DNA based vaccines

Traditionally, vaccines are prepared with killed or attenuated viruses or bacteria, which might have serious security issues for the development of HIV vaccines. Additionally, vector-based vaccines may induce anti-vector immunity, which might interfere the immune responses provoked by vaccines [113]. Thus, DNA vaccines were first created in 1990 with finding that delivery of recombinant plasmid may allow the expression of exogenous antigen protein [114]. Then, the immune responses [115] and protection against lethal influenza by exogenous plasmid DNA were also discovered [116, 117]. Following these studies, DNA vaccines are demonstrated to be effective for the various diseases, such as infectious diseases, cancers, autoimmune diseases, and allergic diseases.

Generally, the optimized antigen DNA and molecular adjuvant are cloned into plasmid backbone, named as recombinant plasmid. After amplification and purification of the recombinant plasmids, they are delivered into host cells. Utilizing the nutrients and materials of host cells, antigens are transcribed, expressed, and assembled. On the one hand, antigen peptides are recognized and presented on major histocompatibility complex (MHC) class I, while secreted antigen proteins are captured and processed by antigen-presenting cells (APCs) and then presented by MHC class II (MHC II). APCs carrying MHC-antigen peptide complex migrate to lymph node to stimulate T cells and mediate cellular immune response. On the other hand, antigen proteins can be recognized and captured by antigen-specific high affinity immunoglobulins on the B cell surface, then provoke humoral immune response, which is assisted by the pre-activated antigen-specific CD4+ T cells (Fig. 15) [118]. Picture loading failed.
Figure 15. General principles of immune responses induced by DNA vaccines [118]. MHC: major histocompatibility complex.

Compared with the traditional vaccines, the immunogenicity of DNA vaccines is quite weak. To enhance the immunogenicity, several strategies are utilized: ① stronger promoters are adopted for the cloning of recombinant plasmid, such as APC-specific promotors; ② optimize the delivery route, transducing DNA vaccines into antigen-presenting cells (APCs), such as dendritic cells, may significantly promote the cytotoxic responses; ③ optimization of multiple antigen sequences; ④ adjuvants are used to prevent tolerance induction and facilitate the innate immune signals induced by DNA vaccines, including alum, liposome, nanoparticles, cytokines, chemokines and pathogen-recognition receptor (PRR) agonists; ⑤ circumvent potential inhibitory effects of the vector [119].

Although DNA vaccines have not been applied widespread due to their weak immunogenicity, promising outcomes are achieved based on improvements the priming high-level antigen specific antibody responses. Some of them are listed in the following Table 8 [120, 121].

Table 8. Examples of clinical trials using DNA vaccine [121]
Disease Antigen Delivery route Status Outcome Reference
HIVEnV, ReVIntramuscularPhase IAb, CTL, T proliferative, chemokine release was observed[122]
HIVgp120, gp160IntramuscularPhase INo Ab response and cellular response were observed[123]
HIVChAdV63IntramuscularPhase IINo intervention-related serious adverse events[124]
38 cytotoxic T cell epitopes and 16 helper T cell epitopes derived from P. falciparum antigens

ElectroporationPhase Ipoorly immunogenic[125]
AnalHPV-16 E7 fragmentIntramuscularPhase I10/12 patients developed antigen-specific immune responses[126]
B-cell lymphomaIdiotypeIntramuscularPhase I/II
1/12 patient developed T-cell response to autologous Id following initial immunization course; 6/12 patients developed anti-Id responses following booster immunization

Breast carcinomaHER2IntramuscularPhase I
3/8 individuals had enhanced CD4+ T cell responses; 3/5 patients have enhanced HER2 Ab responses

Colorectal cancerCEA fused to T-helper epitopeintradermalPhase IErythema at injection site increased over time[129]
Colorectal cancerCEA (along with HBV surface antigen)IntramuscularPhase I4/17 patients developed Hsp65-specific IL-10 responses[130]
Melanomagp 100 (mouse)IntramuscularPhase I
4/27 patients developed gp100 tetramer+CD8+ cells; 5/27 developed IFNγ+CD8+ responses, one of which was tetramer+

Melanomagp 101 (mouse and human)IntramuscularPhase I6/18 patients developed gp100-specific T cell responses[132]
MelanomaTyrosinase (human and mouse)IntramuscularPhase I7/17 patients developed antigen-specific T-cell responses[133]
MelanomaMART-1IntramuscularPhase INo enhancement in antigen-specific immune responses[134]
MelanomaMART-1 and tyrosinase T-cell epitopesIntra-lymph nodePhase I4/19 patients developed immune responses to MART-1[135]
MelanomaEpitopes from five melanoma antigensIntramuscularPhase I22/31 patients developed antigen-specific T-cell responses[136]
Melanomagp100PMEDPhase INo antigen-specific immune responses detected[137]
MelanomaHLA-B7DNA-containing liposomesPhase I2/22 patients developed enhanced TIL cytotoxicity[138]
MelanomaTyrosinase epitopesIntra-lymph nodePhase I11/26 patients had antigen-specific T-cell responses[115]
NSCLCL523SIntramuscularPhase I1/10 patient developed antigen-specific antibody response[139]

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