Protection against dengue disease by synthetic nucleic acid antibody prophylaxis/immunotherapy

Abstract

Dengue virus (DENV) is the most important mosquito-borne viral infection in humans. In recent years, the number of cases and outbreaks has dramatically increased worldwide. While vaccines are being developed, none are currently available that provide balanced protection against all DENV serotypes. Advances in human antibody isolation have uncovered DENV neutralizing antibodies (nAbs) that are capable of preventing infection from multiple serotypes. Yet delivering monoclonal antibodies using conventional methods is impractical due to high costs. Engineering novel methods of delivering monoclonal antibodies could tip the scale in the fight against DENV. Here we demonstrate that simple intramuscular delivery by electroporation of synthetic DNA plasmids engineered to express modified human nAbs against multiple DENV serotypes confers protection against DENV disease and prevents antibody-dependent enhancement (ADE) of disease in mice. This synthetic nucleic acid antibody prophylaxis/immunotherapy approach may have important applications in the fight against infectious disease.

In Vivo Production of Monoclonal Antibodies by Gene Transfer via Electroporation Protects against Lethal Influenza and Ebola Infections

“…We believe our in-depth studies have moved pDNA/EP beyond preliminary reports, placing this platform technology on a solid foundation for clinical development. For our efficacy experiments in mice, we used doses of pDNA (5–10 μg) that are scalable for humans, in contrast to previous studies (25–300 μg) 11, 12, 13, 14, 15, 16, 17. Despite lower inoculum of pDNA, we observed higher mAb expression with mean peak serum concentrations (3–5 μg/mL) (Figure 2) that are 3- to 10-fold higher than previous findings 13, 14, 15, 16, 17.…”

“…For our efficacy experiments in mice, we used doses of pDNA (5–10 μg) that are scalable for humans, in contrast to previous studies (25–300 μg) 11, 12, 13, 14, 15, 16, 17. Despite lower inoculum of pDNA, we observed higher mAb expression with mean peak serum concentrations (3–5 μg/mL) (Figure 2) that are 3- to 10-fold higher than previous findings 13, 14, 15, 16, 17. Furthermore, mAb concentrations remained ∼1 μg/mL for up to 32 weeks (Figure 2), which is more persistent that previously described,14, 16, 17 therefore potentially extending the therapeutic window for treatment and prevention.…”

Gene therapy using plasmid DNA-encoded anti-HER2 antibody for cancers that overexpress HER2

“…26, 27, 28 Recent studies reported that this advanced plasmid DNA delivery technology was used to generate human Fab or immunoglobulin G1 (IgG1) broadly neutralizing antibody against the HIV or Dengue virus, respectively, in mouse sera after a single intramuscular injection and in vivo EP. 29, 30 To date, however, the synthetic DNA-encoded antibody approach, or DNA-based monoclonal antibody (dMAb) technique, has not been applied to tumor gene therapy.…”

Cytomegalovirus Vaccines: Current Status and Future Prospects

“…Nevertheless, the EP vaccine approach does offer the promise of improving responses to DNA vaccination. Recently, a DNA plasmid vaccine against Dengue virus, in conjunction with EP treatment, was shown to confer protection against dengue disease in mice [80]. DNA vaccination with subsequent EP treatment has also been shown to be effective in animal models against chikungunya virus, choriomeningitis, and influenza A [81–84].…”