A Comprehensive Comparison of DNA and RNA Vaccines

Vaccines have experienced a hundred years of development, giving birth to many milestone vaccine types, from the earliest, inactivated and live attenuated vaccines as the representative of the first generation of traditional vaccine types, to the second generation of vaccines dominated by genetic engineering technology in the last century, as well as the birth of nucleic acid vaccines belonging to the third generation of vaccines in recent years. Vaccination is the most effective medical intervention ever, and nowadays vaccines have realized a conceptual shift from the initial empiricism to the current rational design, and the types of vaccines present a wider variety. Here, DNA and RNA vaccines represent a revolutionary change in immunization strategies, offering rapid, scalable, and highly efficient alternatives to traditional vaccine platforms. These nucleic acid-based vaccines use genetic material to direct cells to produce antigens, thereby eliciting an immune response. Although DNA and RNA vaccines have shown promise, each has distinct advantages and challenges that affect their development, production, and application.

Pictures of experimental cancer vaccines.

Nucleic Acid Vaccine

Nucleic acid vaccines are mainly of two types, DNA vaccines and RNA vaccines, and the basic principle is to transfer nucleic acid sequences encoding the target antigen into the cells of organisms through different ways, so as to eXpress the target antigen and then induce an immune response. Meanwhile, nucleic acid vaccines can be categorized into viral vector vaccines, which use viruses as the delivery vehicle, and mRNA vaccines, which use lipid nanoparticles as the delivery vehicle, depending on the delivery vehicle. Due to the rapid and flexible development and production of vaccines based on nucleic acid technology, it is theoretically possible to set up a nucleic acid-based vaccine production line that is compatible with the production of vaccines for different targets, thus drastically reducing the cost and time.

DNA Vaccines

DNA vaccines use plasmids, or circular DNA molecules, to introduce genetic material into host cells. The host cells then eXpress the DNA, producing antigens that invoke an immune response. A major advantage of DNA vaccines is their stability, making storage and transportation much easier than for RNA-based vaccines. However, DNA vaccines often face challenges in terms of delivery efficiency and the requirement for specific delivery methods, such as electroporation or lipid nanoparticles (LNPs).

• Plasmid DNA(pDNA) Vaccines: Plasmid DNA vaccine composition includes plasmids engineered to carry a gene of interest encoding for an antigen-usually a protein-of the disease-causing agent. After administration, the plasmid DNA is taken up by host cells, usually muscle or dendritic cells. These further transcribe and translate the DNA into the antigen, which, when presented on the cell surface or secreted, invokes an immune response.
• Recombinant DNA(rDNA) Vaccines: rDNA vaccines are a subclass of DNA vaccines, wherein the antigen-encoding genes are inserted into plasmids using genetic engineering techniques. These vaccines can be engineered against specific pathogens or diseases, increasing their precision. This is made possible by the use of recombinant DNA technology in producing vaccines for complex diseases with high specificity, thereby reducing adverse reactions.

* Related Products & Services from BOC RNA

RNA Vaccines

RNA vaccines, especially mRNA vaccines, have gained much attention because of their rapid development timelines, especially in the COVID-19 pandemic. mRNA vaccines consist of messenger RNA encoding antigens. After injection, the mRNA instructs cells to produce the antigen, which then provokes the immune response. The advantage of mRNA vaccines is that they can be designed and manufactured so fast, especially when new pathogens emerge. Nevertheless, the instability of mRNA and challenges concerning its delivery and storage, such as ultra-low temperatures, continue to be major setbacks.

• mRNA Vaccines: mRNA vaccines represent a particular form of RNA vaccine that has found broad application, especially in COVID-19. Companies such as Pfizer and Moderna have successfully developed mRNA vaccines, showing the potential of this platform. Advantages of mRNA vaccines include high efficacy, speed of production, and targeting a wide range of diseases. However, there are still challenges that have hindered their wide adoption, such as the need for LNP delivery systems and cold chain storage.

