Covid-19 vaccines thread

[Duda Jarek]

Developing a standard vaccine for coronavirus will take at least a few months - what might be too late.
However, its sequence is already known, and is nearly identical - suggesting recent single point of origin for human host.

So the question is if/how there could be quickly started production of some provisional vaccine - not perfect but fast to introduce? Also exploiting the fact that these viruses are now nearly identical.
For example synthesizing its outside proteins and putting them on liposomes - would its introduction to blood have a chance to prepare immune system for the real virus?

[CharonY]

Well, that is why it takes a while, you'll need to figure out what components create an immune response, but you also want to avoid unspecific inflammation and other adverse effects. The last thing you want is healthy folks suffering from the vaccine especially in a case where the disease is still found to be of relatively low lethality. 

That being said, the fastest development route are probably RNA vaccines, which can produce targets basically overnight. However, safety and efficacy trials would also need to run.  

[Duda Jarek]

15 hours ago, CharonY said:

That being said, the fastest development route are probably RNA vaccines, which can produce targets basically overnight. However, safety and efficacy trials would also need to run.  

Sounds interesting - some interfering RNA?

 

The situation does not look optimistic here, exponential population growth continues ( https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6 ) and standard vaccine development needs a year.

In this moment the virus is still nearly identical: "The researchers also found that the eight complete 2019-nCoV genomes were more than 99.98 percent identical, "
https://www.genomeweb.com/genetic-research/coronavirus-genome-sequencing-finds-distinct-genetic-differences-2003-sars-virus

what is a big advantage for training immune response, but quickly mutations can start - especially with population growth.

What other defense options are there?

Wouldn't e.g. just putting its external proteins on a liposome work as provisional vaccine?

 

 

[CharonY]

9 hours ago, Duda Jarek said:

Sounds interesting - some interfering RNA?

No, the idea is to have mRNA coding for viral structure expressed by the host and presented as an antigen. Just synthesizing a random viral part in vitro usually has very low success rate. You do not know whether the part elicits a suitable response, nor can you always ensure that whatever you synthesize has still its native form. Even worse, injecting it in relative high concentration can also have adverse effects without actually conferring immunity. That is why when you start designing a vaccine you often have to work with the intact virus and either design around an attenuated form or, if you can, isolate a workable part. But that requires time. Even then, if a good target is known the big time consuming step are the trials. In extreme cases there are accelerated trials where requirements are relaxed. Nonetheless you still need to show that it actually  helps. And just sticking a random viral structure in and hope for the best is unlikely to work.

[Duda Jarek]

Sounds interesting, but from one side delivering mRNA to cell's nucleus seems extremely difficult without viral envelope+capsid (?) Ok, they probably use envelope+capsid of other viruses, e.g. used in gene therapy (?) - but it's probably extremely difficult to take it scale required here (?)

From the other side, this way immune system can only learn targeting infected cells (assuming they expose some material) - wouldn't it be better if it could directly target virus in bloodstream?

Coronavirus is enveloped - where is the difficulty in just mounting its external proteins on a liposome to get a fake virus for immune system training?

[CharonY]

Just adding a random virus protein does not guarantee a useful immune response, and it can also cause adverse effects as mentioned. 

In quite a few cases it is necessary to modify the virus capsids in vitro in order to make them useful as vaccines. In vitro synthesis of viral particles can result in quite a different structure than in vivo, but for the latter you need to isolate and propagate the virus.

Moreover glycosylation can make them difficult to be recognized and conversely, viral particles injected in significant amounts can lead to adverse inflammatory responses.

mRNA only needs to be delivered to the cell. The nucleus is not the area where translation happens. 

[Robittybob1]

On 2/1/2020 at 8:52 PM, Duda Jarek said:

Sounds interesting - some interfering RNA?

 

The situation does not look optimistic here, exponential population growth continues ( https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6 ) and standard vaccine development needs a year.

