibodies that recognize proteins on the sporozoite surface and prevent sporozoites from entering liver cells, are important for protection. The main T cells involved are thought to be those that produce the marker protein CD8; these cells recognize parasite peptides that are presented on the surface of infected hepatocytes. The mechanisms underlying the effects of these T cells are not completely understood, but the proteins interferonand interleukin-12 and the small molecule nitric oxide — the latter being an effective killer of the Plasmodium liver stage — are crucial. The features of irradiated sporozoites that are necessary to induce such protective responses are still unclear. However, it is news and views