DNA Vaccines: The Next Stage in the Vaccine Revolution?

Researching vaccine to novel coronavirus 2019-nCoV. Close-up shot of a scientist preparing glass slide.

Over the last two years, there has been an unprecedented frenzy to develop new vaccines due to the COVID-19 pandemic, but DNA vaccines have rather stood in the shadow of their mRNA cousins. With the first DNA vaccine against SARS-CoV-2 now approved in India, what’s next in this field and can these vaccines compete with others on the market?

The first human DNA vaccine, developed by Zydus Cadila, received market approval in India in August for protection against COVID-19. Although several veterinary DNA vaccines have been approved, this is the first ever in humans.

So why is there only one COVID-19 DNA vaccine, out of 22 approved in different countries around the world and why in India?

Helen Horton is chief research officer at Touchlight, a U.K.-base biotech focusing on discovery and development of DNA-based genetic medicines that also synthesizes its own ‘doggybone’ DNA. She has been working on DNA vaccines since the 90’s.

She told Clinical Omics that a key reason DNA vaccines for humans have not reached the market more quickly is because cellular delivery issues meant their efficacy was initially low.

“They were always very safe. We could basically inject milligrams of DNA, but it just wouldn’t do anything. So, it was safe, but it wasn’t very immunogenic because it has to get not only into the cell, but also into the nucleus.”

In order to produce an immune response, some kind of delivery device is needed to help the DNA enter the cells, something that is less of an issue for other vaccines. In recent years several devices have been developed to make this easier, although they are still new to many healthcare providers.

“We have the electroporation devices from people like I-Core and Inovio and now we also have the needle-free injection devices from people like Pharmajet, which is what Zydus Cadila uses,” said Horton. “These ways of basically helping DNA to get into cells have made the difference between an immunogenic, and non-immunogenic DNA vaccine.”

The need for these devices for vaccine rollout is problematic in a pandemic setting, as it’s currently an unfamiliar method for many healthcare providers. Indeed, this unfamiliarity is slowing the rollout of Zydus Cadila in India this month. There is also potentially extra expense involved with purchasing the devices, which may put healthcare providers off.

However, DNA vaccines come with other benefits. In trials so far, they appear to be very safe. “We haven’t really seen safety concerns,” says Horton. “Whereas with the other platforms that are out there—luckily the side effects are rare—but there are some safety issues with both the mRNA and the viral vector vaccines.”

DNA vaccines are also highly stable and do not need the kind of expensive, low temperature storage the two mRNA vaccines require, likely something that factored into Zydus’s decision to develop a DNA vaccine for the Indian population.

U.S.-based firm Inovio Pharmaceuticals is also developing a DNA vaccine for COVID-19, which will soon go into Phase III trials. Kate Broderick, senior vice president, R&D at the company explained: “We don’t require any frozen cold chain to ship or store our vaccines. Our vaccines are stable at room temp for 1 year and at 37°C [99°F] for 1 month. This has significant benefits in the logistical supply of vaccines to meet the urgent needs of communities around the world.”

Caution is being used for storage of the Indian vaccine so far, but it is also much easier to store than others that are currently available. “The Zydus Cadila vaccine at the moment is stored between 2° and 8°C [35°-46°F]. So just in a refrigerator. But they also have data showing that it’s stable for up to three months, even at 22°C [72°F],” added Horton.

Another advantage to DNA vaccines is the kind of immune response they produce from the body. The available mRNA vaccines for COVID-19 produce strong antibody and CD4 T cell responses, but not much in the way of CD8 T cell response. Conversely, the viral vector vaccines produce strong CD8 responses, but less in the way of other immune cells.

“DNA vaccines are able to generate both antibody and T cell responses,” said Broderick, which includes both CD8 and CD4 responses, confirmed Horton. The Zydus Cadila vaccine had moderate 67% efficacy at protecting against symptomatic disease in clinical trials, but this broader immune response may mean the protection it offers lasts for longer (although this has yet to be confirmed).

“It’s probably why DNA vaccines have actually performed quite well in cancer,” says Horton, “there are a number of vaccines that are now in quite late stage trials for cancer that are DNA vaccines.”

Vaccibody is one company pursuing this path. The Norwegian biotech has two therapeutic DNA vaccines for a range of different solid tumors being trialed at Phase II.

Both Horton and Broderick think we will soon see broader DNA vaccine development and rollout, partly due to the increased research and investment that resulted from COVID-19. “I believe we are on the cusp of seeing many DNA vaccines enter the market soon. The COVID pandemic has allowed us to refine our manufacturing strategies and have a global footprint. Additionally, we have demonstrated how our vaccines can remain effective in the face of mutational changes. This can really apply to many viral targets, the flu being an obvious example,” emphasized Broderick.

“It’s actually been really heartening to see how the scientific community have come together… shared information, shared approaches, shared ideas, I think it has helped a lot,” said Horton. “That has really set the stage now for companies like ours, and other small biotechs working on really innovative platforms, to be able to get into the clinic faster and to be able to collaborate more with companies who are interested in using our DNA as a starting material.”

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