Interesting, if I understand correctly this is an mRNA vaccine too, just doesn’t seem to work that well (though I continue to be amazed at how small the sample sizes are).
What are some of the details that make two vaccines work so differently, even if they use the same underlying technology? Production quality, dosage, slight variation in the active ingredients..?
The other two have lots of fancy things done to the mRNA itself, including pseudouridine substitutions, 3 and 5 prime untranslated regions, and a poly-a tail. The payload comes from the NIH, and is modified by them as well with proline insertions to stabilize the spike in the prefusion form. All current EUA vaccines in the US (BioNTech, Moderna, Jansen), plus NovaVax (code not delivered to the user in that case) use some form of the NIH payload, as far as I can tell.
Edit: I forgot about the proprietary mRNA delivery systems as well, I don't really know much about those.
Interesting list, thanks! Do you know of any popular science description of these? I did biology at middle school and not since (but I continue to find the mechanics of low-level biology fascinating).
There were ideas thrown around to do one big study of various vaccines instead of multiple ones. Didn't happen, probably was too much of an organizational challenge and would've required all companies to comply to a protocol made by a third party.
Scientifically it would've been the best idea.
The challenge now is that the more the world gets vaccinated the harder it gets to do any meaningful trial.
Why would the companies producing the vaccine have a say in this? Sure Pfizer might go “nah - we are happy with our trial - we don’t need another”. But come on ..,
Anyway. The public is paying for this in the end. If there is genuine suspicion that these efficacy numbers no longer hold, we should just sponsor a test of it. Otherwise we base our decisions on what to buy and how to roll it out on wrong data.
40,000 yes, big. But when looking at who got Covid, the numbers are tiny. In the end you are comparing who had vaccine/placebo on a group of O(100) people.
It seems these trials aren’t actively monitoring the participants to see who gets even mild Covid, they just look at who ends up sick and tests positive.
> But when looking at who got Covid, the numbers are tiny.
True, of a sample size of 40,000 a small number got COVID. Thankfully it is big enough as the efficacy numbers have proven very accurate in real world measurements.
These Phase III vaccine trials also do weekly symptom monitoring. In order to qualify for lab evaluation for COVID-19, there's criteria for how many symptoms are required and for how long.
The Pfizer trial results were based on 170 confirmed cases but there were “3410 total cases of suspected, but unconfirmed covid-19 in the overall study population, 1594 occurred in the vaccine group vs. 1816 in the placebo group.”[1]
For all we know it's not actually that much worse than the vaccines currently in use since those were tested before the modern variants were in circulation. (The figures for the effectiveness of the other vaccines aren't entirely comparable - they're not from controlled studies and I don't think they cover one of the latest variants that made up a reasonable proportion of infections in this trial.) I wouldn't be surprised if it's still better than the non-mRNA Johnson & Johnson vaccine too...
You have broad vaccinations already in some parts of the world, presumably that means that the variants that are still spreading are the ones that are less susceptible to the vaccinations.
I am not sure, may be it might show the Moderna vaccines are just as ineffective (against the variants circulating now). I am not sure anyone would want that, particularly things like these are cropping up
In practice these big trials are run as sloppily as possible to get the desired result. There’s a whole cottage industry of consultants. Think unclear instructions leading to dosing mixups and such. The type of trial you’re proposing is notorious for sloppiness.
More time and money for data that you could get more efficiently? I mean we have some data on the Pfizer vaccine and new variants and it looks like the Pfizer vaccine works fine.
Do we have another baseline that was conducted in a variant rich environment? In this trial, out of the 134 cases - 124 were due to variants from at least 13 types.
My idea was simply to include an approved wellknown vaccine in the blind trial. So the subject would get either: The new vaccine, the old vaccine, or a placebo.
They received ~252.000.000 Euros from the German government alone in September 2020 [1], and previously another ~560.000.000 Euros from "private" investors in July 2020 (which somehow included another ~300.000.000 Euros from the German government as well)[2].
Unless there were any known reasons at the time as to why CureVac wouldn't be able to create a functioning vaccine, I'm not sure how it's any use to anybody to take this position. There are no sure bets. There are going to be failures. That shouldn't be reason to stop funding companies like this if they otherwise show they're capable. I'd say Germany has more issues around being too conservative and playing it too safe than taking too many risky bets.
If we didn't have the other vaccines, getting 47% efficiency for a billion euros would have been an awesome result. We could have also stopped the pandemic with a 47% effective vaccine. We're just spoiled because the vaccine development efforts did so well in general that 90%+ is now our standard.
Eh, BioNTech got about half a billion from the Germany govt. You win some, you lose some.
Like, should the German government have had its on-staff wizards look into the future to decide which on the face of it very similar mRNA vaccine to fund? They funded two, one worked well and hundreds of millions of doses have been administered. That seems like reasonable value for money, to be honest.
Perhaps they can shift gears and start manufacturing or helping to manufacture the more successful mRNA vaccines, their supply chain might be the saving grace.
> The disappointing efficacy of the shot known as CVnCoV emerged from an interim analysis based on 134 COVID-19 cases in the study with about 40,000 volunteers in Europe and Latin America.
The number of people who had Covid-19 cases seem surprisingly low and there were at least 13 variants amongst 124 cases. The real challenge though lies in the interpretation : is the efficacy due to variants or due to vaccine's inability?
My counter to that question is - does it matter? This is basically a real world test of the vaccine. If it failed to meet it's endpoint for either reason, it's not a suitable vaccine.
I guess it might matter for understanding why it doesn't perform as well, which is a legitimate question to answer that may help guide future vaccine development.
