What′s the science on DNA and RNA vaccines? | Science| In-depth reporting on science and technology | DW | 09.07.2020
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Science

What's the science on DNA and RNA vaccines?

A number of candidate vaccines for COVID-19 use a genetic modification of the virus. It's a relatively new process that scientists say may be safer and cheaper than conventional vaccines. Aren't there any downsides?

Researchers say that gene-based, or DNA and RNA, vaccines are faster and cheaper to produce in large quantities than conventional vaccines. 

Conventional vaccines often use "weakened"  or "killed"  versions of a virus. That means laboratories have to produce huge amounts of the virus. They often also include a protein, which is needed to spark a human immune response. But producing a virus and a viral-protein can be time-intensive and expensive. 

A DNA  or RNA  vaccine, on the other hand, takes a small part of the virus' own genetic information — just enough to spark an immune response — and the protein can be produced directly at the cell. Experts say the virus' genetic information can be replicated and produced relatively easily. And that's what scientists want in a live situation, such as the SARS-CoV-2 / COVID-19 pandemic, where billions of people need protection very quickly. 

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"That's a great advantage of an RNA vaccine," says Peter Doherty, a Nobel Laureate and professor of immunology at Melbourne University, "if it works well." 

A Covid-19 vaccine test volunteer receives an injection at a clinic in South Africa (picture-alliance/AP Photo/S. Sibeko)

Human trials: A Covid-19 vaccine test volunteer receives an injection at a clinic in South Africa

The World Health Organization publishes updates on the so-called "candidate" vaccines for SARS-CoV-2 currently in clinical or pre-clinical evaluation. One of the most recent has about 34 RNA and DNA vaccines on the list. But so far none have been approved for use in humans.

Compared to conventional vaccines

There are many different types of vaccines. "Traditional" or conventional vaccines include live attenuated vaccines, inactivated pathogens (also known as "killed vaccines"), viral-vectored vaccines, and other types known as subunit, toxoid and conjugate vaccines. Some prevent both viral and bacterial infection. The latter two are specific to bacterial infections, such as tetanus and diphtheria.

The oral polio vaccine (OPV), for instance, contains an "attenuated" — or weakened — version of the polio virus. It activates a human immune response, without making the person fully sick.

But a vaccine-virus is also excreted — that is, passed from the body — and in communities where there is poor sanitation that can lead to two things.

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First, it can spread through the community and provide a form of "passive immunization." That's good, but only a short-lived form of immunity. The body has not learnt to recognize the virus and produce its own antibodies. Which means, the body may become vulnerable to that virus again in the future.

And second, if that vaccine-virus lives on long enough in a community without dying out, as it should, it can become a threat in its own right. The World Health Organization (WHO) says: "In very rare instances, the vaccine-virus can genetically change into a form that can paralyze — this is what is known as a circulating vaccine-derived poliovirus."

George Church, a professor of genetics at Harvard Medical School and a pioneer in genetic sequencing says DNA vaccines lie somewhere "between live and dead vaccines," with one pertinent benefit: "They can't replicate, mutate, or escape."

Other advantages of DNA vaccines

DNA vaccines are also said to be more stable than conventional vaccines in warm climates "if kept dry and/or sterile at pH8," says Church.

In Nigeria, children line up for polio vaccine (Imago Images/Zuma)

In Nigeria, children line up for a polio vaccine, but some communities refuse it

"They can be stored at room temperature without losing their activity, whereas traditional vaccines require refrigeration," adds Sarah Gilbert, a professor of vaccinology at the Jenner Institute and Nuffield Department of Clinical Medicine at Oxford University.

They may even be effective against non-infectious conditions such as cancer and autoimmune diseases, where conventional vaccines do not work. 

Church says DNA vaccines "could be used widely."   

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And how do DNA vaccines work?

Instead of using a weakened or dead version of a virus, mixed with protein and other ingredients, the main agent in a DNA vaccine is made from part of the virus' own genetic information. The vaccine uses that DNA or RNA to make the immune system think it's under attack, and that triggers the production of proteins directly in the cell. 

That activates the immune response, and in turn antibodies that fight the virus.

"Viruses can only multiply in living cells. But to do that the virus has to make more protein. So, DNA becomes RNA, which becomes messenger RNA,  and that makes the protein," says Doherty.

The immune response in a little more detail

There are two elements to the immune response, says Doherty. 

The first, he says, is that proteins get turned into small things called "peptides." Those peptides are then presented on the surface of the cell, and they stimulate T cells. 

There are CD8 T cells,  also known as "killer T-cells," and CD4 helper T-cells. You need both to get an antibody response. 

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But you also need protein in the extra-cellular fluid.

