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Duda Jarek

Covid-19 vaccines thread

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Experts say it will still take many months to know if this vaccine, or others also in research, will work. 

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1 hour ago, Duda Jarek said:

ps. It is usually assumed that there are nearly no ribosomes in cytozol (?) - 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?

I asked a similiar question, in short, ribosomes start of in the cytosol, when translation starts a subpopulation of those ribosomes will move to the ER.

Quote

3) technically all eukaryotic ribosomes are cytosolic- they are either free or associated with a membrane. The pathways proteins can take are complex but they can e.g. be directed via endosomal pathways to the Golgi. However, proteins synthesized in the cytosol can also be directed to the ER and from there to the Golgi. There are also a number of non-canonical vesicular pathways, but let's just say that understanding intracellular protein trafficking requires serious reading.

4) There are again multiple models for how ER-localized translation works. In the classical, mRNA-ribosomal complexes are directed to the ER after initiation utilizing so called signal recognition particles. In other words, initiation is assumed to be a fully cytosolic action, the translocation to a membrane occurs afterward. However, there is recent evidence that ER-bound ribosomes also produce non-membrane targeted (i.e. cytosolic) proteins, which challenges some prior assumptions. As a whole, there is more recognition of ribosomal dynamics, which respond to a vast number of cellular cues (such as stress).

by CharonY

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As briefly discussed in dog another thread, this phase I is an abridged trial which is supposed to test safety. Data collection will take at least two month. After that they need another cohort to establish efficacy (and suitable concentrations) which takes even longer. As Kartazion said the projected overall time line is the often mentioned 12-18 months. In addition other trials are underway (many in China) for other vaccinations as well as treatment.

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24 minutes ago, CharonY said:

As briefly discussed in dog another thread, this phase I is an abridged trial which is supposed to test safety. Data collection will take at least two month. After that they need another cohort to establish efficacy (and suitable concentrations) which takes even longer. As Kartazion said the projected overall time line is the often mentioned 12-18 months. In addition other trials are underway (many in China) for other vaccinations as well as treatment.

It does seem like we're making a rather large bet on a rather small probability...

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5 minutes ago, dimreepr said:

It does seem like we're making a rather large bet on a rather small probability...

Actually there are several concurrent bets on the market, assuming that is what you meant.

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Several dips into the lottery, doesn't raise the probability by much. 

Let's say it takes 36 months or 72, when does the bet lose money; even if you win?

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25 minutes ago, dimreepr said:

Let's say it takes 36 months or 72, when does the bet lose money; even if you win?

As usual, I am going to guess what you might mean. If the question is whether it is profitable if it gets developed but too late, the answer is how likely the disease is to become either endemic or perhaps seasonal. In these cases a working vaccination could be quite profitable.

In a broader sense, many of these trials do not make money. This is part of the inefficiency of the pipeline and this is why most companies only commit after at least very promising pre-clinicals. In that respect these approaches are not very different from other biomedical pipelines. SARS vaccines were in development for a long time, but some shut down because there were no major outbreaks and money dried up, for example.

Other than that, having more things in pipelines is generally a good thing, especially novel ones.

 

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2 minutes ago, CharonY said:

Other than that, having more things in pipelines is generally a good thing, especially novel ones.

Indeed and long may it continue, I'm just concerned that our approach in this case, given our proclivity to panic and/or overreact, may lead to our downfall, given enough time and guess'

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36 minutes ago, dimreepr said:

Indeed and long may it continue, I'm just concerned that our approach in this case, given our proclivity to panic and/or overreact, may lead to our downfall, given enough time and guess'

Science doesn't typically "panic/overreact". While everyone about them is losing their heads, the physicians and scientists just keep moving ahead.

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Nah, folks don't panic, they just stock up on essentials, like toilet paper.. oh.

But in all seriousness, the turnaround for vaccines is usually quite a bit faster as desired reaction is (i.e. showing immune responses) is fairly easy to measure (at least in principle). According to Pharm folks quite a few assume that the vaccine is not going to be used recurrently so there is a focus on cheap and easy.

With the accelerated stream efficacy can also be tested faster which basically can allow a fast rollout of phase III. Essentially first a few hundred than a few thousand folks will be treated and tracked. There it will show whether there is a likely acquisition of immunity (i.e. in essence it is already a low roll out of vaccination and at least theoretically this could could happen this year). Say May/June first safety results, if all is well on accelerated Phase II say two months to ensure that titers are there and high enough to indicate immune response. While results roll in start recruiting and one might have the first rollout for III maybe as early as August (say a few hundred patients). If efficacy and safety is still alright at this step a next wave could roll out a few months later with a few thousand patients. While the vaccine is not available for the population as such, I am pretty sure some would claim at that point that success at this point already. However, in principle we would need more time to gather sufficient info from Phase III to evaluate how much protection the vaccine actually delivers. That could be tricky as at that time it is possible if not likely that the number of infections are already declining. Actual full production and rollout normally proceeds after it is known to offer at least some level of protection.

One should also not neglect the psychological value of the development itself. It provides folks with a sense of potential control over the situation and even if it does not come out in time, at least it feels like someone is doing something. Oh, and I should add that the accelerate trials are (AFAIK) all sponsored by the respective governments, so it is not like the involved companies are hurting from doing it.

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2 hours ago, CharonY said:

Nah, folks don't panic, they just stock up on essentials, like toilet paper.. oh.

But in all seriousness, the turnaround for vaccines is usually quite a bit faster as desired reaction is (i.e. showing immune responses) is fairly easy to measure (at least in principle). According to Pharm folks quite a few assume that the vaccine is not going to be used recurrently so there is a focus on cheap and easy.

