Malaria vaccines based on ookinete surface proteins (OSPs) of the malaria parasites block oocyst development in feeding mosquitoes and hence disrupt the parasite life cycle and prevent the disease from being transmitted to other individuals. To investigate whether a noninvasive mucosal vaccination regimen effectively blocks parasite transmission in vivo, Plasmodium yoelii Pys25, a homolog of the Pfs25 and Pvs25 OSPs of Plasmodium falciparum and Plasmodium vivax, respectively, was intranasally (i.n.) administered using a complement-deficient DBA/2 mouse malaria infection model, in which a highly elevated level of oocysts develops in feeding mosquitoes. Vaccinated mice developed a robust antibody response when the vaccine antigen was given together with cholera toxin adjuvant. The induced immune serum was passively transferred to DBA/2 mice 3 days after infection with P. yoelii 17XL, and Anopheles stephensi mosquitoes were allowed to feed on the infected mice before or after serum transfusion. This passive immunization completely blocked oocyst development; however, immune serum induced by the antigen or adjuvant alone did not have such a profound antiparasite effect. Further, when i.n. vaccinated mice were infected with the parasite and then mosquitoes were allowed to directly feed on the infected mice, complete blockage of transmission was again observed. To our knowledge, this is the first time that mucosal vaccination has been demonstrated to be efficacious for directly preventing parasite transmission from vaccinated animals to mosquitoes, and the results may provide important insight into rational design of nonparenteral vaccines for use against human malaria.Malaria is one of the most important infectious diseases, and the levels of mortality and morbidity are high, especially among children in developing countries in Africa, Asia, and South America. Implementation of malaria control measures, such as antimalaria drug chemotherapy and insecticide-treated bed nets, has made a significant contribution to reducing the incidence of malaria in many parts of the world. However, these control measures may not be sufficient, and therefore new tools, including vaccines, should be included in a new malaria control campaign for local elimination and final eradiation of malaria from the globe (7). A promising strategy to counteract global malaria endemicity is to develop highly efficacious vaccines, and several promising candidates have been intensively investigated (7,20); vaccines targeting asexual stages (i.e., sporozoite, hepatic, and erythrocytic stages) are designed to prevent infection and reduce disease severity, while vaccines that target the sexual stage, in which the parasite undergoes sporogonic development in anopheline mosquitoes, prevent vector-mediated transmission of the parasite from person to person (4,8,14,17,25). Although transmission-blocking vaccines do not directly prevent infection, they reduce parasite infectivity for the vector and consequently lower the mosquito infection rate and the freque...