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The First Self-Amplifying mRNA Vaccine
25 Jan 202410:30 AM ET By Derek Lowe3 min read Comments
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If you were reading this site during 2020 and 2021, you'll recall the frequent updates on potential coronavirus vaccines and vaccine technologies. It's easy to forget that until that point, no adenovirus-platformed vaccine had ever been approved for use in humans, nor had any mRNA vaccine candidate made it to that point, either. It was remarkable to see both of those technologies (which had been under development for years) simultaneously reach the point of huge human trials, let alone regulatory approval and going into a substantial fraction of the earth's population.
But while that was going on, there were several other technologies also under investigation. For example, Pfizer and BioNTech had at least four mRNA vaccine candidates at one point before they narrowed down on the one that we all know about. And one of these was a "self-amplifying" version, which is an idea that's been kicking around in the field for some time. A "standard" mRNA vaccine is full of nanoparticles of the appropriate RNA sequence, heavily optimized for stability, cell penetration, and efficiency of protein production once a strand gets in. But the amount of mRNA present in the shot is all you get: these species do degrade with time, and you have to set the dose so that you've given enough to induce the desired immunologic effect.
A self-amplifying mRNA shot, as the name implies, contains the equipment needed to make more of itself once it enters cells. You do this by not only injecting the mRNA for the antigen of interest (such as one that encodes the coronavirus spike protein) but also mRNAs that get translated into replicase proteins that will in turn produce more of the mRNA species. Picture sending someone a sheet of paper with some important information on it, and then imagine that you've sent them a whole pile of copies of that sheet so they can distribute them. Now imagine sending them a bunch of sheets of material that can assemble themselves into a working photocopier and crank out more sheets when they do. That sounds weird and ridiculous, but hey, that's biology for you. It's very, very strange down there in the cell.
Having an mRNA that can make more copies of itself means that (first off) you probably don't have to inject very much. John von Neumann, an early thinker in the field of self-replicating devices, would have been beside himself with excitement. It also means that even with a small initial injection that you might well expect to get a larger and more thorough exposure to your desired antigen protein than you could feasibly inject in a standard all-at-once dose. So although this idea didn't make it into the first round of coronavirus vaccines, it has definitely not gone away, and there have been reports of progress in the field.
Well, the first vaccine of this type has been approved in Japan, and the companies involved (CSL and Arcturus) are seeking European regulatory approval next. Their vaccine (ARCT-154) uses mRNA that codes for replicase proteins lifted from the Venezuelan equine encephalitis virus. Here's a report on a Phase III trial of it versus the Pfizer/BioNTech as a booster, and the self-amplifying one seems to have shown an increased antibody response (which you'd hope would translate to increased protection from disease). It seems to have been well-tolerated, although there was one hepatic event in the self-amplifying group that could have been related to the vaccine, and that will bear watching as it rolls out into a larger population.
But overall, I think this is quite encouraging, to see this vaccination mode reach the real world. There's no telling how much longer it would have taken had things not been so hugely acclerated during the coronavirus pandemic, but I have no doubt that we would not be seeing it as soon as this. My usual analogy is what happened to aircraft design during World War II. Of course, the fact that world wars and global pandemics can have a few positive externalities is not exactly an argument in their favor, but we take what we can get!