ABSTRACT Malaria vaccine RTS,S is a historical milestone to fight malaria. However, we need to continue exploring new antigens and new approaches to fight against malaria because the protection rate of RTS,S is about 37%. The difficulty in developing optimal protection of a malaria vaccine indicates the scarcity of suitable malaria vaccine antigens. Since malaria infection and transmission involve two hosts, malaria transmission through mosquitoes is obligatory for a Plasmodium parasite to complete its life cycle. The complicated malaria life cycle allows us to develop a vaccine that targets malaria transmission at the mosquito stage. We identified mosquito fibrinogen-related protein 1 (FREP1) that facilitates Plasmodium transmission to mosquitoes. FREP1 localizes in the midgut peritrophic matrix; thus, it is easily accessible by antibodies ingested with blood. Sequence alignment identified a highly conserved C-terminal fibrinogen-related domain (FBG) among anopheline mosquito orthologs, and this domain can bind parasites. Notably, antibodies against FBG significantly inhibit the transmission of multiple Plasmodium species (P. berghei, P. falciparum, and P. vivax) to various species of Anopheles (An. gambiae and An. dirus). Moreover, monoclonal antibodies against some specific epitopes on FBG is more active in blocking malaria transmission than polyclonal antibodies, indicating that targeting specific epitopes on FBG will block malaria transmission more effectively. We have also developed a new molecular adjuvant that stimulates the strong humoral and cellular immune response. We hypothesize that combining Anopheles-specific epitopes from FBG and our new molecular adjuvant into one vaccine will trigger a robust immune response to block malaria transmission. We will identify these specific epitopes that can be used to efficiently block malaria transmission from FBG and fuse the epitopes with our molecular adjuvant to generate nanoparticles for vaccination. Our long-term goal is to improve the malaria vaccine protection rate, while our short-term goal is to develop an efficient malaria transmission-blocking vaccine (TBV).