In this moment the virus is still nearly identical: "The researchers also found that the eight complete 2019-nCoV genomes were more than 99.98 percent identical, "
https://www.genomeweb.com/genetic-research/coronavirus-genome-sequencing-finds-distinct-genetic-differences-2003-sars-virus

what is a big advantage for training immune response, but quickly mutations can start - especially with population growth.

What other defense options are there?

Wouldn't e.g. just putting its external proteins on a liposome work as provisional vaccine?

 

Where or when did the first case occur?

 

[Duda Jarek]

3 hours ago, CharonY said:

Just adding a random virus protein does not guarantee a useful immune response, and it can also cause adverse effects as mentioned. 

In quite a few cases it is necessary to modify the virus capsids in vitro in order to make them useful as vaccines. In vitro synthesis of viral particles can result in quite a different structure than in vivo, but for the latter you need to isolate and propagate the virus.

Moreover glycosylation can make them difficult to be recognized and conversely, viral particles injected in significant amounts can lead to adverse inflammatory responses.

mRNA only needs to be delivered to the cell. The nucleus is not the area where translation happens. 

I am not saying about just releasing random proteins, but trying to recreate its viral envelope - doesn't it look like liposome? - part of the membrane of cell which produced it.

Doesn't this viral envelope have something additional like proteins for targeting? If so, couldn't we just put these external proteins on a liposome to get a fake virus?

Wanting to target enveloped virus in bloodstream, we need to target the envelope - or maybe it is just too difficult for immune system, so in practice it can only target infected cells?

I thought ribosomes are mainly in nucleus and ER (...mitochondria, chloroplasts), that free ribosomes in cytosol are relatively rare in eucariote (?) and capsid's purpose is usually to get material to the nucleus(?) But still - how to get this mRNA into cells? If using other viruses, I believe it is extremely difficult/time consuming to make it work, and seems nearly impossible for mass production in millions (?)

 

1 hour ago, Robittybob1 said:

Where or when did the first case occur?

I have seen hypothesized that in November, being nearly identical suggests single point of origin - like jumping from an animal host (bat?).

Fresh Science article: https://www.sciencemag.org/news/2020/01/mining-coronavirus-genomes-clues-outbreak-s-origins

[CharonY]

I may not understand you correctly, but you may have a number of misconceptions regarding viral surfaces. A couple of points:

-   virus envelopes are typically formed by elaborate protein structures and they do not have a membrane as such

- these proteins have complex three-dimensional structures (as other proteins) and often require additional proteins to be folded correctly and can be decorated 

- as such, the interplay between different viral proteins (and host mechanisms) are required to give viruses their final shapes

- the immune response is dependent on the recognition of specific shapes (epitopes) 

- producing a viral part in vitro does not guarantee to provide the correct shape to recognize a life virus

In addition, as mentioned you have to make sure that whatever you use as a vaccine does not induce harmful events. So again, just pulling proteins from a sequence and then releasing it into the bloodstream does not easily work, rather it would need quite a long process to make sure that it works and that it is not harmful.

On the other points, eukaryotic cells do have free ribosomes but are also part of the rough ER. There are various options for RNA delivery including liposomes. That being said, I think while there are quite a few clinical trials for mRNA vaccines, they have not been approved yet (but some are fast-tracked).

[Duda Jarek]

1 hour ago, CharonY said:

virus envelopes are typically formed by elaborate protein structures and they do not have a membrane as such

Sounds like you are writing about capsid (?), viral envelopes are rather not made of proteins: https://en.wikipedia.org/wiki/Viral_envelope

Quote

Some viruses (e.g. HIV and many animal viruses) have viral envelopes covering their protective protein capsids.^[1] The envelopes are typically derived from portions of the host cell membranes (phospholipids and proteins), but include some viral glycoproteins. They may help viruses avoid the host immune system. Glycoproteins on the surface of the envelope serve to identify and bind to receptor sites on the host's membrane. The viral envelope then fuses with the host's membrane, allowing the capsid and viral genome to enter and infect the host.

