DNA and RNA vaccines use genetic material to deliver information to human cells and elicit an immune response. DNA vaccines are safe, easy, affordable to produce, and, unlike RNA vaccines, are stable at room temperature. These attributes make them more promising for rapidly immunizing populations, especially in resource-limited settings.

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How do DNA vaccines work? Read our explainer to find out. Image credit: Bloomberg Creative/Getty Images

DNA vaccines use small, circular DNA molecules, called plasmids, to introduce a gene from a bacterium or virus to trigger an immune response.

For example, ZyCoV-D, the recently developed COVID-19 DNA vaccine authorized in India, consists of a plasmid that carries a gene that codes for the SARS-CoV-2 spike protein.

After entering a human cell, the plasmid must make its way through the cytoplasm, cross the nucleus membrane, and enter the cell nucleus.

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Enzymes in the nucleus convert the viral or bacterial gene that the plasmid carries into messenger RNA (mRNA). The mRNA must then travel to the cytoplasm, where enzymes convert into a bacterial or viral protein.

The immune system identifies the bacterial or viral protein as a foreign body and elicits an immune response.

The response tends to be gradual because the immune system has not previously encountered the bacterial or viral protein.

Vaccination causes memory immune cells to form. When an infection occurs, these cells quickly recognize the bacterium or virus and prevent severe disease.

Plasmid DNA degrades within a few weeks, but these memory immune cells provide continued immunity against the pathogen.

Similar to DNA vaccines, mRNA vaccines deliver genetic material to human cells to synthesize into one or more viral or bacterial proteins.

While DNA and mRNA vaccines have several similarities, there are notable differences between these genetic vaccines.

For DNA vaccines to be effective, the plasmid DNA must cross the cell membrane, enter the cytoplasm, and then reach the cell nucleus by crossing the nucleus membrane.

In contrast, an RNA vaccine only needs to cross the cell membrane to enter the cytoplasm. The cytoplasm contains enzymes that use the genetic information in the mRNA molecules to synthesize the bacterial or viral proteins.

Because DNA vaccines need to go through the extra step of entering the cell nucleus, they produce a much lower immune response than mRNA vaccines.

However, a single plasmid DNA can produce numerous copies of mRNA. Once a plasmid DNA enters the nucleus, it can produce more bacterial or viral protein than a single molecule of an mRNA vaccine.

Speaking to Medical News Today, Dr. Margaret Liu, chair of the board at the International Society for Vaccines, noted that DNA vaccines are “inherently not as immunostimulatory as mRNA [vaccines], but [it is] not clear [that] this is a disadvantage, as the inflammation of mRNA vaccines may limit their applications.”

While people may tolerate inflammation of the muscles and other side effects that RNA vaccines cause in the context of the COVID-19 pandemic, these side effects may limit their use against non-pandemic diseases, explained Dr. Liu.

mRNA vaccines are fragile and require storage and transportation at cold or ultra-cold temperatures. In contrast, DNA vaccines have greater stability and are easier to store and transport than mRNA vaccines.

Dr. Liu noted that the logistics of the storage and transportation of mRNA vaccines had impeded the distribution of vaccines to low-income nations. The temperature-stable DNA vaccines offer a viable alternative.

For example, the COVID-19 DNA vaccine ZyCoV-D remains stable at room temperature for at least 3 months and even longer at 2–8°C (35.6–46.4°F), making it invaluable for settings with limited resources.

However, there are some concerns regarding the safety of DNA vaccines. Dr. Jeremy Kamil, associate professor at Louisiana State University Health Shreveport: noted:

“There are regulatory concerns that foreign DNA would recombine or integrate with our own DNA. At the end of the day, current mRNA vaccine technology has a much more straightforward route to success because it can directly be translated to protein and doesn’t need to make it to the nucleus for that to happen.”

Both DNA and mRNA vaccines are genetic vaccines that have numerous advantages over other conventional vaccines.

Some conventional vaccines use weakened or inactivated viruses or bacteria to stimulate the immune system. The use of inactivated or killed pathogens may result in a weaker than desired immune response.

Recombinant subunit vaccines use viral or bacterial proteins that yeast or bacteria synthesize. Subunit vaccines do not produce a strong immune response and often require multiple booster shots. Furthermore, the design and production of subunit vaccines can be time-consuming and challenging.

Unlike vaccines using weakened pathogens, DNA and RNA vaccines only carry the information needed to produce one or more bacterial or viral proteins and cannot generate the entire pathogen. Moreover, genetic vaccines activate all components of the immune system to offer better protection than inactivated pathogens and subunit vaccines.

Also, the manufacturing process for DNA and RNA vaccines is inexpensive and simpler than the one for subunit and other conventional vaccines. Furthermore, it is possible to manufacture DNA and RNA vaccines on a large scale.

DNA and RNA vaccines use strands of DNA or RNA that carry information about the desired bacterial or viral protein. Manufacturers can synthesize these from scratch using a chemical process, which means they can rapidly adapt the DNA and RNA vaccine-making process to respond to the emergence of a new variant or virus.

Scientists have carried out considerable research during the last 3 decades to address concerns about the limited immune response evoked by DNA vaccines. These approaches include improving the stability of the plasmid to slow its degradation, changing the DNA sequence to increase protein expression levels, and using adjuvants to enhance the immune response produced by the vaccine.

A significant amount of research has also focused on improving delivery methods for DNA vaccines to produce a more potent immune response. While conventional approaches involve injecting the DNA vaccine under the skin or into muscle, researchers are investigating some injection-free methods.

Until recently, DNA vaccines only had approval for veterinary use due to the limited immune response generated in humans. The COVID-19 DNA vaccine developed by Zydus Cadila is the first DNA vaccine to receive approval for use in humans and represents a significant step forward for DNA vaccines.

Notably, administration of the ZyCoV-D vaccine involves using a simple, needle-free device that uses high pressure to help the vaccine penetrate through the skin surface.

Several human trials are currently underway to evaluate the potential of DNA vaccines candidates against various infectious diseases. These include vaccines against infectious diseases caused by HIV, Ebola virus, Zika virus, influenza, herpes virus, and human papillomavirus.

Researchers are also studying DNA vaccines against various types of cancer, including pancreatic, breast, and cervical cancer. Tumor cells express different proteins than healthy cells, and DNA vaccines can teach the immune system to recognize and eliminate tumor cells.

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