The first next-generation Covid vaccine is on its way to authorization in the European Union. Recently rolled out in Japan, the self-amplifying…
Self-amplifying mRNA Covid Vaccine: An Introduction
One of the critical ways a next generation Covid vaccine can improve on the original vaccines is to be more durable and “variant-proof.” That is one of the main goals of self-amplifying (m)RNA vaccines (saRNA, also called samRNA or SAM, and self-replicating RNA). We now have evidence that one of this next generation of vaccines can actually do that, outperforming the BNT/Pfizer vaccine, and for at least 12 months, with only some waning. It has other major advantages, too. And access to it may spread dramatically in 2025.
As I explained in my Covid vax update this month, marketing authorization is pending for 30 European countries by the end of February. The vaccine was developed by Arcturus Therapeutics in the US, and the trade name is Kostaive. An application to the US FDA has been planned for 2025. Another US-developed saRNA vaccine has been available in India since 2022.
So far, the Arcturus vaccine has only been available in Japan. And it arrived with an anti-vax campaign on steroids. As the vaccine spreads, we can expect anti-vax fear-mongering along with it, especially with the changes to US health agencies the incoming administration is heralding.
This post is one of a pair I’ve written this month to get ready for the wider rollout of this vaccine. The first is a deep dive into fear-mongering for current mRNA vaccines. This one is all about saRNA, covering:
- How saRNA vaccines work.
- The 2 saRNA Covid vaccines authorized so far.
- Other saRNA Covid vaccines in clinical trials.
- Safety and fear-mongering about saRNA.
How saRNA vaccines work
Self-amplifying RNA vaccines don’t just produce short-lived mRNA, as the first mRNA Covid vaccines do. As chemist Derek Lowe explained, “A self-amplifying mRNA shot, as the name implies, contains the equipment needed to make more of itself once it enters cells.”
These vaccines mimic the way viruses work, so that your body can keep producing mRNA after vaccination, and, potentially, more mature kinds of immune response that could last. The Arcturus saRNA vaccine, for example, includes components of an equine virus, that enable it to replicate inside cells. Printers are often used as an analogy for how this works. Lowe again:
“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.”
Self-amplifying RNA vaccines aim to improve on mRNA vaccines in several ways. You need much less active ingredient to make a dose. That could reduce adverse reactions and, importantly, make the vaccine cheaper to produce. The expense and complication of needing to be kept super-cold also doesn’t apply, and the vaccines are stable for longer. The Arcturus vaccine, for example, is already available in powder form.
As with any vaccine type, there is no guarantee that every saRNA vaccine will deliver the hoped-for results. For example, in 2022, I described an ambitious goal to sidestep the pharmaceutical industry with a public saRNA Covid vaccine at Imperial College London as “the one that struggled.” In the end, the immune responses in the phase 2 trial were disappointing, and the trial was discontinued.
Finally, I haven’t seen studies of intranasal saRNA vaccine yet. That could, theoretically, enable this type of vaccine to reduce the risk of infection, as well as disease.
The 2 saRNA Covid vaccines authorized so far
The first saRNA vaccine for Covid was authorized in India in 2022. It was developed by a biotech company in Seattle (USA), called HDT Bio Corp. They licensed Gennova, a manufacturer in India, to develop it there. India authorized the vaccine on relatively little data, so I can’t tell you much about this vaccine. Its trade name is Gemcovac.
The phase 2 to 3 trial of the vaccine was based on safety and signs of immune response alone, comparing the vaccine to the Oxford/AstraZeneca vaccine. That was a lower bar than comparing it to an mRNA vaccine. There were only 3,140 people in the group studied for safety, and only 420 people in the immune response analysis.
(You can see all the records I have for this vaccine in my collection here.)
The Arcturus vaccine is the first saRNA vaccine authorized by a drug regulator designated by WHO as stringent, or listed. That first authorization was in Japan, and the vaccine was rolled out earlier this year. This month, the vaccine got the necessary scientific approval from the European Medicines Agency to proceed to market authorization before the end of February 2025. When that happens, the vaccine would be authorized in 30 European countries, and the first detailed independent scientific analysis of the vaccine will be public. (European assessment reports are typically much more detailed than those from other stringent regulators, including Japan.)
You can read more about this in my update post this month. In summary, there have been over 20,000 participants in phase 3 trials of the Arcturus vaccine. It has been shown to outperform the BNT/Pfizer vaccine as a booster in people previously vaccinated with mRNA vaccine. In a small trial with 12 months of follow-up so far, immune responses against strains including Omicron were stronger, with little waning. The concentration of mRNA is lower, too: 5μg compared to 30μg in the BNT/Pfizer vaccine. That translates into a lower rate of severe adverse reactions.
The Arcturus vaccine is based on the spike (S) protein of the Covid virus. Its international non-proprietary name for the active ingredient in the Arcturus vaccine is zapomeran, and its trade name is Kostaive.
(You can see all the records in my collection for this vaccine here.)