They have some glycoproteins, which could be put on a liposome to get a fake virus ...

[koti]

@CharonY, thank you for your input in this thread, I've glanced through it and underastand probably around 15% to 20% of what you wrote, will have another go in the evening.

BTW...The same guy whom I mentioned in my vaccine thread from a few yeras back who made millions selling intravenous VitC allegedly curing cancer and pushed tens (if not hundreds) of thousands of people into the anti vax movement decided a few days ago that he is going to cure 2019-nCoV with H2O2 intravenous feeds. They locked his youtube channel, hopefuly he is going to be finaly prosecuted soon. 

[CharonY]

You are right, it was my mistake. I was thinking of capsids as I am more familiar with those as vaccination targets and have muddled up things, including the fact that coronavirus is in fact enveloped. My apologies. Recombinant envelope proteins have also been used but often are trickier to handle. And again, the issues are the same, even in native form they may not be recognized well, a synthetic form may not correspond well to the native form (i.e. your "fake virus" may not result in the desired recognition) and it may actually be harmful. So at this point I can just re-iterate that synthesizing a protein in vitro does not necessarily make it the same as what the virus does in a cell. This is why we still have attenuated vaccines rather than just taking a pathogen protein and call it a day, for example. The target folks are focussed most on in coronavirus are the spike proteins that target ACE receptors. But even then, getting the antigen just right is difficult. So to re-iterate, taking a protein (envelope, capsid, or whatever) based on its DNA sequence does not make it suitable vaccination substrate.

14 minutes ago, koti said:

@CharonY, thank you for your input in this thread, I've glanced through it and underastand probably around 15% to 20% of what you wrote, will have another go in the evening.

BTW...The same guy whom I mentioned in my vaccine thread from a few yeras back who made millions selling intravenous VitC allegedly curing cancer and pushed tens (if not hundreds) of thousands of people into the anti vax movement decided a few days ago that he is going to cure 2019-nCoV with H2O2 intravenous feeds. They locked his youtube channel, hopefuly he is going to be finaly prosecuted soon. 

Jesus, that should be criminally persecuted, no doubt.

[poo thrower]

On 2/3/2020 at 5:01 PM, Duda Jarek said:

Sounds like you are writing about capsid (?), viral envelopes are rather not made of proteins: https://en.wikipedia.org/wiki/Viral_envelope

They have some glycoproteins, which could be put on a liposome to get a fake virus ...

wouldn't that just test the immune response though ?; like saying "boo to a goose" (and for no reason) - our bodys already know that they are harmful...

On 1/31/2020 at 7:47 AM, Duda Jarek said:

So the question is if/how there could be quickly started production of some provisional vaccine - not perfect but fast to introduce? Also exploiting the fact that these viruses are now nearly identical.

no... because "nearly" / not "perfect" is not good enough; you can't learn this one mutation down the line...

[Duda Jarek]

"Researchers rush to test coronavirus vaccine in people without knowing how well it works in animals" https://www.statnews.com/2020/03/11/researchers-rush-to-start-moderna-coronavirus-vaccine-trial-without-usual-animal-testing/

Good video about mechanisms of COVID-19: https://www.youtube.com/watch?v=Eeh054-Hx1U

[Duda Jarek]

From today: https://www.theguardian.com/world/2020/mar/16/first-participant-us-coronavirus-vaccine-trial-moderna-dose

First participant in US coronavirus vaccine trial to be given dose

The first participant in a clinical trial for a vaccine against Covid-19 will receive an experimental dose on Monday, according to a US government official.

The trial, taking place at the Kaiser Permanente Washington Health Research Institute in Seattle, will involve 45 young, healthy volunteers who will be given shots of the vaccine.

[CharonY]

Just so you know, the phase I trial (which tests for safety) has a completion date in June. However, the follow up is supposed to take about a year.

