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COVID-19 medical discussion


wild_turkey

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5 minutes ago, Bevo said:

 

It may be true but it is a dumb thing to say if you are trying to get published. Technically, the data looks pretty sound although, I would have to give it a lot of thought to determine if her conclusions are correct.

I honestly tried to give the paper another shot, but I couldn't make it past this without tuning out again...

Screenshot-2020-09-15-165217.jpg

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4 hours ago, Brisketexan said:

"Scientists have discovered limitless renewable energy, but the Globalists don't want you to know about it!  Watch our video to find out more!"

The internet is a chocolate fountain of bullshit.

Well, the idea that limitless cheap energy exists is a sucker concept that only California would buy.  But the idea that this virus is created, which is well within China's power, is not farfetched at all.  I don't know if they did or not, and my guess is that if they did, it was an accidental release as opposed to purposeful.  I'm not sure why the proposition that China engineered the virus has become political, but I stay off the hellhole that is the politics board, so I won't post here on the subject again. I find it to be a very interesting topic.

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1 hour ago, Anastasis said:

I agree with this.  

Yeah, I am not into conspiracy theories. But, I think China should be held responsible if the lab did accidentally release it - especially if it was engineered to any extent. It won't happen, though unless you consider a sternly worded letter as China being held responsible. Plus, it would be a complete shit-show.

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17 hours ago, JohnLocke said:

https://www.zerohedge.com/medical/rogue-chinese-virologist-joins-twitter-publishes-evidence-covid-19-created-lab

The receptor-binding motif of SARS-CoV-2 Spike cannot be born from nature and should have been created through genetic engineering.

 

15 hours ago, Bevo said:

That is an interesting paper.

https://www.thedailybeast.com/steve-bannon-linked-groups-push-study-claiming-china-manufactured-covid?ref=home?ref=home

"The study is the work of the Rule of Law Society and the Rule of Law Foundation, sister nonprofit organizations that Bannon was instrumental in creating. According to documents posted on the Society’s website last year, he served as that group’s chair."

Idk about y'all, but it trips my bullshit meter

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https://www.thedailybeast.com/steve-bannon-linked-groups-push-study-claiming-china-manufactured-covid?ref=home?ref=home
"The study is the work of the Rule of Law Society and the Rule of Law Foundation, sister nonprofit organizations that Bannon was instrumental in creating. According to documents posted on the Society’s website last year, he served as that group’s chair."
Idk about y'all, but it trips my bullshit meter

Trips? It blew the top right off the gauge.

Come the fuck on, people. Fuck giving shit from an avowed chaos propagandist even a millisecond of credibility.
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This new-to-me news and the CV-19 virus might be equally organic, yet today’s date infers otherwise, IMO. I suspect there’s something there, there. Whether truth is ultimately involved may or may not play a role. I don’t know.  If you do know, enjoy today. Answers will inevitably become more complicated to share with others.

There are vacuums, there are coincidences, and there’s other stuff. Mostly, there’s other stuff.

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Protocol discussion...

https://blogs.sciencemag.org/pipeline/archives/2020/09/21/the-vaccine-protocols

 

The Vaccine Protocols

By Derek Lowe 21 September, 2020

We now have the official clinical trial designs for the three biggest and most advanced coronavirus vaccine trials: Moderna, Pfizer/BioNTech and Oxford/AstraZeneca. Now, as for you, J&J, Novavax, Merck, and all the others that are pushing into efficacy trials as fast as possible – don’t think for a moment that you won’t be expected to do the same. But this is a good start. So how do these trials differ?

Let’s start off with some background, starting with “vaccine efficacy” (VE), which is pretty much what it sounds like: the percentage difference of infection by the virus between the vaccinated group and the unvaccinated control group. The FDA has already said that they want to see 50% at least (i.e., the vaccine cuts the rate of coronavirus infection at least in half). All of these trials have different subgroups, especially broken out by age and/or pre-existing conditions, and there will be not only an overall VE for the trial but separate VEs determined for all of the predefined subgroups. As is standard, the trials will be using what’s called a Cox proportional hazard regression model to assess the differences between the various groups – I won’t go into the details here, but that’s how you get the eventual figures of “Group A is 2.1x less likely to get infected than Group B” and so on. The Cox model actually gives you the “hazard ratio” (HR) which is just the opposite of the VE, so a 60% HR would mean a 40% VE.

