An engineered Plasmodium vivax Duffy binding protein (DBPII) vaccine bypasses DBP strain variability and has enhanced reactivity to naturally acquired long-term antibody responses

Background: In natural infections, the Plasmodium vivax Duffy binding protein II (DBPII), which is a leading vivax vaccine candidate, is weakly immunogenic and induces strain-specific immunity. DEKnull-2 is a next generation engineered DBPII vaccine with modified strain variant surface residues that can elicit broadly neutralizing, strain-transcending anti-DBP inhibitory antibodies. DEKnull-2 evolved from proof-of-concept studies that demonstrated that a synthetic DBPII allele (DEKnull), which lacked the dominant variant B-cell epitope can induce in mice more broadly inhibitory anti-DBP antibodies. Here, we investigated whether DEKnull and DEKnull-2 are immunogenic in individuals naturally exposed to malaria in the Brazilian Amazon region. Materials and Methods: ELISA-detected IgG antibody responses to non-mutated DBPII variants (Sal-1 and Brazil-I) and to synthetics DBPII immunogens (DEKnull and DEKnull-2) were evaluated in a native Amazonian community with long-term exposure to malaria. The study design included five cross-sectional surveys, three carried-out during the first year (baseline, 6 and 12 months), and two carried-out 6 and 7 years later, at the time that malaria transmission had declined dramatically in the study area. Results: During the first follow-up year, consecutive serological surveys demonstrated that while few exposedindividuals responded to the original DEKnull, similar frequencies of responders (~ 50%) were obtained by using either enhanced DEKnull-2 immunogen or native DBPII variants; of interest, the levels of DEKnull-2 IgG antibodies was much more higher that those obtained from native DBPII variants. Six to seven years later, the number of responder to native proteins decreased significantly, however, the levels and frequency of responders to the DEKnull-2 remained relatively stable. Remarkable, long-term DEKnull-2 responders with high levels of antibodies (reactivity index >20 in ELISA) were individuals able to produce broadly reactive inhibitory binding antibodies (DBPII BIABs as detected by COS cell assay). Conclusion: DEKnull-2 is highly immunogenic in naturally exposed-individuals, suggesting that this engineered vaccine could be a promising candidate towards the development of protective blood-stage vivax malaria vaccines. Financial