[Duda Jarek]

They skipped animal trials so maybe it could be quickened, especially that this is just injecting mRNA ... and that Trump wants vaccine before November elections.

Personally I would gladly volunteer to such trials if having an opportunity - in current situation of likely soon being infected with the real virus.

[CharonY]

It won't happen before November, and in this case in collaboration with the NIH, the pre-clinicals will run in parallel to phase I. Roughly speaking, the next steps tend to be more expensive (money and time wise) before a full roll-out can happen. Always assuming that these vaccines actually work.

Also note that they are testing three different concentrations to ascertain safety and there is not guarantee that an of them will elicit an immune response (though they will also look at that as a secondary goal at day 57). 

[Duda Jarek]

Unfortunately we are no longer talking about a hypothetical situation from some utilitarianism economy textbook, but about a real one with daily deaths in thousands.

Balancing medical trials, these deaths can be seen as casualties of waiting.

mRNA is rather less toxic than the actual virus. If such vaccine would be e.g. toxic for elderly, applied to the young ones it could build a herd immunity (better than Johnson's way) - there are many ways to optimize the "economy of waiting" for the main priority here: minimization of the number of deaths.

Anyway, there are probably ongoing dozens of trials to get a vaccine, in various regulatory environment (like China) - I believe that before November there will be widely used some vaccine, at least as phase III trial on millions in potentially endangered regions.

Edited March 16, 2020 by Duda Jarek

[koti]

Somebody please tell me this isn’t for real:

"German ministers have reacted angrily following reports US president Donald Trump offered a German medical company “large sums of money” for exclusive rights to a Covid-19 vaccine"

First published on Mon 16 Mar 2020 02.56 GMT

https://www.theguardian.com/world/2020/mar/16/not-for-sale-anger-in-germany-at-report-trump-seeking-exclusive-coronavirus-vaccine-deal

[StringJunky]

6 minutes ago, koti said:

Somebody please tell me this isn’t for real:

"German ministers have reacted angrily following reports US president Donald Trump offered a German medical company “large sums of money” for exclusive rights to a Covid-19 vaccine"

First published on Mon 16 Mar 2020 02.56 GMT

https://www.theguardian.com/world/2020/mar/16/not-for-sale-anger-in-germany-at-report-trump-seeking-exclusive-coronavirus-vaccine-deal

Yep. Gun sales have spiked there as well. It seems they need to protect themselves from their fellow Americans as things get in short supply from panic buying.

Quote

Virus fears fuel spike in sales of guns and ammunition

BOISE, Idaho (AP) — The world’s largest gun store, in metro Atlanta, has had lines that are six and eight people deep. A gun store in Los Angeles had lines that stretched down the block. And at least one store in Idaho put limits on sales after its shelves were nearly cleared out.

Just as grocery stores have been stripped bare by Americans panicked by coronavirus, guns and ammunition have started flying off the shelves. Retailers say the buying frenzy is being fueled by consumers who are worried that people are becoming so desperate and unpredictable, they need to ensure they can protect themselves.

“It’s been insane,” said Jay Wallace, who owns Adventure Outdoors in Smyrna, Georgia, adding that his ammunition sales are up more than five times the usual numbers. “This is like a Rod Serling ‘Twilight Zone’ episode.”

https://apnews.com/9402d0680bbd3f27836a283c1956d671

 

Edited March 16, 2020 by StringJunky

[CharonY]

8 hours ago, Duda Jarek said:

Unfortunately we are no longer talking about a hypothetical situation from some utilitarianism economy textbook, but about a real one with daily deaths in thousands.

Balancing medical trials, these deaths can be seen as casualties of waiting.

mRNA is rather less toxic than the actual virus. If such vaccine would be e.g. toxic for elderly, applied to the young ones it could build a herd immunity (better than Johnson's way) - there are many ways to optimize the "economy of waiting" for the main priority here: minimization of the number of deaths.