* Related Products & Services from BOC RNA

DNA Vaccines vs RNA Vaccines

Vaccine Development Time

DNA and RNA vaccines both reduce vaccine development times significantly compared to the traditional approach. However, RNA vaccines have a faster turnaround because they can be synthetically produced in the lab without needing extensive cell culture processes. For example, mRNA vaccines against COVID-19 went from the very first genome sequencing of the virus to clinical trials in a fraction of the time it took traditional vaccine technologies.

DNA vaccines, although faster, still have some hold-ups compared to the conventional ones. This is because there are complications in the production and purification of plasmid DNA and in the insertion of the gene of interest into plasmids. Nonetheless, their development time remains competitive, especially with continuous improvements in plasmid manufacturing technologies.

Cost of Vaccine Development

DNA vaccines are, on the whole, less expensive to produce. The process of manufacturing DNA vaccines is relatively simple, involving the synthesis of plasmid DNA, bacterial fermentation, and plasmid purification. However, this process can become more expensive during scale-up or when vaccine candidates require complex optimization.

RNA vaccines, in turn, tend to be more expensive in production. The synthesis of mRNA, the formulation of the active ingredient into lipid nanoparticles, and cold storage raise the production costs. Despite that, efficiency and speed of development and adaptation to new pathogens often make the higher initial investment justifiable.

Vaccine Storage and Transportation

One of the major challenges facing RNA vaccines is storage and transportation. mRNA vaccines, in particular, require ultra-cold storage conditions, approximately -70°C, to maintain stability, especially when in lipid nanoparticle formulations. This requirement presents logistical challenges, especially in regions that have limited access to refrigeration infrastructure.

DNA vaccines have better stability at higher temperatures and can be stored and transported at standard refrigerator temperatures of 2-8°C. This makes DNA vaccines more accessible, especially in low-resource settings where refrigeration may be limited.

Vaccine Efficacy

RNA vaccines have also shown much better efficacy in various clinical trials, especially the mRNA COVID-19 vaccines that showed over 90% efficacy in preventing symptomatic infection. This is generally attributed to the fact that mRNA vaccines are able to elicit a strong and rapid immune response by leveraging both humoral and cellular immunity pathways.

DNA vaccines have usually showed good efficacy but tend to give relatively more modest immune responses than mRNA vaccines. Nevertheless, continuous optimization of DNA vaccine elements and new modes of delivery are improving their immunogenicity.

Vaccine Safety and Regulatory

While DNA and RNA vaccines do face strict regulatory scrutiny before licensure, RNA vaccines more often face and endure an extra degree of scrutiny concerning their safety, being relatively new. Regulatory bodies like the FDA and EMA have issued Emergency Use Authorizations for mRNA COVID-19 vaccines, citing their safety and efficacy based on large-scale clinical trial data.

DNA vaccines are not as new as RNA vaccines, but they also face regulatory challenges regarding genomic integration and interaction with the immune system. However, their long history of use in veterinary medicine and straightforward manufacturing processes have paved the way for their use in human clinical trials.

Vaccines Optimization Strategies

RNA Vaccines Optimization Strategies

The optimization of RNA vaccines mainly focuses on modifications of RNA sequences, delivery systems, and the selection and combination of antigens.

• First, some RNA modifications such as 5-methylcytosine and pseudouridine can decrease the immunogenicity of mRNA and enhance translation efficiency to elevate the eXpression of antigens. Besides, codon optimization will improve the level of protein eXpression and guarantee effective antigen production in mammalian cells.
• In delivery systems, LNPs represent the main carriers for mRNA. They protect mRNA against degradation and help it enter the cells. The optimization of LNPs aims at the enhancement of delivery efficiency with minimal potential toxicity. Moreover, other delivery methods include extracellular vesicles, lipid-like materials, and other biomaterials, aiming to enhance biocompatibility and tissue targeting.
• It is also further confirmed that combining mRNAs encoding multiple antigens in one vaccine can induce a broader immune response. For instance, recent studies have demonstrated that the combination of mRNAs encoding different influenza subtypes significantly improved immune protection against both influenza A and B viruses.

