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At the risk of diverging from the topic, I think many regulations are too conservative, and mainly serve to keep competition away from the pharma giants.

Regulations can prevent a generic manufacturer from coming out with a drug for long after a patent has expired, or force the generic manufacturer to spend nearly as much money as the patent holder did, too open the drug up to all the generic market (ensuring that they will never recoup their investment)

And the PV system, often way overdone IMO.

Good for the Russians for not letting over conservative regulations from stopping them from addressing a public health crisis.

Edited by KerikBalm
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6 hours ago, Dragon01 said:

At this point, the worst thing that could happen is to give people a vaccine that's no good, and given the benefits of getting the vaccine out, it might .

Nah, the worst that could happen is to give people a vaccine that's no good, while they behave as if it was good. "I'm vaccinated, now I can safely lick the handrails of the escalators on the Moscow metro!"

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8 minutes ago, Codraroll said:

Nah, the worst that could happen is to give people a vaccine that's no good, while they behave as if it was good. "I'm vaccinated, now I can safely lick the handrails of the escalators on the Moscow metro!"

 

3rubjribr7h21.png

 

If life has taught me anything it is that humans often show a lack of fear of their own demise, which often leads to it.

Alls well until... it isn't.

Time and again. Should have listened.

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1 hour ago, Codraroll said:

Nah, the worst that could happen is to give people a vaccine that's no good, while they behave as if it was good. "I'm vaccinated, now I can safely lick the handrails of the escalators on the Moscow metro!"

That's basically a given no matter if it works or not. I already alluded to it with the "complacent asymptomatics" comment. Yes, there will be complacency, and even a working, but imperfect vaccine will be serious trouble when that happens. OTOH, thanks to that effect we should know if it's a dud particularly quickly.

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1 hour ago, Dragon01 said:

That's basically a given no matter if it works or not. I already alluded to it with the "complacent asymptomatics" comment. Yes, there will be complacency, and even a working, but imperfect vaccine will be serious trouble when that happens. OTOH, thanks to that effect we should know if it's a dud particularly quickly.

 

Nice..  so there can be positives to human stupidity.

They die so that those who are wise won't do whatever they did and survive.

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Some positive news from the United States. After the massive spike in new cases per day starting in early-mid June, it’s started to level off over the last two weeks, with a mean of ~65k cases/day. Yes, that’s really high, but the increasing trend appears to have stopped. It took a nosedive to only 47k new cases yesterday, the lowest daily total in weeks. The Big Four of this second wave — Arizona, California, Florida, and Texas — have either leveled off or have shown a slight decrease in new cases per day, signaling that their exponential COVID growth has ended. The Northeast states have remained stable throughout all of this (Connecticut has kept a daily positivity rate of 0.5-1.2% since June), and some other states are showing signs of slowing down; these include Oregon, Idaho, Arkansas, Ohio, Alabama, and more. 

Edited by ProtoJeb21
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https://ria.ru/20200811/1575635481.html / https://www.bbc.com/news/world-europe-53735718

Sputnik V has been registered one day ahead of promises - smoothed over by a testimonial from Putin regarding one of his daughters (probably Maria Vorontsova the geneticist, but could be either).

Edited by DDE
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At this point, concerns are not about safety, but efficacy, so that means little. We're fairly certain it's not gonna make things worse (other than inducing complacency), but we need it to make them better.

Ultimately, IMO this is just names. They're not going to have enough of the vaccine to give it to more people than a large Phase III trail would involve. By the time they do they'll know if it works or not.

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The use of human adenoviruses as vectors is safe because these viruses, which cause common cold, are not novel and have been around for thousands of years.

Red flag right here. Common vector with a long history in humans. There's no way they'll get 100% success rate with this approach. Some people will have caught the thing before, and their immune system will just clobber the vector without giving it a chance to do its thing. Now, using two different ones is an interesting (if pretty obvious) way of helping this, and it should guarantee at least some immunity after two shots (though there will still be people with antibodies to both), but it's unlikely to be the silver bullet. This is also a concern with one of the Chinese vaccines, and the Oxford one uses a simian adenovirus to avoid this problem.

