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Drug delivery


EU: the first DNA vaccine to reach clinical trials in Europe. Companies that reached the same point last year could hardly move without attracting funding. For example, Inovio Pharmaceuticals’ DNA vaccine, which uses very similar technology to Takis Biotech’s, won a $71m contract with the US Department of Defense in June 2020. But, given the speed with which most rich countries have since vaccinated their populations, the billions have stopped flowing quite so freely into new pharmaceutical technologies.


In fact, in August it was the Indian pharma giant Zydus Cadila that received the first emergency approval for a DNA Covid vaccine. What India understands better than any other country that has produced a Covid vaccine so far is that, while viral vector and mRNA vaccines easily won the race to market, two-thirds of the planet is still susceptible to Covid – and each technology has limitations that could slow the process of changing that fact.


“What we have, potentially, is a vaccine that only requires one dose, and that can be shipped at room temperature or in a refrigerator... That’s what we think the world needs right now.”


Hong Jiang, Aegis Life $71m


Value of contract awarded by the US Department of Defense to Inovio Pharmaceuticals to develop its DNA vaccine.


Inovio Pharmaceuticals 12


Even within cells, most RNA molecules degrade in about two minutes. DNA, however, can be recovered from the mortal remains of creatures that died millions of years ago. That helps explain why viral vector vaccines, which use modified viruses to transport DNA into cells, are easier to store and ship than their mRNA equivalents. But those vectors can prompt immune responses of their own. Some people have pre-existing immunity to vectors adapted from viruses that naturally affect humans, while repeated use of any vector increases the chances that recipients will stop responding to it. Even under the most favourable conditions, viral vector vaccines for Covid variants take far longer to develop and produce than mRNA ones, and, as the pandemic stretches on, it’s possible that vector immunity could force companies to start all over again with new viruses. Disconnected from those vectors, though, the stability of DNA molecules at higher temperatures could make them even easier and cheaper to manufacture than mRNA. As testified by Takis’ rapid pivot to a phase II trial of a booster shot specifically targeting the Delta variant, a DNA vaccine could combine the advantages and minimise the limitations of the other two approaches. Still, it hasn’t turned heads in quite the same way as either did on its own. “A lot of us in the US are pretty myopic,” says Jiang at Aegis Life,


which also has a DNA Covid vaccine in clinical trials. “We’re like, we have the mRNA, and it works, and we have the freezer infrastructure to get it everywhere in the country, so we think the problem is solved and the pandemic is over.”


On one side, then, the developed world’s pharma industry is slipping back towards its old inertia, with a sense that perhaps a third new vaccine technology is a bit much for one pandemic. On the other, the virus keeps mutating. If anyone’s feeling complacent, they can look to the devastation wrought by the Delta variant in India – or, if they’re on Wall Street, the various ways it has interrupted New York’s attempts to fully reopen. Since that started, Jiang explains, US investors have changed their tune. The longer it takes to suppress Covid worldwide, they’ve realised, the greater the chances of a mutation that resets the vaccination counter to zero. DNA vaccines could be the best way to prime the rest of the planet’s immune systems. But first, they have a lot of catching up to do.


Guns, drills and zappers


While injections of large quantities of raw DNA in saline solutions were first shown to work in animal models in the early 1990s, responses in humans and other primates have rarely proved strong enough to protect against disease. Viral vectors get around this issue by exploiting the process natural viruses use to merge with cells, splicing the DNA sequence for creating the Covid spike protein into a harmless, non-replicating adenovirus.


Cells copy these DNA molecules into mRNA strands, which catalyse the production of spike proteins the immune system can learn to recognise and combat. Moderna and Pfizer-BioNTech’s vaccines engage the body’s manufacturing systems one step downstream by inserting mRNA directly into cells using lipid nanoparticles tuned to sneak past the immune system and push through cell membranes. Unfortunately, you can’t just swap DNA into Pfizer or Moderna’s LNPs. The dose each can contain is already limited by the toxicity of their constituent lipids, which prevent them from being used systemically, and DNA payloads instantly push them over into intolerability. Instead, most companies developing DNA vaccines have focused on using specialist delivery devices to overcome formulation issues. Most prominently, Zydus Cadila uses pressurised steam to fire large amounts of DNA through pores in the skin with a needle-free injector. For their part, Takis and Inovio both use electroporation guns to zap intradermally or intramuscularly injected DNA across cell membranes.


In both cases, the unconventional method of administration ensures enough DNA plasmids enter cells to induce a robust immune response. Although it is the more established vaccination technology –


World Pharmaceutical Frontiers / www.worldpharmaceuticals.net


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