Yes, it does. The other vaccines weren't tested on "real world" either. Therefore, a comparison to the "standard of care" (other vaccines) instead of control.
All the existing, currently approved vaccines weren't tested in the current real world in this way - their clinical trials were done in an environment that mostly predated the modern variants, which is where the numbers for them in the article come from. We know they're less effective against the variants but don't know how well they'd do in a present-day clinical trial like this one.
Doesn't matter as much, now that there are other vaccines on the market. Any new vaccine candidates will be compared against the existing ones as a golden standard and any candidate that doesn't improve on the existing options significantly along some dimension is not likely to get approved.
The desperate scramble to reopen the world led to record development and approval times BY A FREAKING MILE. HN discourages caps but it's hard to overstate just how unprecedented these approvals were. The top 10 list of fastest drug approvals is just a list of chemotherapy drugs and the median time for novel vaccine discovery lies somewhere between decades and centuries. Now that the world is returning to normal, the standards for premarketing approval are too.
Just jumping in to say that the successes of Pfizer/Moderna/AstraZeneca et al may have primed us to think that vaccines are usually successful but the reality is that these are the exceptions (happy ones!) [0] . I can't find the exact source but most clinical trials don't even move to Phase-3. So failures like CureVac - while sad news indeed - happen :(
I wonder if it's possible that CureVac had to take some extra risks to be competitive this late in the race. With the Pfeizer/Moderna results already in, may be they aimed to deliver a lower dose vaccine with less side effects that would be more desirable, but that didn't pay off.
Vaccines usually are successful (like 80% in phase 3 make it out?) - it’s cancer drugs that ruin the averages since they are very common and never work.
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[ 3.6 ms ] story [ 102 ms ] threadWhat are some of the details that make two vaccines work so differently, even if they use the same underlying technology? Production quality, dosage, slight variation in the active ingredients..?
Edit: I forgot about the proprietary mRNA delivery systems as well, I don't really know much about those.
https://berthub.eu/articles/posts/part-2-reverse-engineering...
https://berthub.eu/articles/posts/reverse-engineering-source...
https://berthub.eu/articles/posts/curevac-vaccine-and-wonder...
https://berthub.eu/articles/posts/genetic-code-of-covid-19-v...
https://blogs.sciencemag.org/pipeline/archives/2021/06/17/cu...
”…an interim analysis based on 134 COVID-19 cases in the study with about 40,000 volunteers in Europe and Latin America.”
The sample size is 40000 is it not? That’s as big as they come.
I remember a year ago the Chinese shutting down a covid19 study in China because their infection rates went to zero.
Right now the efficacy numbers seem be affected by when and where the studies were done.
Scientifically it would've been the best idea.
The challenge now is that the more the world gets vaccinated the harder it gets to do any meaningful trial.
Because, if I am not mistaken, these studies are funded by the companies themselves.
So its really upto them if they want to do another trial, right? At least as per current law..
It seems these trials aren’t actively monitoring the participants to see who gets even mild Covid, they just look at who ends up sick and tests positive.
True, of a sample size of 40,000 a small number got COVID. Thankfully it is big enough as the efficacy numbers have proven very accurate in real world measurements.
But are you considering the fact that breakthrough infections are counted using comparitively low CT values in RT-PCR tests?
Do we know how it will affect the positive rates of the test?
The Pfizer trial results were based on 170 confirmed cases but there were “3410 total cases of suspected, but unconfirmed covid-19 in the overall study population, 1594 occurred in the vaccine group vs. 1816 in the placebo group.”[1]
[1]: https://blogs.bmj.com/bmj/2021/01/04/peter-doshi-pfizer-and-...
Interesting, why? In the UK at least, they now hand out Covid tests like candy.
I guess this is what people were saying about Absolute vs Relative risk reduction. If that is so, your explanation makes it much more clear.
That would show whether the result is due to new variants of the virus or just different efficacy of the new vaccine.
https://austingwalters.com/covid19-vaccine-risks/
The power of your trial comes from the "events", i.e. number of people who got symptoms of covid-19. Have 2 vaccinated groups? Not many events.
That would give a hint on what is going.
I'm sure the German tax payers are delighted.
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[1] https://www.reuters.com/article/us-health-coronavirus-german...
[2] https://www.curevac.com/en/2020/07/21/curevac-raises-a-total...
(Pfizer did conduct the trial afaik, so maybe that is where the expertise is lacking.)
Like, should the German government have had its on-staff wizards look into the future to decide which on the face of it very similar mRNA vaccine to fund? They funded two, one worked well and hundreds of millions of doses have been administered. That seems like reasonable value for money, to be honest.
We really are, thanks for assuming.
The number of people who had Covid-19 cases seem surprisingly low and there were at least 13 variants amongst 124 cases. The real challenge though lies in the interpretation : is the efficacy due to variants or due to vaccine's inability?
https://www.curevac.com/en/2021/06/16/curevac-provides-updat...
So test new vaccines as the Curevac was tested. If it fails we have all the info we need for that vaccine.
https://www.ctvnews.ca/health/coronavirus/vaccines-effective...
The manufacturer tried to explain that away, that 41% is still extremely good, compared to other vaccines. Nobody followed him there
The desperate scramble to reopen the world led to record development and approval times BY A FREAKING MILE. HN discourages caps but it's hard to overstate just how unprecedented these approvals were. The top 10 list of fastest drug approvals is just a list of chemotherapy drugs and the median time for novel vaccine discovery lies somewhere between decades and centuries. Now that the world is returning to normal, the standards for premarketing approval are too.
But, this clinical trial didn't compare to existing ones.
[0]https://www.centerwatch.com/articles/12702-new-mit-study-put...