Also, calling it a "sputnik moment" is a bit misleading. That one involved a significant technical achievement, this one is a rubber stamp that was stamped on earlier than usual. I suppose this is an achievement of sorts, but speeding that up isn't hard, it's more of a question if it should be done than if it could. 

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An interesting new prophylaxis option is being investigated, namely nanobodies. Those are stripped-down antibodies, basically. The nice thing about them is that they have a ridiculous binding affinity, and they can completely shut down the infection machinery of SARS-CoV2. If this gets approved, it could be an easily applied method of destroying virus particles both in human bodies and in air and on surfaces. It's not a vaccine nor a conventional antibody treatment, but besides them, it could be a very useful tool in eradicating the disease.
https://blogs.sciencemag.org/pipeline/archives/2020/08/13/nanobodies-against-the-coronavirus-something-new

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On 8/11/2020 at 1:35 PM, Dragon01 said:

Red flag right here. Common vector with a long history in humans. There's no way they'll get 100% success rate with this approach. Some people will have caught the thing before, and their immune system will just clobber the vector without giving it a chance to do its thing. Now, using two different ones is an interesting (if pretty obvious) way of helping this, and it should guarantee at least some immunity after two shots (though there will still be people with antibodies to both), but it's unlikely to be the silver bullet. This is also a concern with one of the Chinese vaccines, and the Oxford one uses a simian adenovirus to avoid this problem.

I don't think we've ever deployed anything via adenovirus broadly, but to be fair, that is becoming the standard way of delivering genetic payloads to non-stem cells for all kinds of gene therapy and has an excellent record so far.

Given the sheer magnitude of risk if something does go wrong, I still consider this broad distribution with such small amount of testing to be irresponsible and unethical, but in terms of pure likelihood, it will probably be alright.

If you'll allow me a Machiavellian moment, from perspective of anyone not living in Russia, having close relatives there, or being close to the border and risking being caught in border disputes if there is destabilization, this is all wonderful news. Because Russia is basically taking on the risk of stage 4 testing not only a COVID vaccine, but adenovirus as delivery method. Something we absolutely would not have for years without it. And if everything goes well for Russia, not only will every other country have similar vaccines within months, but it opens up doors for the rest of the world to develop cures for such things as lactose intolerance via very simple, very safe genetic mod, with the only known potential risk being adenovirus delivery itself.

That is, of course, a very cynical take on situation, because an untold number of lives are on the line if this goes sideways.

For these interested in more background, here is a video of a biohacker engineering his own version of adenovirus to cure his own lactose intolerance, as well as a follow up video on results.

Spoiler

 

 

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12 hours ago, K^2 said:

If you'll allow me a Machiavellian moment, from perspective of anyone not living in Russia, having close relatives there, or being close to the border and risking being caught in border disputes if there is destabilization, this is all wonderful news. Because Russia is basically taking on the risk of stage 4 testing not only a COVID vaccine, but adenovirus as delivery method.

While, if I understand all prior posts correctly, this particular adenovirus does not involve 'gene splicing' - if it did, you'd be hearing an earful about it from our press. This is primarily because genetic engineering is in the vogue in the Kremlins:

https://meduza.io/en/feature/2020/04/29/putin-s-eldest-daughter-is-set-to-become-the-curator-of-a-russian-genome-project-rosneft-could-invest-up-to-a-billion-dollars-in-the-venture

What's particularly interesting is that this initiative is very closely tied to Putin's above-mentioned elder daughter.

And now for the hottest of all takes! https://www.thedailybeast.com/is-putins-fascination-with-genetics-just-eugenics-in-disguise

Spoiler

190507-putin-dna-tease_zvrwgw

I couldn't make a better recruitment poster for the Science Companies of the Russian army if I tried

 

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19 minutes ago, DDE said:

While, if I understand all prior posts correctly, this particular adenovirus does not involve 'gene splicing' - if it did, you'd be hearing an earful about it from our press.

Well, you have to splice adenovirus' genes at a very minimum. The way this delivery method works is that there are known sequences on adenovirus' genome that mark beginning and end of a "payload". Normally, payload contains genes that when expressed make the capsid proteins, but you can put basically anything you want there instead. What they've done with Sputnik V is grabbed the sequence for one of the proteins on the surface of COVID that it uses to bind to cells, one they're calling S protein on the site, and placed that sequence in the payload of adenovirus.

