Vector Design for Improved DNA Vaccine Efficacy, Safety and Production

Abstract

DNA vaccination is a disruptive technology that offers the promise of a new rapidly deployed vaccination platform to treat human and animal disease with gene-based materials. Innovations such as electroporation, needle free jet delivery and lipid-based carriers increase transgene expression and immunogenicity through more effective gene delivery. This review summarizes complementary vector design innovations that, when combined with leading delivery platforms, further enhance DNA vaccine performance. These next generation vectors also address potential safety issues such as antibiotic selection, and increase plasmid manufacturing quality and yield in exemplary fermentation production processes. Application of optimized constructs in combination with improved delivery platforms tangibly improves the prospect of successful application of DNA vaccination as prophylactic vaccines for diverse human infectious disease targets or as therapeutic vaccines for cancer and allergy.

Vector optimization and needle-free intradermal application of a broadly protective polyvalent influenza A DNA vaccine for pigs and humans

“…These new vectors have in previous studies demonstrated increased in vivo gene expression compared to conventional vectors. 16 In this study, we have not assessed the expression level from the vectors, but we could not see a clear increase in immunogenicity of these new vectors with equimolar dosage. This may in part be due to the reduced DNA amount with new vectors (e.g., 125 mg vs. 200 mg for NTC9385R versus pSSI, respectively) because the adjuvant activity of the plasmid backbone (through activation of cytoplasmic DNA sensing innate immune receptors) may be dependent on the total amount of DNA.…”

“…16 There are regulatory guidelines recommending the elimination of antibiotic-resistance genes, 56,57 and in addition, these selection markers can have a negative impact on gene expression. 15 Inserting our DNA vaccine genes into 2 next generation vectors, the antibiotic-free vectors NTC8385-VA1 and NTC9385R, resulted in a similar antibody response compared to vaccine genes in conventional pSSI expression vector with antibiotic-resistance gene using equimolar dosages.…”

“…7,8 Many influenza plasmid DNA vaccine candidates have demonstrated promising results in animal models, and improved DNA vaccines have reached sufficient potency in clinical trials. [9][10][11][12][13] One improvement to increase both the antigenicity and the immune response of a DNA vaccine is codon optimization, where the antigen coding sequence is optimized for efficient expression in the mammalian host cells [14][15][16] ; this has demonstrated beneficial effects in several influenza DNA vaccine studies. 9,11,[17][18][19][20][21] A complementary method to increase the immunogenicity is to optimize the DNA vaccine vector backbone.…”

“…So-called 'next generation' vectors under development will increase antigen expression, manufacturing yield and quality and follow regulatory compliance standards. 16 In addition, the delivery mode of a DNA vaccine is a relevant factor in eliciting the proper immune response. A needle and syringe is the conventional method of vaccination, including for DNA-based vaccines.…”

“…These optimizations, next generation vectors and convenient needle-free delivery, would greatly enhance a realistic mass-vaccination of pigs with an efficient broad influenza DNA vaccine. 16 (Nature Technologies Corporation, Lincoln, NE, US). The genes were synthesized using only codons from highly expressed human or mammalian genes (codon optimized).…”