June 13, 2024

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What are the Pros and Cons of DNA Vaccines?

What are the Pros and Cons of DNA Vaccines?  A Brief Analysis of the Past and Future.

What are the Pros and Cons of DNA Vaccines?  A Brief Analysis of the Past and Future.

DNA vaccines, a novel vaccine type developed in the 1990s, represent the third generation of vaccines following attenuated vaccines and genetic engineering vaccines.

The concept of DNA vaccines was first introduced in 1990 when the Wolff group discovered that injecting plasmid DNA directly into muscle tissue could lead to the expression of protective antigenic proteins within eukaryotic cells.

This process stimulates the host to generate long-lasting specific humoral and cellular immune responses and can induce cytotoxic T lymphocytes (CTLs) with cell-killing capabilities.

DNA vaccines have therapeutic and prophylactic potential against infections caused by viruses, intracellular bacteria, and parasites.



What is DNA vaccine?

A DNA vaccine, composed of plasmid DNA containing one or more foreign genes (originating from bacteria) and various genetic elements such as a eukaryotic promoter and polyadenylation signal, can express the relevant antigenic proteins in various mammalian cells.

By directly introducing plasmids carrying genes encoding foreign antigens into the cells of humans or animals through a specific method, the host cells’ transcriptional machinery synthesizes antigenic proteins in vivo, thereby eliciting an immune response.


CpG Immune Stimulation

A crucial structural element in DNA vaccines responsible for immune stimulation is the non-methylated CpG motif, also known as immunostimulatory sequences (ISS). The exact mechanism of oligonucleotide immune stimulation is not yet fully understood. Oligonucleotides containing CpG sequences can stimulate the proliferation of mouse B cells and the production of immunoglobulins. They can also induce the secretion of certain cytokines by T cells, B cells, and natural killer cells both in vitro and in vivo.

In vertebrate immune systems, recognition of the non-methylated CpG core sequence in prokaryotic DNA can trigger immune responses and different types of cytokine secretion depending on the nucleotide sequence flanking the CpG motif on either side.


Immune Response Mechanism of DNA Vaccines

After DNA plasmids are introduced into host cells, gene segments encoding pathogen antigens are expressed within host cells and antigens are synthesized. These processed, modified antigens are then presented to the immune system, triggering an immune response. This process is similar to natural infection by pathogens or the administration of attenuated live vaccines. As a result, DNA vaccines can effectively stimulate both humoral and cellular immunity, particularly with their ability to activate cytotoxic T lymphocytes.


Advantages and Safety of DNA Vaccines

1. Advantages of DNA Vaccines:

i) Reduced reliance on attenuated pathogens (bacteria and viruses) or recombinant proteins compared to other methods.
ii) Cost-effective production of plasmid DNA.
iii) Relative ease of storage of plasmid DNA.

Plasmid DNA delivery to organs induces antigen-induced immune responses, effectively functioning as “bioreactors.” Furthermore, antigen presentation through both MHC class I and II pathways activates all aspects of the immune response, including helper T cells, cytotoxic T lymphocytes, and humoral immunity.

The ease of handling and stability of plasmid DNA contribute to its relatively low production cost, paving the way for widespread use of DNA vaccines in developing countries. DNA’s immunogenicity relies on its expression within host cells, a process similar to natural viral infection, which results in a robust immune response.

Recombinant plasmid DNA persists in the host’s body, continuously stimulating widespread humoral and cellular immune responses, leading to long-lasting immunity. DNA vaccines can also induce mucosal immunity and immune memory responses. They have potential applications in challenging diseases such as cancer and can be valuable for preventing diseases caused by pathogens with high mutation rates or multiple serotypes. The lack of immunogenicity of plasmid DNA allows for repeated use, which is crucial for animals with maternal antibodies.


2. Safety of DNA Vaccines:

DNA vaccines offer several advantages over traditional vaccines but also raise several issues when applied to humans. Integration of carrier DNA into the host genome poses a potential risk of unfavorable transformations. If gene vaccine DNA spreads to reproductive cells and integrates, the consequences could be profound. Immune enhancement remains an area for improvement, with larger experimental animals showing poorer gene immune responses. In mouse experiments, high antibody responses were observed, but the effects were less pronounced in larger animals. Concerns exist regarding anti-DNA immune responses and whether plasmid DNA might induce autoimmunity, potentially leading to autoimmune diseases like systemic lupus erythematosus.




DNA Vaccines and In Vivo Electroporation

In vivo electroporation is a technique that involves introducing foreign genes into target tissues or organ cells of animals through the action of an electric field.