Now, I don't know if this applies to all adenoviruses or not, but the main reason adenoviruses got popular in gene modification is that they're good at sneaking payload into cell nucleus and getting it incorporated in the genes of the cell. This is useful when you want the cell to keep expressing a particular gene long after the therapy. It's possible that this particular variant of the virus doesn't do this, so in that sense, it wouldn't be splicing your genes. But there are other viruses in your cell that have no qualms about grabbing stray DNA like this and adding it to your gene sequence. Like another adenovirus that you're already infected with, and most people are. So it's not like you can guarantee that it won't be happening. Of course, this sort of thing happens naturally as well, but that never stopped people complaining about genetic modifications.

And yeah, technically speaking, unlike some other forms of gene therapy, it's entirely unnecessary to try and incorporate the payload into human genome. All this really does is emulates infection without infecting you. The protein in question ends up on the surface of affected cells, and immune system will produce antibodies regardless of whether the S protein got there because you're infected with COVID, or because it was made from a snippet of code snack by adenovirus. I suspect, depending on the dose, fever and inflammation, possibly even pneumonia, are possible side effects, but you wouldn't get the same lung tissue scarring, so I don't think it's a problem for healthy individuals.

Outside of something really out of the left field, the ways this can backfire that I can think of are that S protein sequence does get incorporated into your genome in enough of your lung cells to just continually trigger immune response. Then you either die of your lungs filling with fluid, or they pump you full of immunosuppressants, and you die of a cold, or something. The other possibility is causing false resistance, potentially turning people into carriers without symptoms, potentially making  outbreak worse.

Both of these are pretty unlikely, but the fact that these things do happen is the reason these kinds of things usually take a lot longer to test properly and safely.

If there are no devastating side effects, however, I expect this to work. There's no way to tell how well it will protect any given individual, but if enough people get the vaccine, herd immunity will make short work of the pandemic. Which is probably why Russian gov't is willing to roll the dice on this. Economy is doing rather badly, which is always a risk of unrest, especially with what's going on in Belarus right now. On the other hand, if vaccine works and gets people back to work before neighboring countries, it's a great trade advantage. So the gov't might look at this as being worth the risk.

 

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2 hours ago, K^2 said:

Now, I don't know if this applies to all adenoviruses or not, but the main reason adenoviruses got popular in gene modification is that they're good at sneaking payload into cell nucleus and getting it incorporated in the genes of the cell. This is useful when you want the cell to keep expressing a particular gene long after the therapy.

Not so much. Adenoviruses are pretty good at getting DNA into cells, but not into the nucleus per se, and certainly not getting incorporated into the host cell genome. If you want to do that, Lentiviruses are preferable. In fact,, Adenoviruses are attractive because they do not integrate - this makes them safe, although only transiently effective. But if you want to do expermentation, and not deal with the hassle and blowback of making GMO humans, non-integrating viruses are obviously attractive.

Personally, I've made a few variants of Ad5 - but these were not for gene therapy per se. They were CRAds- conditionally replicating Adenoviruses... Ads are widely used to make oncolytic viruses. Ad normally encodes anti-apoptotic proteins to stop a cell from killing itself when the infection is detected. Cancer cells likely already have their apoptosis pathway disabled. Productive infections in tumors would result, but not in healthy cells. This modification is ismply deletion of an Ad protein. Then you can also change the sequence of the fiber knobs that attach to the cell surface to get the virus to target different cells for entry. You can also replace the viral promoter with human promoters. The viral promoter is a general promoter that would have high transcriptional activity in pretty much all conditions. If you instead replace it with... say a promoter for Telomerase that is normally not active in human cells (only stem cells, and many cancer cells), then the viral proteins shouldn't get made after entering. But what about if it enters a human stem cell? well, then change a different viral promoter to something that is only active in differentiated cells.... say the promoter for a gene involved in making melanin if targetting Malignant Melanoma... then essential viral proteins won't get made in stem cells because the melanin promoter isn't active in those cells, and the virus won't replicate in normal skin cells because the telomerase promoter isn't active in those cells...

