Intranasal DNA Vaccine for Protection against Respiratory Infectious Diseases: The Delivery Perspectives

Xu, Yingying; Yuen, Pak-Wai; Lam, Jenny Ka-Wing

Early studies showed that DNA vaccines are poorly immunogenic with low levels of antigen expression. To improve the immunogenicity of DNA vaccines, CpG motifs are commonly employed in the construct of the plasmid backbone [20] . Bacterial or viral DNA contains unmethylated CpG motifs, whereas in mammalian cells, CpG dinucleotide motifs are rare and are usually methylated [21] . It has been demonstrated that the unmethylated CpG motifs have immunostimulatory effect and are considered by mammalian cells as pathogen-associated molecular patterns (PAMPs). Unmethylated CpG activates innate immune cells through binding to Toll-like receptor 9 (TLR-9), which is constitutively expressed in the endosomal compartments of APCs and B cells. Once bound to the DNA that is rich in CpG motifs, TLR-9 activates the immune system by initiating pro-inflammatory response that result in the production of cytokines such as interferon (IFN)-γ and interleukin (IL)-12. However, it was found that TLR-9 deficient mice also responded to DNA vaccines, suggesting that TLR-9 may not be the sole mediator of the adjuvant effect [22, 23] . DNA vaccines also interact with cytoplasmic DNA sensors including TANK-binding kinase 1 (TBK1) [24] and stimulator of IFN genes (STING) [25] , activating TLR-independent pathways and inducing IFN-γ. These pathways are crucial in contributing to the immunogenicity of DNA vaccines.