Although these are the first 2 saRNA vaccines to be authorized in humans, they’re not the first saRNA vaccines. Developers have been experimenting with this type of vaccine since at least 2003 – like this one for HIV. This type of vaccine is in development for a range of other conditions, including for cancer.
Other saRNA Covid vaccines in clinical trials
As far as I know, no other saRNA Covid vaccines are in advanced stages. There are 2 other saRNA Covid vaccines that have completed phase 1 clinical trials.
Gritstone Bio (USA)
This vaccine is based on the spike (S) protein of the Covid virus, as well as some T-cell components. The developers published the results of one of their phase 1 trials in June 2023.
In September, Gritstone Bio announced they had received funding from the US government’s Project NextGen to run a phase 2b “mini-efficacy” trial in the US. Early this year, they announced this was running behind schedule. Their current Project NextGen contract goes to the end of March 2025. If milestones are reached by then, the vaccine could proceed to a 10,000-participant phase 2b “mini-efficacy” trial in the US.
(Records in my collection for this vaccine are here.)
GSK (UK)
GlaxoSmithKline (GSK) is the only major pharmaceutical company with an saRNA Covid vaccine that reached a clinical trial. GSK developers reported on the development of an saRNA platform back in 2017, and they published a report of preclinical results for an saRNA Covid vaccine in 2022.
The company ran a phase 1 trial in the US with 40 participants in 2021-2022. I couldn’t find the vaccine listed in their current pipeline. I hope they have a publication in the works, or it will be fertile ground for conspiracy theories.
(Records in my collection for this vaccine are here.)
Safety and fear-mongering about saRNA
In clinical trials, saRNA Covid vaccines have caused less severe adverse reactions than current mRNA vaccines. The vaccine also passed the scrutiny on safety of regulators in Japan and Europe. However, we won’t have a detailed enough independent report on safety until the European Medicine Agency releases their public report. That is pending, dependent on the marketing authorization decision in the coming weeks. I’ll update this post then. I’m also hoping we learn more about how this vaccine works exactly.
We have already had a preview of the fear-mongering to come, though, based on the campaigning in Japan when the vaccine was rolled out there a few months ago. It was so successful, that some businesses were banning vaccinated people from their premises. The claim that caused this was that “the vaccine will make an infinite number of proteins in the body or its components will be transmitted to others.”
As I wrote at the time, a major influence was the Japan Nursing Ethics Association. In August, they released a statement expressing concern about the safety and ethics of introducing this vaccine, and it’s an extraordinary document to come from a professional association. It uses hot button language (like genetic engineering) and a kind of conspiracist pseudoscience.
Their first argument is that there’s something suspicious about this US-developed vaccine only being available in Japan, and it shouldn’t be trusted as a result. Arcturus is advancing the vaccine itself in some areas, and licensed it to Meiji Seika Pharma in Japan, and Australia’s global biotech, CSL Seqirus.
I don’t think Japan being first to get to market is at all suspicious. It’s gotten truly bizarre though. I won’t link to the US anti-vax websites that are promoting this idea, but they’re throwing around language like “third atomic bomb” and the destruction of humanity.
There were 2 key elements to the campaign to shake confidence in the vaccine, both drawn from misinformation and conspiracy theories about the original mRNA vaccines. I dug into these claims in my recent compendium of mRNA fear-mongering. You can jump straight into those sections with these links:
- Claims that mRNA vaccines enter or otherwise modify DNA, and
- Claims that vaccinated people “shed” dangerous genetic material onto unvaccinated people.
It was reassuring to find out these fears don’t have any solid basis. The compendium covers a lot of other issues too – including the way that people come up with extravagant claims of disability and death from trawling databases. I think we should be prepared for the whole playbook – and a bunch of new conspiracy claims, too.
I hadn’t been familiar with a lot of these claims in the anti-mRNA-vax discourse. Spending so much time immersed in it made it clear how easy it is to prey on people’s fears here. You can make anything that happens inside the body sound sinister, given that by and large, our knowledge of the biology of our immune systems and organs is very shallow. That is especially true when it comes to the cellular level.
While many people are impressed or excited by modern vaccine development, plenty are easy to scare when genetic material is involved. The anti-vax literature plays this to the hilt – like calling saRNA vax “replicon vaccine.” Replicon is a decades-old term for a section of DNA and RNA that replicates, which isn’t an ominous phenomenon at all. But you can make it sound like a villain from a science fiction movie! I think we can expect it to hear that framing a lot.
The novelty of all this will take time to subside. A rollout in Europe could be a major help, as we can expect a lot of independent study of the vaccines. I look forward to trying to keep up with it!
You can keep up with my work at my newsletter, Living With Evidence. I’m active on Mastodon: @hildabast@mastodon.online, and less so on Bluesky.
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Disclosures: My interest in Covid-19 vaccine trials began as a person worried about the virus, as my son was immunocompromised: I have no financial or professional interest in the vaccines. I have worked for an institute of the NIH in the past, but not the one working on vaccines (NIAID). More about me.
The cartoon is my own (CC BY-NC-ND license). (More cartoons at Statistically Funny.)