Comparing the effect of Toll-like receptor agonist adjuvants on the efficiency of a DNA vaccine

Abstract

We have investigated whether poly(I:C) Toll-like receptor 3 (TLR3) and resiquimod Toll-like receptor 7 (TLR7) agonists can serve as vaccine adjuvants and promote the efficiency of therapeutic DNA vaccination against tumors expressing the human papilloma virus 16 (HPV-16) E7 protein. For this purpose, C57BL/6 mice were inoculated with 2 × 10(5) TC-1 cells, and they were then immunized with HPV-16 E7 DNA vaccine alone or with 50 μg of resiquimod or poly(I:C) individually. We found that poly(I:C) and resiquimod could induce more antigen-specific lymphocyte proliferation and cytolytic activity compared to vaccination with E7 DNA alone. While E7 DNA had no significant inhibitory effect on tumor growth, co-administration of poly(I:C) and resiquimod with E7 DNA induced significant tumor regression. Peripheral and local cytokine assays demonstrated that co-administration of poly(I:C) and resiquimod with E7 DNA induced circulating antigen-specific IFN-γ and nonspecific intratumoral IL-12. TLR3 and TLR7 agonists can be used to enhance the immune response to DNA vaccine immunogens. Taken together, these data indicate that combined vaccination with DNA encoding HPV-16 E7 plus TLR agonists provides a strategy for improving the efficacy of a vaccine as a possible immunotherapeutic strategy for cervical cancer.

DNA vaccines for prostate cancer

“…Therefore, activation of TLRs promotes both innate inflammatory responses and the induction of adaptive immunity. Stimulating TLR signaling during DNA vaccination can enhance the induction of vaccine-specific responses (Gableh et al, 2016; Pavlenko et al, 2007; Sajadian et al, 2014). As described above, plasmid DNA vaccines naturally stimulate TLR9, which interacts with unmethylated CpG DNA from bacteria, some viruses and plasmid DNA.…”

“…Sajadian and colleagues also demonstrated that the use of either TLR3 and/or TLR7 agonists in combination with a DNA vaccine encoding the HPV E7 antigen enhanced the anti-tumor capabilities of the vaccine to eliminate HPV-induced tumors in mice. Specifically, they showed that DNA vaccine alone resulted in no significant inhibitory effects on TC-1 cells in C57BL/6 mice, but the addition of poly (I:C) (TLR3 agonist) or resiquimod (TLR7 agonist) resulted in significant tumor regression (Sajadian et al, 2014). More recently, Gableh and colleagues found that stimulation of TLR4 with monophophoryl lipid A (MPL) significantly increased lymphocyte proliferation, CTL activity, IFN-γ, IL-4 and IL-12 responses, and tumor protection against TC-1 cells (Gableh et al, 2016).…”

DNA Vaccines: How Much Have We Accomplished In The Last 25 Years?

“…Adjuvanting a DNA vaccine with the TLR9 agonist, CpG oligodeoxinucleotides (ODN), at the time of priming enhanced CD8 + T cell responses and control of viral load after SIV challenge in rhesus macaques [88]. A recent study showed that the TLR3 agonist poly (I:C) and the TLR7 agonist resiquimod were both able to induce significant tumor regression when administered together with a DNA vaccine against a model tumor expressing the HPV-16 in mice [89]. However, when a SIV DNA vaccine was administered together with poly (ICLC), a stabilized poly (I:C) analogue, in rhesus macaques, no improvement in immunogenicity was observed [90].…”

Electroporation as a vaccine delivery system and a natural adjuvant to intradermal administration of plasmid DNA in macaques

“…However, despite their high immunogenicity in murine models, DNA vaccines have shown poor efficacy in large animal models and humans 2 . New strategies to improve DNA vaccines include the optimization of transcriptional control elements and codons 3–5 , the use of adjuvants, such as Toll-like receptor (TLR) ligands 6 , cytokine expressing plasmids 7–9 or apoptosis-based adjuvants 10–12 and the choice of an appropriate delivery system such as local electroporation (EP) 13–15 .…”