Illustration 2019 Novel Coronavirus Sars-CoV-2 (imago/Science Photo Library)

RNA instructs the cell to make the protein and "for SARS-CoV-2 vaccines, that's the spike protein," says Prof. Sarah Gilbert

The RNA in a vaccine has to cause the protein to get out of the cell and into the extra-cellular fluid so that B cells, or so-called "memory" cells, can grab hold of it, says Doherty. Because without that, your body will have little or no memory of the virus and will be unable to protect you if you ever get infected for real.

Any downsides to DNA vaccines?

The WHO says many aspects of the immune responses caused by DNA vaccines are not yet fully understood. But that has "not impeded significant progress towards the use of this type of vaccine in humans," it says.

In addition, Gilbert says that DNA vaccines usually only encode one protein from the pathogen. "So, they may not be so good if you need to make an immune response against multiple proteins to get protection, but that can be dealt with by mixing multiple vaccines together," she says. 

A researcher at Arcturus Therapeutics, a company working on a RNA vaccine for the novel coronavirus COVID-19 (Reuters/B. Guan)

Arcturus Therapeutics is one of at least 30 labs working on a RNA or DNA vaccine for the novel coronavirus COVID-19

Delivery methods vary and may need to be refined over time and with more experience.

Some use a DNA "plasmid," a molecule that's basically as a transportation vehicle for the vaccine. Others use "electroporation" — electric pulses that create temporary openings in the cell membrane to let the vaccine get inside.

"Scary" misconceptions about DNA vaccines 

Often when we think of DNA or genetics in any form, we think of scary "designer babies," and worry whether our altered DNA will get passed onto future generations.

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"Anything to do with genetics, or DNA, is somehow conflated in many people's minds. They look at these technologies, whether it's germline-heritable editing or somatic gene-therapy that isn't heritable but might help with diabetes, or changing the genetics of a plant so that it resists pests, or changing the genetics of an animal so that it produces less phosphorus in its feces," says Alta Charo, a professor of law and bioethics at the University of Wisconsin at Madison. 

"And all these things get lumped together in the category of genetics, and very closely linked to genetics is scary. Or at least worrisome. And that's why we have to help people distinguish between the various categories," Charo says.

DNA vaccines aren't heritable

If there are ethical concerns in genetics, they might apply to techniques like human-gene editing, where a person's DNA is altered to cut out a gene that might make you prone to a particular cancer. And those alterations can be passed on through generations. 

But that's not the case with DNA vaccines. 

"They don't alter a person's DNA at all. They provide a temporary addition in a small number of cells," says Gilbert. "DNA vaccines do not enter the genome."

Antibody Test Coronavirus (Imago Images/B. Hake)

Prof. Peter Doherty says COVID-19 antibody tests tend to only show antibodies in the blood, but not whether the immune system is sufficiently primed for a secondary attack

They merely imitate what happens when we get infected by a virus. A virus inserts its DNA into our cells to enable it to replicate and spread. And a vaccine has to do that as well, but in a controlled manner. As Charo puts it, you retain "the shell of the virus but take away the guts" — the really dangerous stuff that makes you sick.

"When we get a viral infection, genetic material (DNA or RNA) from the virus is there inside our cells, but most viral infections don't then leave DNA that becomes part of the genome, although that does happen in some cases," says Gilbert. 

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HIV, for instance, has a "reverse transcriptase," which copies the viral genetic material back into the genome. But viruses like the coronavirus or influenza don't have that, says Doherty.

"So, we're not going to copy the genetic material back into the human genome. But quite frankly, if you made a RNA vaccine and you gave it to people and it transmitted to other people, that would be a good thing," he says. "But I don't see why it should happen anyway." 

When will we see gene-based vaccines for COVID-19?

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Some DNA vaccines have been approved for veterinary use. And there are many others in clinical trials for human use, including those for SARS-CoV-2. 

Many will use what's called an "adaptive clinical trial design" to speed up the process from discovery to development to trial and approval to production. 

Charo says adaptive trials are a less "static" approach than conventional ones. They allow researchers to respond to data and adapt as they go along, whereas you would normally take every step in sequence, and over time.

But in a live pandemic, time is at a premium. An adaptive trial design makes it effectively possible to approve a vaccine before all the testing is complete.

"There would be a requirement to do follow-up research to confirm early indications, known as surrogate markers" says Charo, "and if that research fails to confirm those indications, then the drug or vaccine can be withdrawn."

In any case, you're only likely to see the full effects of a vaccine once it's out in the community. As Doherty puts it, "it's all one enormous experiment. People are trying to be safe, but even a partially effective vaccine might be useful. We'll have to see how that's evaluated by the regulatory bodies and the people making the vaccines." 

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