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1 hour ago, KerikBalm said:

Personally, I've made a few variants of Ad5 - but these were not for gene therapy per se. They were CRAds- conditionally replicating Adenoviruses... Ads are widely used to make oncolytic viruses. Ad normally encodes anti-apoptotic proteins to stop a cell from killing itself when the infection is detected. Cancer cells likely already have their apoptosis pathway disabled. Productive infections in tumors would result, but not in healthy cells. This modification is ismply deletion of an Ad protein. Then you can also change the sequence of the fiber knobs that attach to the cell surface to get the virus to target different cells for entry. You can also replace the viral promoter with human promoters. The viral promoter is a general promoter that would have high transcriptional activity in pretty much all conditions. If you instead replace it with... say a promoter for Telomerase that is normally not active in human cells (only stem cells, and many cancer cells), then the viral proteins shouldn't get made after entering. But what about if it enters a human stem cell? well, then change a different viral promoter to something that is only active in differentiated cells.... say the promoter for a gene involved in making melanin if targetting Malignant Melanoma... then essential viral proteins won't get made in stem cells because the melanin promoter isn't active in those cells, and the virus won't replicate in normal skin cells because the telomerase promoter isn't active in those cells...

Imagine having this chat ten, twenty years ago.

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3 hours ago, DDE said:

Imagine having this chat ten, twenty years ago.

Almost exactly twenty years ago, I remember splicing GPF gene into a plastid, using electrophoresis to find the correct size fragments, and adding these to e. coli to make a glowing test tube. It was an AP bio class, the whole experiment came in a kit, and things you could do with this technique were pretty limited, because there were no simple, generic ways to find sequences you wanted, but the basics were very similar to what you still do today.

Don't get me wrong, stuff that's being done is still super impressive. From techniques for getting the exact sequence you want into exact place you want, to methods of sequencing. 20 years ago, electrophoresis was still the main way of gene sequencing! Something like 23 and Me seemed absolutely impossible. But writing was on the wall for the direction things are going. Given that at the time I had a flip phone with no camera, because that just wasn't a thing, and it was considered advanced because it could talk to mail server, watching things develop along side with electronics, some part of me is even disappointed with advancements in gene editing. It's not a rational part, but it's there, kind of like flying cars.

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Yea, you could modify your face to look disappointed in a silly way. You would be genetically disappointed. And you could use your phone and make it change your face temporarily to an emote. You could then text with your face!

tenor.gif

Clint Eastwood level of disappointment! By that time emotes will have enough pixels to do memes like this. And hence realistic facial features.

Edited by Arugela
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  • 3 weeks later...

Sputnik V creators, now at The Lancet.

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31866-3/fulltext

Quote

Between June 18 and Aug 3, 2020, we enrolled 76 participants to the two studies (38 in each study). In each study, nine volunteers received rAd26-S in phase 1, nine received rAd5-S in phase 1, and 20 received rAd26-S and rAd5-S in phase 2. Both vaccine formulations were safe and well tolerated. The most common adverse events were pain at injection site (44 [58%]), hyperthermia (38 [50%]), headache (32 [42%]), asthenia (21 [28%]), and muscle and joint pain (18 [24%]). Most adverse events were mild and no serious adverse events were detected. All participants produced antibodies to SARS-CoV-2 glycoprotein. At day 42, receptor binding domain-specific IgG titres were 14 703 with the frozen formulation and 11 143 with the lyophilised formulation, and neutralising antibodies were 49·25 with the frozen formulation and 45·95 with the lyophilised formulation, with a seroconversion rate of 100%. Cell-mediated responses were detected in all participants at day 28, with median cell proliferation of 2·5% CD4+ and 1·3% CD8+ with the frozen formulation, and a median cell proliferation of 1·3% CD4+ and 1·1% CD8+ with the lyophilised formulation.

 

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Good numbers, except the "76 participants" one. :) Not a very powerful study. Seems to work as good as the other candidates, with similar side effect profile. It'll probably work just as well as the other adenovirus candidates, but we've yet to see what exactly does this mean. 

I do hope adenovirus ones work out, because they're relatively undemanding in terms of refrigeration. DNA and RNA ones will require freezer or even dry ice temperatures, making distribution though. 

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