Jon Kelvey Freelance Writer GEN
Best Positioned for Diseases that Require a Rapid Response
Immunologist Wolfgang Leitner, Ph.D., still remembers his reaction at being offered a chance to work on a DNA vaccine. This is an approach where instead of injecting, for example, an attenuated pathogen in hopes the immune system will mount a response to an antigen the pathogen presents, you inject the DNA sequence that codes for the antigen of interest, transfect a cell, and have the body produce and then react to the antigen on its own.
“I thought it was the dumbest idea ever,” Dr. Leitner says. “Based on how we understand the immune response to a vaccine, there is no way this can work.”
Vaccines must have two components, he explains: the antigen (to which you hope the body will learn to mount an antibody response) and an adjuvant (a trigger for the innate immune system that kicks off an inflammatory response). “If you’re not triggering the inflammatory response, the immune system sees no reason to respond.” And yet, other researchers were getting positive results with DNA vaccines.
At that time in 1992, Dr. Leitner was a postdoctoral researcher at Walter Reed Army Institute, studying malaria, when another lab approached him about working on a DNA vaccine for the mosquito-borne parasite. They needed an immunologist, even a skeptical one. “I ended up with the first DNA vaccine for P. berghei malaria. It’s one of the test systems for malaria vaccines, a rodent malaria strain,” he says. “It worked beautifully.”
It was a discovery that would set the course of Dr. Leitner’s career, from malaria vaccines at Walter Reid to melanoma vaccines at the National Institutes of Health (NIH) and to his current role as chief of the innate immunity section at the National Institute of Allergy and Infectious Disease at the NIH.
It would later become clear that DNA itself was triggering an innate immune response through the discovery of a slew of innate immune-system receptors, such as Toll Like Receptor 9 (TLR9), Dr. Leitner says, which is directly sensitive to DNA. DNA belongs in the cell nucleus, he says, and DNA in cellar cytoplasm is a sign that something is wrong. But the efficacy of DNA vaccines, such as Dr. Leitner’s in animal models, drove initial interest in the research.
Dr. Leitner’s malaria vaccines wound up going nowhere due to patent issues with the gene gun technology he used to administer it. So in 1998, he moved on to the NIH to begin applying the DNA vaccine approach to cancer, and specifically melanoma. “With malaria, or any infectious disease, you’re immunizing with a foreign antigen,” he says. “In the case of cancer you trying to convince the immune system to go after a self-antigen, so the bar is so much higher.”
To reach that bar, Dr. Leitner tried something different: a self-replicating DNA construct that mimics the action of an RNA alpha virus, such as Zika or Chikungunya, when it infects a cell. These viruses deliver their own enzymes that replicate their RNA genome in a cell’s cytoplasm, he says. “I converted that into DNA, put it into a plasmid, the plasmid makes one copy of that, what looks like viral RNA, and then the cell starts copying that RNA,” he continues. “That turned out to be one of the most potent vaccines we had ever seen and it worked beautifully in animal models against melanoma.”
Dr. Leitner’s enthusiasm for the approach even inspired his former mentor, Josef Thalhamer, Ph.D., at the University of Salzburg, to begin researching DNA vaccines for use in allergy treatments. “In a collaboration with him, we constructed the first anti-allergic, self-replicating DNA vaccines,” Dr. Thalhamer says. “The deciding factor to start DNA vaccination in my lab was the trust in Wolfgang and his personal assessment of this new and revolutionary approach.”
And yet, as of 2018, there are no DNA or RNA vaccines approved for use in the clinic. What happened?
Early DNA vaccines generally suffered from several key limitations, most especially potency in humans, says John Mascola, M.D., director of the Vaccine Research Center at NIAID. “In a mouse, for example, one can induce very high, robust immune responses, and it’s both T-cell immunity and antibody immunity, which is good,” he says. “When one brings it all the way to humans, the level of overall immune response that is generated is a lot lower.”
And yet interest in DNA vaccines remains, if just because of their potential advantages.
Despite initial concerns that they might integrate into patients’ genomes, DNA vaccines have proven remarkably safe; for instance, making them ideal in cancer immunotherapy or for vaccinating people with weakened immune systems, says David Weiner, Ph.D., executive vice president and director of the Vaccine and Immunotherapy Center at the Wistar Institute. “Our goal in vaccines is to make things that are safer than water,” he says. “DNA has an extraordinary safety profile so far in the clinic. I think we are well over 35,000 people without a single major adverse event related to product.”
Live attenuated virus and recombinant protein vaccines are also time consuming and expensive to produce, whereas DNA vaccines are simple to produce and extremely flexible. Once a DNA plasmid has been developed for one disease, Dr. Leitner says, retooling it for another is just a matter of swapping out the gene insert that codes for the antigen of interest.
Obtaining and inserting that gene is easy nowadays, Dr. Weiner says. “The day you order your synthetic, optimized, formulated DNA is the day you have a vaccine.”
That speed and flexibility in the DNA vaccine platform allows for rapid prototyping in response to emerging diseases. Dr. Weiner and his colleagues developed an Ebola vaccine in just 18 months. Dr. Mascola and his team were able to rapidly shift a DNA plasmid platform used for a West Nile Virus DNA vaccine to target Zika. “Within 3.5 months, we were in a Phase I human trial,” he says. “That’s really unprecedented speed for a vaccine.”
Those benefits, plus answers to the DNA vaccine potency problem, have kept Dr. Leitner excited about these technologies.
Electroporation, a technique that uses electric pulses to increase the uptake of DNA plasmids by cells, has been shown to dramatically increase potency in humans, Dr. Weiner says.
Another approach getting results, called heterozygous prime boost, uses DNA vaccinations to “prime” the immune system for a recombinant vaccine, according to Dr. Leitner. “You are starting with a DNA vaccine, and then you are coming back with a conventional vaccine and getting the best of both worlds.”
Today, Dr. Leitner keeps up on the DNA vaccine field, helping direct funding to the work necessary to help the technology mature. He believes that maturation is only a matter of time: DNA vaccines are already in use for veterinary medicine and are making it possible for countries without much bioscience funding to get into the game, thanks to the low cost of producing of DNA vaccines. As new diseases such as Zika emerge and require rapid responses, Dr. Leitner says DNA vaccines are best positioned to be developed and fielded on the quick.
“In the next 20 years, I hope we will see at least one—the first licensed DNA vaccine for people,” Dr. Leitner says. “I hope there will be more.”
Jon Kelvey is a freelance writer focused on the biosciences, technology, and aerospace. His work has also appeared in Slate, Smithsonian and Air & Space Magazine. He graduated from U.C Berkeley in 2009 with a B.A. in cognitive science and is now based in northern Maryland.