Have mRNA vaccines sentenced DNA vaccines to death?

Figures & data

Figure 1. Enhancing genetic vaccine design: strategies to boost immunogenicity. several strategies can be used to elicit higher immunogenicity of genetic vaccines at the design level, such as (a) codon optimization (fine-tuning the genetic code for heightened expression), (b) compact DNA plasmid backbones (employing smaller, more efficient genetic constructs), (c) utilization of cell-free products (enhancing vaccine components), (d) encoding chimeric proteins (combining beneficial elements for a stronger response), (e) optimized UTR in mRNA sequences (improving translation efficiency), and (f) enhanced culture yields (increasing the availability of essential components for vaccine production). Figure created with BioRender.

Figure 2. Summary of possible common and individual improvements that may be underway for DNA and mRNA vaccines. common improvements for genetic vaccines could be achieved by advanced codon optimization, optimized dosage, and different routes of administration. However, while DNA vaccines may potentially achieve improved safety and immunogenicity with smaller templates or minicircles, encapsulation into LNP and addition of adjuvant encoding sequences, specific improvements for mRNA vaccines may instead require technology advances and sequence modifications aimed at improving stability and at reducing levels of inflammation and potential side effects. Figure created with BioRender.

Table 1. Summary of the advantages, disadvantages, and potential improvements of genetic vaccines.

DNA vaccines			mRNA vaccines
Advantages	Disadvantages	Potential improvements	Advantages	Disadvantages	Potential improvements
Long-lasting immune responses	Limitedimmunogenicity	Genetic adjuvants	Highly immunogenic	Short-lived immune responses	Optimization of number of doses, genetic sequence, route of administration
Very safe, as shown by multiple clinical trials	Delivery challenges	Encapsulation	Generally safe, as shown by multiple clinical trials	Storage, cold-chain requirements	Uncharted technology improvements
Easiness to design and produce	Host genome integration risk	None, risk considered extremely low	Easiness to design and produce	Delivery, i.e. needs to be delivered with LNPs to protect from degradation	Modification of UTR sequences
Multivalency, i.e. the same vaccine can carry multiple antigens, co-express antigens and molecular adjuvants, etc.	Specific cellular targeting, e.g. APCs	Encapsulation, design which includes an APC-targeting molecule	Flexibility, i.e. the same platform can be applied to multiple pathogens or cancer	Limitation in the number of antigens or adjuvant molecules that can be present in the same formulation	Optimization of genetic sequence and delivery agents
Low cost of production	Regulatory issues	Lessons learned from genetic vaccines approved during SARS-CoV-2 pandemic	Rapid Development, once the target pathogen or cancer antigens are identified	Accessibility, i.e. costs associated with mRNA production and storage	Uncharted technology improvements, optimization of genetic sequence
Highly stable