Molecules that play a role in Plasmodium merozoite invasion of host red blood cells represent attractive targets for blood-stage vaccine development against malaria. In Plasmodium vivax, merozoite invasion of reticulocytes is mediated by the Duffy binding protein (DBP), which interacts with its cognate receptor, the Duffy antigen receptor for chemokines, on the surface of reticulocytes. The DBP ligand domain, known as region II (DBPII), contains the critical residues for receptor recognition, making it a prime target for vaccine development against blood-stage vivax malaria. In natural infections, DBP is weakly immunogenic and DBPII allelic variation is associated with strain-specific immunity, which may compromise vaccine efficacy. In a previous study, a synthetic vaccine termed DEKnull that lacked an immunodominant variant epitope in DBPII induced functional antibodies to shared neutralizing epitopes on the native Sal1 allele. Anti-DEKnull antibody titers were lower than anti-Sal1 titers but produced more consistent, strain-transcending anti-DBPII inhibitory responses. In this study, we further characterized the immunogenicity of DEKnull, finding that immunization with recombinant DEKnull produced an immune response comparable to that obtained with native recombinant DBP alleles. Further investigation of DEKnull is necessary to enhance its immunogenicity and broaden its specificity.T he global control of malaria is threatened with the spread of drug-resistant parasites and insecticide-resistant mosquitoes. The impact of this on the public health infrastructure and economic stability of the countries most affected is a cause for concern. Vaccines are an attractive mode of control since they are cost-effective and easily administered. Despite years of research, effective malaria vaccines have remained elusive and none has been introduced as a commercial product. However, efforts to develop a vaccine remain optimistic for a number of reasons. First, individuals in regions where malaria is endemic develop naturally acquired immunity to clinical manifestation of the disease (1, 2). Second, passive transfer of IgG from immune individuals conveyed protection to naive individuals (3). Third, vaccination with attenuated sporozoites induced partial protection (4). Finally, naturally and artificially acquired antibodies to different Plasmodium antigens have been shown to inhibit parasite invasion of erythrocytes, as well as parasite growth and development, in vitro (5-8).Successful host red blood cell invasion by Plasmodium merozoites depends on specific ligand-receptor interactions (9, 10). In Plasmodium vivax, a critical step in the invasion of reticulocytes during asexual blood-stage infection is the interaction between the merozoite Duffy binding protein (DBP) and its cognate receptor, the Duffy antigen receptor for chemokines (DARC), on the reticulocyte surface. It is believed that DBP plays an essential role during the irreversible process of junction formation just before invasion (11,12). This is evident in the v...