Comparative functional potency of DNA vaccines encoding Plasmodium falciparum transmission blocking target antigens Pfs48/45 and Pfs25 administered alone or in combination by in vivo electroporation in rhesus macaques

Abstract

Antibodies recognizing conformational epitopes in Pfs48/45, an antigen expressed on the surface of Plasmodium falciparum gametes and zygotes, have firmly established Pfs48/45 as a promising transmission blocking vaccine (TBV) candidate. However, it has been difficult to reproducibly express Pfs48/45 in a variety of recombinant expression systems. The goal of our studies was to evaluate functional immunogenicity of Pfs48/45 using DNA vaccine format in rhesus macaques. An additional goal was to ensure that when used in combination with another malarial antigen, specific immunity to both antigens was not compromised. For testing combination vaccines, we employed Pfs25 DNA plasmids that have previously undergone evaluations in rodents and nonhuman primates. Pfs25 is expressed on the surface of parasites after fertilization and is also a lead TBV candidate. DNA plasmids based on codon-optimized sequences of Pfs48/45 and Pfs25 were administered by in vivo electroporation, followed by a final recombinant protein boost. Our studies demonstrate that Pfs48/45 encoded by DNA plasmids is capable of inducing potent transmission blocking antibody responses, and such transmission blocking immune potency of Pfs48/45 was not compromised when tested in combination with Pfs25, These findings provide the evidence in favor of further studies on Pfs48/45 and Pfs25, either alone or in combination with other known malaria vaccine candidates for developing effective vaccines capable of interrupting malaria transmission.

Effective Functional Immunogenicity of a DNA Vaccine Combination Delivered via In Vivo Electroporation Targeting Malaria Infection and Transmission

“…We have shown improved functional immunogenicity of the Pfs25 DNA vaccine through codon-optimization and in vivo electroporation (EP) [ 26 , 27 ] and by a heterologous DNA prime-protein boost regimen in higher mammals [ 25 ]. Pfs25 DNA vaccine has also been evaluated by immunization in mice and nonhuman primates when combined with another TBV DNA vaccine, Pfs48/45, and specific antibody responses to both antigens and transmission-blocking activity were not compromised [ 28 , 29 ]. These studies provide compelling rationale for combining Pfs25 with other vaccine candidates targeting different lifecycle stages for developing more effective vaccines.…”

Improving rigor and reproducibility in nonhuman primate research

“…8.1 | Use of pilot grant programs to provide an opportunity for discovery and collaboration Indeed, numerous successes in animal model development (Burwitz, et al, 2017a(Burwitz, et al, , 2017bLopez et al, 2014), vaccine testing (Coban et al, 2004;Datta et al, 2017;Petersen et al, 2014), and drug treatment efficacy have arisen from NHP pilot studies. Examples of pilot studies that successfully utilized limited numbers of macaques include a study of five macaques that demonstrated the persistence of the Lyme disease pathogen following a recommended treatment protocol (Embers et al, 2012a) and subsequently devised a strategy for diagnostic test development (Embers et al, 2012b), and a study of four macaques that demonstrated expression of the human NTCP receptor on hepatocytes is sufficient to support full HBV infection of macaques (Burwitz et al, 2017a).…”

Safety and Immunogenicity of an In Vivo Muscle Electroporation Delivery System for DNA-hsp65 Tuberculosis Vaccine in Cynomolgus Monkeys

“…One approach is to increase the efficiency of plasmid-based DNA vaccination by electroporation (EP). In vivo EP is an efficient vaccine strategy that enhances cell permeability, local tissue inflammation, and immunogenicity in experimental animals [ 22 , 23 , 24 , 25 , 26 , 27 ] and in humans [ 28 , 29 , 30 , 31 ]. When EP is applied to the target organism, the encoded antigens are expressed and elicit the corresponding immune response, with the potential to induce antibody-mediated, helper T cell-mediated, and cytotoxic T cell-mediated immune responses [ 32 ].…”