Anyway, there are probably ongoing dozens of trials to get a vaccine, in various regulatory environment (like China) - I believe that before November there will be widely used some vaccine, at least as phase III trial on millions in potentially endangered regions.

That is why they allowed the phase I to proceed, there was a balance between need and risk. However, phase II is still needed. In this phase folks look into whether it actually has an effect. A harmless but useless vaccine can exposure folks to additional risk, as they think they are safe, while they are not. It is likely that Phase III can be cut short, essentially because there is nothing to compare it to. But again, the ~12-18 months time line is roughly what is needed to get the minimum information (and you also need to ramp up production) It does not really matter under which regulatory guideline you fall into. You always have to make sure that a) whatever you inject is not worse than the disease  b) that it actually does something and c) figuring how and how much you need to apply to get and maintain the desired response. Just observing the responses even if you could inject everyone instantenously would take some time, otherwise you have no clue how you should deploy a potential vaccine.

 With regard to China I think I mentioned earlier that there are Chinese trials underway using a variety of approaches (inkl. using specific candidate antigens, most within Shenzhen). But as mentioned, I would be extremely surprised if someone somehow could bring anything to market by November (therapies would potentially be something, if only for severe cases). 

I should also add that having an immunogenic response does not mean that immunity has been acquired.

On top there are international efforts in testing existing antiviral therapies some of which are intervention studies (i.e. they recruit sick folks as part of the cohort).

[koti]

Although I don't understand half of it, I find the technology used to develop the vaccine fascinating:

https://en.wikipedia.org/wiki/Molecular_clamp

[Duda Jarek]

4 hours ago, koti said:

https://en.wikipedia.org/wiki/Molecular_clamp

Interesting, if I properly understand, there are two forms of the virus membrane proteins: the pre-fusion ones in virus have stored energy to enable fusion with cell membrane, the post-fusion in infected cell have lower energy ... and the problem is that they are a bit different from perspective of antibodies.

While it is much easier to produce the lower energy form, vaccine based on it would not protect against free virus, only would allow to mark the infected cells - these molecular clamp polypeptides are claimed to allow to produce pre-fusion ones. It is aminoacid sequence self-assembling into double helix rod-like structure ... I don't understand how it can help forming meta-stable higher energy protein forms?

I see that this higher energy meta-stable form is originally prepared in ER membrane, somehow encapsulated from inside - from https://en.wikipedia.org/wiki/Coronavirus :

ps. It is usually assumed that there are nearly no ribosomes in cytosol (?) - that some viruses have these complex capsides e.g. using pH difference to get into the nucleus ... so is the above diagram correct, or does coronavirus RNA have to get to ER or nucleus first?

Update: ok, it seems there are free ribosomes in cytosol: https://en.wikipedia.org/wiki/Ribosome#Free_ribosomes

So the most questionable part in this Moderna vaccine - just mRNA if I properly understand (?), is getting it into a cell:

Quote

In theory, if this synthetic mRNA is injected into a person, it should enter their cells and programme them to build proteins that look like the virus's receptor surface

So can free mRNA get into a cell?

But generally it could only give this weaker (?) post-fusion protection (assuming they go also to external membrane - not only ER suggested by diagram above) ... and could be also made by just putting these proteins on a liposome - I have started this thread with.

A related idea is just putting ACE2 on liposome - getting a trap for this virus, it couldn't resist with mutations ...

ps2: Also, the diagram above suggests that fusion requires binding with multiple ACE2 receptors, hence their concentration is a critical parameter ... which is said to be modulated by some common medicines used e.g. by high blood pressure and diabetic patients - suggesting a hypothesis that this might be a  reason for increased mortality for them. Good lecture with commentary:

 

Edited March 17, 2020 by Duda Jarek
free ribosomes

[studiot]

https://www.bbc.co.uk/news/health-51906604

 

To be tested on volunteers in the US