CureVac Comes Up Short

 By Derek Lowe

I wasn’t planning on having this turn into Coronavirus Vaccine Week again around here, but we do have some news. Yesterday afternoon CureVac, the German mRNA vaccine company, reported results of their Phase III trial in 40,000 patients around the world. They weren’t good. And the data that have come out today don’t make things look any better.

The figure that came out last night was 47% efficacy, which doesn’t reach anyone’s cutoff for approval, not even for emergency use. And the slides that have been released this morning show that there are still a number of cases that are being evaluated, so that number is very likely to go down. Here’s one tweet speculating that the final number might be as low as 40%. At any rate, the big question is why this mRNA candidate is so much worse than the Moderna or Pfizer/BioNTech ones.

Actually, the first question on that topic is whether it is worse in the first place. CureVac has spent a lot of time in its public statements talking about the variants that its trial ran into and saying that these are the reason for the lower efficacy. Implicit in that is the idea that if you ran the other two mRNA vaccines in a trial right now, you’d come out with similar numbers. But I have trouble believing that. The real-world protection that we’re seeing in mRNA-vaccinated populations simply does not reflect an underlying efficacy in the 40% range. That’s the biggest argument right there.

We also have a lot of evidence that blood serum from vaccinated patients can indeed neutralize the newer variants of the coronavirus – here’s one of those papers that just came out, and there are many others. The neutralization is lower, to be sure, but still well above the range that should be protective. (And remember, that’s just the antibody side of the story – the T-cell side of things looks robust as well, although it’s harder to study). So there is evidence both in the lab and out in the streets that the existing mRNA vaccines are (so far) able to continue performing in the face of the variants. I cannot accept the hypothesis that the CureVac vaccine is functionally identical to the Moderna and Pfizer/BioNTech ones, not on the data we have now.

So if it really is inferior, then why? What are the differences between this one and the other two mRNA agents? The biggest one that I can see is that the CureVac vaccine does not use any modified mRNA bases – in fact, they have pointed to this as a feature, in the hopes that this will induce a more wide-ranging immune response. Meanwhile, the other two have made extensive use of bases like N-methylpseudouridine, in an effort to improve stability. So one possibility – a pretty likely one, in my view – is that the all-natural RNA idea has turned out to be a mistake, and that the CureVac agent is getting broken down too quickly to be effective, both inside and outside cells.

There’s also the possibility that the lipid nanoparticle formulation they’re using is in some way less effective than the ones used by the other companies. I find this less likely. For one thing, both the Pfizer/BioNTech and Moderna vaccines seem to work very well, despite being different lipid mixtures, which at least says that there not One Single Formulation that works. Second, CureVac has, as I understand it, been working with Acuitas for this part of their vaccine, the same company that has been involved with the Pfizer/BioNTech vaccine. So they would have brought their own considerable expertise to bear, you would have to think.

For now, then, I think the most likely possibility is that CureVac’s vaccine is indeed notably less effective than its competitors, and that this is due to its unmodified RNA composition. The result of all this is particularly unfortunate, since the EU and others had been counting on this one to deliver. That brings up another point that has to be emphasized again: we have been extremely fortunate.

It should be obvious by now, given the number of prominent failures, that generating an effective coronavirus vaccine is not something you can just stroll up to. As we’ve found, it’s definitely not impossible – and remember, there were plenty of doomsayers last year who were trying to tell everyone that it was, and that we’d never be able to get a vaccine at all. But it’s no sure thing, either, far from it. Ask Merck, ask GSK, ask Sanofi, ask Queensland, ask plenty of other players who have dropped out, and now ask CureVac. This also points up the crucial nature of taking all those shots on goal. There are a lot of factors that are literally beyond our control when such therapies get into clinical trials, and there are other things that we have to learn the hard way so that we can control for them the next time around. The fact that we have any vaccines at all is worth celebrating, and the fact that we have some that work so well, and with such good safety records, is a world-historical stroke of good news.

https://blogs.sciencemag.org/pipeline/archives/2021/06/17/curevac-comes-up-short