The trials will be doing a similar analysis for different endpoints as well. For example, rather than calculate what effect the vaccine had on just sheer infection by the coronavirus, they will also be checking how many of the infected cases were severe (as opposed to those cases in the placebo group), how many asymptomatic cases there were, how these categories might look under alternate diagnostic criteria, the comparisons between these figures and different immunological readings (neutralizing antibody titers, for example), how many deaths took place, and so on. The same sorts of calculations will be going on for adverse events, looking for differences between the vaccinated and placebo groups and how these differences might change across the various subgroups. We’re talking a lot of data for any given trial, and with the number of trials going on, it’s going to be an absolute downpour of information.

The next thing to go into is statistical power. I will again avoid breaking out any equations, but the idea is that given a certain rate of infection in a population that you need enough patients in such a trial to demonstrate a given level of VE within given statistical bounds. The key to a controlled clinical trial is to lay out your statistical landscape in detail before you start, defining what success and failure will look like, and making sure that you have enough patients (and will see enough events) to distinguish them to an acceptable amount of rigor after a given amount of data gets collected.

All three trials have basically the same definition of failure, which would be a VE of 30% or worse. And they are all designed to have greater than 90% chance of demonstrating that the VE is better than that (if in fact it really is, and it had better be!) That’s the first thing you have to make sure of: to be able to say if the vaccine has succeeded or failed, and it should go without saying that if such a trial just enrolled (say) 100 people that it would be impossible to make such a call. And it would be even more impossible to say anything about safety in such a small study – adverse events are expected to be rare (but by no means impossible!) and you’ll thus need a sample size that can at least let you set some lower bounds on their frequency.

So all these trials are enrolling at least 30,000 people. Moderna is dividing their enrollees into 15,000 treatment patients and 15,000 controls. Pfizer is also 1:1, but AstraZeneca is going 2:1 treatment/placebo (more on that in a moment). That sample size is also related to how quickly you’ll be able to determine success, as you would figure. Remember, in a trial like this you’re waiting for people to get infected with the coronavirus – the number of people infected in the treatment group versus the control group is the most important data point in the entire trial. That’s why you want not only to have a lot of people, but to run the trial in areas where the virus is actively spreading.

Another important thing is the how you specify the interim analyses. Clinical trials often aren’t run “straight through” to the final data collection while flying blind the whole way. There are independent groups that keep an eye on the data (and on the adverse events), variously known as Data Monitoring Committees or Data and Safety Monitoring Boards, etc. These people are kept separate from the investigators, obviously. You need to lay out your plans for such interim looks at the data in advance, to avoid the temptation to move the goalposts once you’ve seen what’s going on. Note that none of these trials going to stop the study if they see good results early on – they’ll continue to collect data, but in the knowledge that they’re on to something effective. That’s both to get better statistics on the efficacy and to keep an eye out for safety: all these trials have prespecified alerts and stopping criteria if the DSMB sees a given number of adverse events as well.

So for Moderna’s trial, they have estimated that they are likely to see about 150 infection events during the whole trial. They have specified an interim analysis at 53 events (35% of the way through) and another at 106 events (70% of the way). At that first IA, the study will be considered to be already declared a success (rejecting the null hypothesis that the VE is only 30% or below) if the p-value for such a rejection is less than 0.0002. That would mean that the vaccine itself would be at least 74% effective. If the efficacy doesn’t meet the cutoff at the first IA, success will be declared at the second one if the p-value for rejecting the null hypothesis is less than 0.0073, which would mean a VE of at least 56.5%. If they have to go all the way to the end, then they’ll need a p-value of less than 0.0227 to reject the null, and that would mean a VE of 50% (the FDA’s floor, and it is no accident whatsoever that these two coincide).

As for Pfizer/BioNTech, they have a somewhat more aggressive approach. They calculate that they’ll hit 164 cases by the end of the study, and they have four IAs planned, at 32, 62, 92, and 120 cases. If they can reject the null hypothesis at that first one, that will be considered “overwhelming efficacy”, with a VE of at least 77%. The VEs if they clear the bar at the later analyses instead are 68%, 63%, and 59%, and if they make it only at the end of the study that would be a VE of 52%.

And the Oxford/AstraZeneca trial also estimates that they’ll see 150 cases by end of the study, and they have one interim analysis set at the 75-case mark. They estimate that will give them > 70% power to detect a VE of 70% and > 90% power to detect a VE of 75%. By the end of the trial, they believe that they’ll have a 90% chance of being able to say if the VE is 60% or greater.

