title: Immunogenicity and malaria transmission reducing potency of Pfs48/45 and Pfs25 encoded by DNA vaccines administered by intramuscular electroporation.
abstract: Pfs48/45 and Pfs25 are leading candidates for the development of Plasmodium falciparum transmission blocking vaccines (TBV). Expression of Pfs48/45 in the erythrocytic sexual stages and presentation to the immune system during infection in the human host also makes it ideal for natural boosting. However, it has been challenging to produce a fully folded, functionally active Pfs48/45, using various protein expression platforms. In this study, we demonstrate that full-length Pfs48/45 encoded by DNA plasmids is able to induce significant transmission reducing immune responses. DNA plasmids encoding Pfs48/45 based on native (WT), codon optimized (SYN), or codon optimized and mutated (MUT1 and MUT2), to prevent any asparagine (N)-linked glycosylation were compared with or without intramuscular electroporation (EP). EP significantly enhanced antibody titers and transmission blocking activity elicited by immunization with SYN Pfs48/45 DNA vaccine. Mosquito membrane feeding assays also revealed improved functional immunogenicity of SYN Pfs48/45 (N-glycosylation sites intact) as compared to MUT1 or MUT2 Pfs48/45 DNA plasmids (all N-glycosylation sites mutated). Boosting with recombinant Pfs48/45 protein after immunization with each of the different DNA vaccines resulted in significant boosting of antibody response and improved transmission reducing capabilities of all four DNA vaccines. Finally, immunization with a combination of DNA plasmids (SYN Pfs48/45 and SYN Pfs25) also provides support for the possibility of combining antigens targeting different life cycle stages in the parasite during transmission through mosquitoes.
authors.affiliation: Department of Tropical Medicine, School of Public Health and Tropical Medicine and Vector-Borne Infectious Disease Research Center, Tulane University, New Orleans, LA, United States.
authors.forename: Dibyadyuti
authors.initials: D
authors.lastname: Datta
authors.affiliation: Department of Tropical Medicine, School of Public Health and Tropical Medicine and Vector-Borne Infectious Disease Research Center, Tulane University, New Orleans, LA, United States.
authors.forename: Geetha P
authors.initials: GP
authors.lastname: Bansal
authors.affiliation: Foundation for Applied Molecular Evolution, Alachua, FL, United States.
authors.forename: Dietlind L
authors.initials: DL
authors.lastname: Gerloff
authors.affiliation: ICHOR Medical Systems Inc., San Diego, CA, United States.
authors.forename: Barry
authors.initials: B
authors.lastname: Ellefsen
authors.affiliation: ICHOR Medical Systems Inc., San Diego, CA, United States.
authors.forename: Drew
authors.initials: D
authors.lastname: Hannaman
authors.affiliation: Department of Tropical Medicine, School of Public Health and Tropical Medicine and Vector-Borne Infectious Disease Research Center, Tulane University, New Orleans, LA, United States. Electronic address: nkumar@tulane.edu.
authors.forename: Nirbhay
authors.initials: N
authors.lastname: Kumar
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology; D018562:Disease Transmission, Infectious / Q000517:prevention & control; D018274:Electroporation; D005260:Female; D017780:Malaria Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D016778:Malaria, Falciparum / Q000517:prevention & control* / Q000635:transmission; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D008807:Mice, Inbred BALB C; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000276:immunology*
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D008562:Membrane Glycoproteins; C071284:Pfs25 protein, Plasmodium falciparum; D015800:Protozoan Proteins; D019444:Vaccines, DNA; C084847:pfs48-45 protein, Plasmodium falciparum
keywords: Combination antigens; DNA vaccine; Electroporation; Glycosylation; Malaria