In recent years, in vivo electroporation has gained prominence in gene research and has shown significant advantages in medical applications, making it an effective method for gene delivery in living organisms.

What are the Pros and Cons of DNA Vaccines?  A Brief Analysis of the Past and Future.



Gene Therapy and DNA Vaccines

Gene therapy is a clinical strategy that involves transferring genetic material into somatic cells to correct genetic disorders. Its primary mechanisms include:
i) Correcting cellular dysfunction by expressing defective genes.
ii) Enhancing cellular functions by transferring foreign genes.
iii) Suppressing detrimental cellular actions by introducing counteracting genes.
In recent years, gene therapy has expanded its applications to include acquired diseases such as cancer, infectious diseases, and vascular disorders.

The gene therapy process generally consists of three steps:
1. Delivering therapeutic genes to the surface of target cells.
2. Introducing genes into cells.
3. Integrating genes into the cell nucleus.

The advent of electroporation technology has greatly improved the second step.

Since the emergence of electroporation technology, it has been widely used for transfecting cells in vitro. Subsequently, many studies have shown that in vivo electroporation technology can significantly enhance the expression levels of DNA vaccines or therapeutic DNA plasmids in various target tissues, including muscle, skin, liver, tumors, and other tissues, indicating promising clinical applications. Currently, in vivo electroporation technology is extensively utilized in research related to DNA vaccines and gene therapy.


Delivery of DNA Vaccines: Electroporation Technology

The principle of immunization involves inducing the production of memory T cells and B cells and generating neutralizing antibodies in the serum after the administration of foreign proteins. Experiments have shown that direct in vivo gene transfer of recombinant DNA can lead to the in-situ expression of proteins, thus giving rise to DNA vaccines. As a means of generating immunity against infectious pathogens or tumor antigens, DNA vaccine administration is simple, versatile, and safe, prompting continuous research.

DNA vaccines are effective in rodents, but in larger animals and humans, they face challenges due to lower gene transfer efficiency and replicability. Typically, multiple immunizations with high DNA doses are required to achieve a moderate response, especially in primates.

One reason for the lack of efficacy of DNA vaccines in large animals and preliminary human clinical trials appears to be the inefficient uptake of muscle tissue DNA. This efficiency varies between small and large animal species.

Studies have indicated that the level of antibody production with DNA vaccines is directly related to the level of antigen expression. Hence, various methods have been explored to enhance the efficacy of these vaccines, including particle bombardment, lipofection, ultrasound, needle-free injection, gene gun, nanoparticle delivery, and in vivo electroporation, with the latter being one of the most effective methods.


Mechanism of Electroporation Technology

Electroporation enhances the uptake of DNA by cells, leading to increased antigen expression and more effective activation of the immune system, significantly enhancing the immune response induced by nucleic acid vaccines.

Additionally, the electric current causes cell damage, triggering local tissue inflammation and the infiltration of numerous inflammatory cells, including macrophages, which are antigen-presenting cells, thereby improving the efficiency of antigen presentation.

This is an important mechanism by which electroporation enhances the immune response to nucleic acid vaccines.


Research on Electroporation-Based DNA Vaccines

Research on electroporation-based nucleic acid vaccines has been attempted in rodents and birds, primarily focusing on large mammals with lower immune responses to nucleic acid vaccines, such as livestock and primates (some progress has been made in clinical trials involving human volunteers).

These studies, particularly those addressing nucleic acid vaccines against significant animal infectious diseases like tuberculosis and malaria, provide valuable insights for the development of nucleic acid vaccines against other diseases.


Numerous results have shown that the application of in vivo electroporation significantly improves plasmid delivery in all animal models, addressing the issue of low immunogenicity in DNA vaccines for large animal models. Moreover, it demonstrates good safety, laying the foundation for entering clinical trial phases.

Early preclinical trial results also demonstrate substantial enhancements in immune efficacy when using in vivo electroporation technology for DNA vaccine delivery.


DNA vaccines have opened new frontiers in immunology and vaccinology. While DNA vaccines have shown promising results in immune defense, they also present challenges, such as understanding the immunological mechanisms of DNA vaccine administration and addressing theoretical safety concerns related to nucleic acid vaccines.

Current consensus suggests that DNA vaccines should be used initially against pathogens and diseases that are not effectively managed using traditional methods, such as HIV, tuberculosis, malaria, and Ebola.

On the other hand, DNA vaccines hold promise for therapeutic applications. With further research, DNA vaccines may continue to address existing challenges and find applications in various fields.


What are the Pros and Cons of DNA Vaccines? 

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