DNA Vaccines Optimization Strategies

DNA vaccine optimization primarily involves the selection of antigens, DNA vector design, delivery methods, and the use of adjuvants. Similar to RNA vaccines, DNA vaccines also require the selection of appropriate antigens to induce a strong immune response.

• In terms of DNA vector design, optimizing the coding sequences (such as codon optimization) can enhance antigen eXpression. Additionally, using specific promoters and enhancers can further stabilize gene eXpression.
• For delivery, DNA vaccines face the challenge of needing to enter the cell nucleus for eXpression. Common delivery methods include electroporation and nanoparticle-based systems. Electroporation opens temporary pores in the cell membrane using electric pulses, allowing DNA to enter the cell. This method has shown good results in clinical trials. Nanoparticle delivery is also widely used in DNA vaccines, as it effectively promotes DNA uptake by cells and enhances immune responses.
• Finally, DNA vaccines can be enhanced by incorporating adjuvants. For example, chemical adjuvants like aluminum hydroxide and immune stimulatory molecules (such as cGAMP) are used to activate antigen-presenting cells (APCs), enhancing T-cell recruitment and polarization.

Both RNA and DNA vaccine optimization strategies depend on the enhancement of antigen eXpression, the improvement of delivery systems, and the promotion of immune responses. Improvements in the efficacy and safety of vaccines are being achieved by RNA sequence modifications, the optimization of DNA vector design, better methods of delivery, and new adjuvants.

* Related Products & Services from BOC RNA

New Development of Nucleic Acid Vaccines

Self-Amplifying RNA (saRNA) Vaccines

Self-amplifying RNA (saRNA) is a next-generation RNA vaccine platform designed to overcome the limitations of traditional mRNA vaccines. saRNA vaccines include genetic material taken from self-replicating viruses, for example, alphaviruses. It allows them to proliferate inside the host cell. Such replication amplifies antigen production, enabling lower doses of saRNA to reach similar or even superior immune responses compared to conventional mRNA vaccines. This makes the saRNA vaccine a potential breakthrough in terms of dose-sparing strategies and cost-effectiveness.

Circular RNA (circRNA) Vaccines

Circular RNA (circRNA) is another innovative RNA vaccine platform that features a covalently closed loop structure, making it more stable than traditional linear RNA. CircRNA vaccines have the potential to eXpress antigens in a manner that is less susceptible to cellular nuclease degradation. The increased stability enables the production of antigens in host cells for a longer period, which may enhance the immune response over a longer period. The closed structure of circRNA makes it more resistant to degradation, hence offering enormous advantages regarding vaccine stability and efficacy.

Minicircle DNA Vaccines

Minicircle DNA (mcDNA) vaccines are smaller, more efficient forms of DNA vaccines. By deleting bacterial sequences not required for mammalian eXpression, the mcDNA vectors decrease the size of the DNA construct, therefore enhancing the efficiency of gene delivery and eXpression. Further, mcDNA vaccines have a better safety profile, as immune responses against the bacterial sequences are avoided. However, challenges in large-scale production and purification have further limited wider clinical applications for mcDNA vaccines.

Nanoparticle Plasmid DNA Carriers

Nanoparticle plasmid DNA carriers, by contrast, are a more recent approach intended to get around manufacturing constraints of mcDNA vaccines. These nanoparticles are small in size (<500 bp), exhibit increased transfection efficiencies, enabling stronger immune responses and better delivery to target cells. So far, nanoparticle DNA vaccines have shown promise in preclinical studies and are being explored for application against diseases like influenza and Zika virus.

* Related Products & Services from BOC RNA

A Comprehensive Comparison of DNA and RNA Vaccines

- mg g kg ton

We recommend you to leave us your work email address so that we can serve you better. Please leave your organization information here if you don't have a work email address.

SUBMIT