So how quickly will these trials hit these readouts? That depends completely on the attack rate of the virus in the study population, as mentioned above. The more you are testing in viral hotspots, the faster you will collect data. If you decide to test in New Zealand, on the other hand, you will probably never hit the cutoffs at all. Pfizer has said several times that they expect to get a first readout by the end of October, and Moderna has said that they expect to get a look by the end of November. AstraZeneca, with only one interim analysis, will probably have to wait a bit longer from the start of their trial, although they did start on the early side. I would expect the companies involved to announce a positive result if they do make any of these interim analysis hurdles, though (wouldn’t you?)

So that’s roughly where things stand, and I hope this gives people a clearer picture of what’s going on. Now, as with all trials, we just have to wait for the data to come in. . .

 

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UK apparently moving forward with vaccine challenge trials. 


https://www.ft.com/content/b782f666-6847-4487-986c-56d3f5e46c0b

London is to host the world’s first Covid-19 human challenge trials — in which healthy volunteers are deliberately infected with coronavirus to assess the effectiveness of experimental vaccines. The UK government-funded studies are expected to begin in January at a secure quarantine facility in east London, according to several people involved in the project, which will be announced next week. The researchers, who did not want to comment publicly ahead of the launch, said the trials would play a vital role in narrowing the large field of promising Covid-19 vaccines likely to move into clinical testing early next year. Volunteers will be inoculated with a vaccine and a month or so later receive a “challenge” dose of Sars-Cov-2, the virus that causes Covid-19, under controlled conditions. About 2,000 potential volunteers have signed up for challenge studies in the UK through the US-based advocacy group 1Day Sooner, which campaigns for Covid-19 infection trials and has enlisted 37,000 people worldwide. Traditional clinical trials need tens of thousands of participants and researchers would struggle to attract enough for multiple vaccine studies.

 

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  • 2 weeks later...

EMA (European FDA) starts rolling review of AZ and PFE Vaccines to expedite approval...

https://www.fiercebiotech.com/biotech/biontech-pfizer-start-rolling-ema-approval-filing-for-covid-19-vaccine

BioNTech, Pfizer start rolling EMA approval filing for COVID-19 vaccine

by Nick Paul Taylor | 

Oct 6, 2020 8:10am

 

BioNTech and Pfizer have started a rolling submission of their COVID-19 vaccine BNT162b2 to the European Medicines Agency (EMA). The news comes days after EMA named AstraZeneca's AZD1222 as the first COVID-19 vaccine to start the rolling review process.

The EMA uses rolling reviews to start assessing data on an experimental candidate before all the evidence needed to make a final decision is available, cutting the time it takes to decide whether to approve a prospect once the pivotal clinical trial results are submitted to the agency. The pressing need for COVID-19 vaccines potentially makes the mechanism important to the current crisis.

After receiving the first part of a rolling submission, the EMA’s Committee for Medicinal Products for Human Use has begun evaluating the preclinical evidence on mRNA vaccine BNT162b2. The rolling review format provides opportunities to file additional data before the complete application. Each cycle typically requires a two-week review. The duration of the review of the final application will depend on the proportion of data already assessed by EMA under the rolling review. 

The EMA accepted BNT162b2 for rolling review on the strength of the preclinical and early clinical data on the vaccine. BioNTech and Pfizer have linked BNT162b2, which encodes a SARS-CoV-2 spike glycoprotein, to antibody and T-cell responses in people dosed in early-phase trials. The data led the partners to start a phase 3 clinical trial.

That trial has now enrolled around 37,000 participants at sites in countries including the U.S., Brazil, South Africa and Argentina, with centers in Turkey coming online to help push BioNTech and Pfizer to their enrollment target of 44,000 subjects. More than 28,000 participants have received their second dose. BioNTech and Pfizer originally planned to enroll 30,000 subjects.

The enrollment figures suggest BioNTech and Pfizer are closing in on the release of top-line data from the trial. Exactly how long the partners need to wait for efficacy data will depend on the extent to which participants have been exposed to the virus and the effectiveness of the vaccine. BioNTech and Pfizer are set to perform interim efficacy analyses when there are 32, 62, 92 and 120 COVID-19 cases in the trial.

BioNTech and Pfizer shared news of the rolling review days after the EMA said it had begun looking at data on AstraZeneca’s AZD1222. The EMA is reviewing preclinical data on AZD1222 while waiting for AstraZeneca to generate pivotal safety and efficacy results. AstraZeneca resumed dosing in a trial of AZD1222 in Japan late last week, but the U.S. study remains on hold.

Shares in BioNTech rose around 10% in premarket trading. The stock is up more than 100% this year.

