Co-Administration of Molecular Adjuvants Expressing NF-Kappa B Subunit p65/RelA or Type-1 Transactivator T-bet Enhance Antigen Specific DNA Vaccine-Induced Immunity

Abstract

DNA vaccine-induced immunity can be enhanced by the co-delivery of synthetic gene-encoding molecular adjuvants. Many of these adjuvants have included cytokines, chemokines or co-stimulatory molecules that have been demonstrated to enhance vaccine-induced immunity by increasing the magnitude or type of immune responses and/or protective efficacy. In this way, through the use of adjuvants, immune responses can be highly customizable and functionally tailored for optimal efficacy against pathogen specific (i.e., infectious agent) or non-pathogen (i.e., cancer) antigens. In the novel study presented here, we examined the use of cellular transcription factors as molecular adjuvants. Specifically the co-delivery of (a) RelA, a subunit of the NF-κB transcription complex or (b) T-bet, a Th1-specific T box transcription factor, along with a prototypical DNA vaccine expressing HIV-1 proteins was evaluated. As well, all of the vaccines and adjuvants were administered to mice using in vivo electroporation (EP), a technology demonstrated to dramatically increase plasmid DNA transfection and subsequent transgene expression with concomitant enhancement of vaccine induced immune responses. As such, this study demonstrated that co-delivery of either adjuvant resulted in enhanced T and B cell responses, specifically characterized by increased T cell numbers, IFN-γ production, as well as enhanced antibody responses. This study demonstrates the use of cellular transcription factors as adjuvants for enhancing DNA vaccine-induced immunity.

Construction of a fusion plasmid containing the PSCA gene and cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and its anti-tumor effect in an animal model of prostate cancer

“…This is very important in a disease such as prostate cancer where symptoms from the disease are generally not present until the late stages (14). However, many studies have indicated that a vaccine containing only an antigen is not effective enough to induce an anti-tumor immune response (4,15). …”

Engineering DNA vaccines against infectious diseases

“…Examples of adjuvants [19][20][21][22][144][145][146]. reported nanoparticles of chitosan combined with tripolyphosphate and hemagglutinin (HA) induced a two-fold increase in the number of splenocytes that secrete IFNc in mice infected with the influenza virus when compared with a nonadjuvanted HA vaccine [20].…”

“…Kalams, et al also evaluated the positive impact of EP delivery methods for the HIV-1 Gag antigen/IL-12 adjuvant plasmid vector in a phase I clinical trial. Other studies have also assessed the immunogenicity of DNA vaccines containing chemokine-expressing sequences for HIV-1 immunization [144][145][146]. The CpG oligodeoxynucleotide (ODN) is another common genetic adjuvant used for DNA vaccines [9,147,148].…”

Molecular mechanisms for enhanced DNA vaccine immunogenicity

“…NF-κB is a master innate immune regulator. A recent study showed that co-administration of a plasmid expressing NF-κB subunit p65/ RelA enhanced DNA vaccine immunogenicity [107]. A T-cell transcription factor, Tbet was effective in driving a Th1 response against an Ag85B DNA-based tuberculosis vaccine [108,109].…”