DNA vaccine cocktail expressing genotype A and C HBV surface and consensus core antigens generates robust cytotoxic and antibody responses in mice and Rhesus macaques

Abstract

There are well over a quarter of a billion chronic hepatitis B virus (HBV) carriers across the globe. Most carriers are at high risk for development of liver cirrhosis and subsequent progression to hepatocellular carcinoma. It is therefore imperative to develop new approaches for immunotherapy against this infection. Antibodies and cytotoxic T cells to different HBV antigens are believed to be important for reducing viral load and clearing HBV-infected cells from the liver. Some of the major challenges facing current vaccine candidates have been their inability to induce both humoral and cellular immunity to multiple antigenic targets and the induction of potent immune responses against the major genotypes of HBV. In this study, highly optimized synthetic DNA plasmids against the HBV consensus core (HBc) and surface (HBs) antigens genotypes A and C were developed and evaluated for their immune potential. These plasmids, which encode the most prevalent genotypes of the virus, were observed to individually induce binding antibodies to HBs antigens and drove robust cell-mediated immunity in animal models. Similar responses to both HBc and HBs antigens were observed when mice and non-human primates were inoculated with the HBc-HBs cocktails. In addition to the cytotoxic T lymphocyte activities exhibited by the immunized mice, the vaccine-induced responses were broadly distributed across multiple antigenic epitopes. These elements are believed to be important to develop an effective therapeutic vaccine. These data support further evaluation of multivalent synthetic plasmids as therapeutic HBV vaccines.

A synthetic consensus anti–spike protein DNA vaccine induces protective immunity against Middle East respiratory syndrome coronavirus in nonhuman primates

“…The consensus sequence for the MERS-CoV S protein vaccine was generated after analysis of the S protein genomic sequences, which were deposited in the GenBank-NCBI (National Center for Biotechnology Information) database. In previous reports, it was described that such consensus immunogens can induce broad cellular and humoral immune responses against diverse virus strains/isolates (24)(25)(26)(27). Sequences from both clades A and B were included in the construct design.…”

Cationic Lipid-Formulated DNA Vaccine against Hepatitis B Virus: Immunogenicity of MIDGE-Th1 Vectors Encoding Small and Large Surface Antigen in Comparison to a Licensed Protein Vaccine

“…Only low amounts of S-specific and no PreS1- and PreS2-specific IFN-γ-secreting PBMC were detected. In mice, strong S-specific [32], [33] and negligible PreS1/PreS2-specific [33] cellular responses have been described after immunization with DNA vaccines expressing non-secreted L proteins. The comparably high DNA doses applied in those studies (15 µg [33] or 100 µg DNA [32] for a ∼20 g mouse) as opposed to 333 µg DNA for a ∼20 kg pig used in our study might explain the different level of S-specific cellular immune responses.…”

Identification of Pre-Erythrocytic Malaria Antigens That Target Hepatocytes for Killing In Vivo and Contribute to Protection Elicited by Whole-Parasite Vaccination

“…This technique consists of the rapid injection of a large volume of plasmid DNA into the tail vein, resulting in uptake of the DNA into the cytoplasm of liver cells [35], and has been widely used in recent years to deliver DNA and RNA for gene function, gene therapy and for establishment of disease animal models (reviewed in [47]). Although HTVI is a valid approach to deliver antigens directly into the liver, it has been recently shown that it does not constitute and effective vaccination strategy because it leads to defective CD8 + responses [48]. In contrast, this method has been used to show that immunization of mice with adenovirus vectors that encode for the well-established P. yoelii PE antigens Py CSP or Py CelTOS, followed by HTVI challenge with the same proteins as luciferase fusions results in significant reductions in the luciferase signal in the liver [49].…”