With the accelerated stream efficacy can also be tested faster which basically can allow a fast rollout of phase III. Essentially first a few hundred than a few thousand folks will be treated and tracked. There it will show whether there is a likely acquisition of immunity (i.e. in essence it is already a low roll out of vaccination and at least theoretically this could could happen this year). Say May/June first safety results, if all is well on accelerated Phase II say two months to ensure that titers are there and high enough to indicate immune response. While results roll in start recruiting and one might have the first rollout for III maybe as early as August (say a few hundred patients). If efficacy and safety is still alright at this step a next wave could roll out a few months later with a few thousand patients. While the vaccine is not available for the population as such, I am pretty sure some would claim at that point that success at this point already. However, in principle we would need more time to gather sufficient info from Phase III to evaluate how much protection the vaccine actually delivers. That could be tricky as at that time it is possible if not likely that the number of infections are already declining. Actual full production and rollout normally proceeds after it is known to offer at least some level of protection.

One should also not neglect the psychological value of the development itself. It provides folks with a sense of potential control over the situation and even if it does not come out in time, at least it feels like someone is doing something. Oh, and I should add that the accelerate trials are (AFAIK) all sponsored by the respective governments, so it is not like the involved companies are hurting from doing it.

Even if this development phase is too late, the donkey work will be done and it can be modified more straightforwardly if/when it mutates, won't it?

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Well, that depends. When it comes to vaccines much of the donkey work is done anyway. E.g. safety of certain adjuvants or delivery methods  is pretty well established, though it is still generally required to provide data that in combination they still remain safe (but requirements at that point are fairly low). Assuming it was effective to begin with, the question with mutations is why it renders it ineffective. And it is possible that new antigens need to be targeted then. And then one has to check whether the new target is actually effective. 

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6 minutes ago, CharonY said:

Well, that depends. When it comes to vaccines much of the donkey work is done anyway. E.g. safety of certain adjuvants or delivery methods  is pretty well established, though it is still generally required to provide data that in combination they still remain safe (but requirements at that point are fairly low). Assuming it was effective to begin with, the question with mutations is why it renders it ineffective. And it is possible that new antigens need to be targeted then. And then one has to check whether the new target is actually effective. 

OK.

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But the good news is that with multiple directions to develop a vaccine we might have an better idea what works better.

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Sounds like the 90 days fast track is for Phase I, similar to the other one. Rather obviously it will (not "potentially") take longer to test efficacy and there is a further timeline before first applications (which would be in the III).

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“Given the urgent global need for a human coronavirus vaccine, we are doing everything we can to accelerate development,” MIGAL CEO David Zigdon said. The vaccine could “achieve safety approval in 90 days,” he said.

It is hard to tell how to interpret it, but the life cost (also economical) is just too high to allow for 18 month trials to satisfy regulations - "casualties of waiting" should be included in calculations.

If being at least a bit promising and excluding toxicity, I believe massive usage will start - to test it in the field in endangered regions.

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The trial is not "just" to satisfy regulations-they are to figure out whether they work in the first place. At this point we do not know if any of these work. It does not make sense to mass produce something if you do not know whether it at least elicits a significant immune response. And even then it is not clear whether that response will create immunity, but in an accelerated scheme hundreds to thousands would be tested within phase III (so it is not really waiting - it is data gathering).  

27 minutes ago, Duda Jarek said:

If being at least a bit promising

Again, this is the big thing, the a bit promising is about creating an immune response, and that will be ascertained primarily in Phase II and secondarily in Phase I with a relative handful of folks.

The big problem is of course is if after committing to one particular vaccine if folks in PhaseIII still get sick- which could take a while to figure out, depending on exposure in a given test population. Therefore it is important to have several options in the pipeline.

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A lot is now being done where schools and business are closing although some business are doing their best to keep open and active. In my trade the government control us and are currently advising that we can't stop Statutory testing and examining motor vehicles. Today I've read about some businesses saying that they are asking customers to turn off their heaters and remove any items in the vehicles like food stuff, cans, cups etc. How serious should this vivid 19 be taken as a working class person dealing directly with the public!

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I'm no expert, but you should be taking this very seriously. Gloves, masks, regular washing of hands, social distancing should all be adhered too. Granted, it's easier to say than it is to do, do you even has access to face masks and gloves? I don't nor can I get any.

The moderator Charon Y is a good person to follow on this subject. Very knowledgeable and informative. Try reading through the corona virus mega thread.

Take care. Stay safe. 🙏🏻

 

Edited by Curious layman

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On 3/20/2020 at 3:48 PM, Casio said:

A lot is now being done where schools and business are closing although some business are doing their best to keep open and active. In my trade the government control us and are currently advising that we can't stop Statutory testing and examining motor vehicles. Today I've read about some businesses saying that they are asking customers to turn off their heaters and remove any items in the vehicles like food stuff, cans, cups etc. How serious should this vivid 19 be taken as a working class person dealing directly with the public!

I think by now interactions will or should be severely limited. As others have said, it should be taken seriously, if not a a risk to yourself it poses to those you interact with. There are already a ton of good advise posted basically everywhere (keep distance, wash hands, do not touch your face etc.). 

Trying to remove infectious material should also help. One should try to avoid touching things with our hands (e.g. opening doors hands-free if possible, use elbows to operate switches or doors etc.). One of the habits I picked up during lab work is to use the non-dominant hand as designated "dirty" hand (assuming that you are less likely to touch yourself with that hand, which might not be true for everyone) and then make a fist with that hand whenever you are not using it (I often imagine holding something in the fist). I try to keep it up until I disinfect/glove/whatever needs to be done. What I also train students is to lock their hands when they are not supposed to touch anything (e.g. when they are gloved) to keep them from touching themselves, their clothes and so on.

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