CureVac fails in pivotal Covid-19 vaccine trial with 47% efficacy | Hacker News Reader

CureVac fails in pivotal Covid-19 vaccine trial with 47% efficacy

reuters.com

60 pointsmartinlaz60 comments

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 :(

[0]https://www.centerwatch.com/articles/12702-new-mit-study-put...

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.

Maybe they should include a baseline vaccine (say pfizer biontech) in their trails instead of just placebo and their own vaccine.

That would show whether the result is due to new variants of the virus or just different efficacy of the new vaccine.

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.

Maybe I am naive but what is wrong with this idea?

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

https://austingwalters.com/covid19-vaccine-risks/

You need huge trials to do this.

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.

You need 50% more subjects goes my calculation.

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.

That would give a hint on what is going.

And it’s routinely done in clinical trials called “Standard of Care” - good idea!

> 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?

https://www.curevac.com/en/2021/06/16/curevac-provides-updat...

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.

But they are producing follow up data for new variants. They are still effective against new variants.

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...

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.

This question is answered in the press release. The new variants don't explain this low number alone.

The manufacturer tried to explain that away, that 41% is still extremely good, compared to other vaccines. Nobody followed him there

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.

It matters a lot because for the ‘gold standard’ existing ones the scare story is they aren’t effective against the variants either.

> Any new vaccine candidates will be compared against the existing ones as a golden standard

But, this clinical trial didn't compare to existing ones.

The results of the trial will be, just like we are doing right now

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).

I found this being a very good explanation for the technically inclined: https://berthub.eu/articles/posts/reverse-engineering-source...

Should be a good start.

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...

Thanks, these are really good reads.

Another good and accessible discussion of what went wrong with this vax is Derek Lowe's "In the Pipeline" blog:

https://blogs.sciencemag.org/pipeline/archives/2021/06/17/cu...

> I continue to be amazed at how small the sample sizes are

”…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.

You can presume that a large percentage of that 40,000 weren't exposed to covid19 during the study.

I remember a year ago the Chinese shutting down a covid19 study in China because their infection rates went to zero.

Could be interesting to see comparative studies of vaccines.

Right now the efficacy numbers seem be affected by when and where the studies were done.

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 ..,

> Why would the companies producing the vaccine have a say in this..

Because, if I am not mistaken, these studies are funded by the companies themselves.

Sure but they do them because they are required by law to do so.

Sure, that is what I meant, they are required by law to show the benefit of the drug once.

So its really upto them if they want to do another trial, right? At least as per current law..

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.

> 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?

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]

[1]: https://blogs.bmj.com/bmj/2021/01/04/peter-doshi-pfizer-and-...

> there's criteria for how many symptoms are required and for how long.

Interesting, why? In the UK at least, they now hand out Covid tests like candy.

> In the end you are comparing who had vaccine/placebo on a group of O(100) people.

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.

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...

A glance at what could have been, showing us how lucky we really got with >3 working vaccines deployed within a year.

I wonder if CureVac can come back from this, or are they toast?

I think they raised a lot of money an IPO last year.

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].

I'm sure the German tax payers are delighted.

[1] https://www.reuters.com/article/us-health-coronavirus-german...

[2] https://www.curevac.com/en/2020/07/21/curevac-raises-a-total...

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.

Maybe someone is forgetting that the COVID19-vaccine Pfizer produces is on license from German BioNTech.

(Pfizer did conduct the trial afaik, so maybe that is where the expertise is lacking.)

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.

They were the most promising vaccine company at one point. So promising that Trump tried to buy them.

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.

> I'm sure the German tax payers are delighted.

We really are, thanks for assuming.

My bet is on toast, technically. Gov. money (i.e. taxpayers money) will still keep them afloat though, because they love to keep a 2nd local option.

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.

Reply on news.ycombinator.com