 

 

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  • 2 weeks later...

PFE will wait until after election to submit their EUA application; however, initial efficacy data will read out earlier.

https://www.statnews.com/2020/10/16/pfizer-wont-apply-for-covid19-vaccine-authorization-before-mid-november/

Bourla’s letter includes three new details:

— Pfizer and BioNTech will have two months of safety data on half the patients in their 44,000-patient vaccine study in the third week of November, based on current enrollment rates. This would allow the companies to file for an emergency use authorization.

— The independent data safety monitoring board, a panel of experts monitoring the study, will conduct interim analyses of the effectiveness of the vaccine. This is what originally drove the October timeline.

— Pfizer said that it “will share any conclusive readout” from these interim analyses, be they positive or negative, but that the study will continue until its conclusion.

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MRNA hits last patient in. 

https://endpts.com/on-morning-of-fda-covid-19-adcomm-moderna-completes-phiii-enrollment-putting-them-neck-and-neck-with-pfizer/

Weeks away from a potential EUA application, Moderna announced they have completed enrollment in their 30,000-person Phase III Covid-19 vaccine trial, with over a third of volunteers non-white and a quarter over the age of 65.

The announcement caps what has been the most closely-watched recruitment race in the history of drug development, as Pfizer and Moderna rushed to get enough volunteers to prove whether or not experimental vaccines could actually protect people from contracting Covid-19. Pfizer reached that mark on Sept. 15. Moderna said around the same time that they would slow down enrollment to ensure they enrolled enough participants from minority and at-risk groups.

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Appears to be some good news on the immune response front:

https://science.sciencemag.org/content/early/2020/10/27/science.abd7728

Robust neutralizing antibodies to SARS-CoV-2 infection persist for months

 

Abstract

SARS-CoV-2 has caused a global pandemic with millions infected and numerous fatalities. Questions regarding the robustness, functionality, and longevity of the antibody response to the virus remain unanswered. Here we report that the vast majority of infected individuals with mild-to-moderate COVID-19 experience robust IgG antibody responses against the viral spike protein, based on a dataset of 30,082 individuals screened at Mount Sinai Health System in New York City. We also show that titers are relatively stable for at least a period approximating 5 months and that anti-spike binding titers significantly correlate with neutralization of authentic SARS-CoV-2. Our data suggests that more than 90% of seroconverters make detectible neutralizing antibody responses. These titers remain relatively stable for several months after infection.

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  • 2 weeks later...
34 minutes ago, Liquor and Poker said:

Anyone else see this nasal spray article from NYT last week?  Daily nasal spray makes sense given the worries about waning antibodies.  
 

I just want my ferret to feel safe again. 
 

https://www.nytimes.com/2020/11/05/health/coronavirus-ferrets-vaccine-spray.html

 

I saw end of November as a possibility to start distribution. Making substantial progress in controlling this would be a nice national Christmas present.

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2 hours ago, Anastasis said:

I like traditional approaches but the mRNA vaccine is interesting. mRNA surprisingly enters cells readily without a vector or lipid transfection agent. Designing is a little difficult in that it needs extra stuff like CAPS that effect translation and half-life/longevity of the mRNA. Otherwise, it looks pretty safe so I wouldn't hesitate to get vaccinated.

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1 hour ago, DaysOff said:

mRNA is the future of all vaccines, yes? The traditional vaccine seems like late 18th century technology now.

Maybe. A lot of it may depend on how the FDA regulates it. Generally, with pharmaceuticals each pharmaceutical agent needs to be tested so a cocktail of say 2 monoclonal antibodies is hard to get approved. So, if mRNA for a single protein (like the spike protein in COVID) is viable as a vaccine then approval is straightforward. However, if multiple mRNAs and hence multiple proteins are necessary, things might get dicey depending on FDA rules. Technically, I do think that it will be the future. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597572/

 

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On 11/9/2020 at 11:02 AM, Bevo said:

Maybe. A lot of it may depend on how the FDA regulates it. Generally, with pharmaceuticals each pharmaceutical agent needs to be tested so a cocktail of say 2 monoclonal antibodies is hard to get approved. So, if mRNA for a single protein (like the spike protein in COVID) is viable as a vaccine then approval is straightforward. However, if multiple mRNAs and hence multiple proteins are necessary, things might get dicey depending on FDA rules. Technically, I do think that it will be the future. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597572/

 

I had a dream last night regarding mRNA vaccines and Lupus. I think I read that only 9.2% of patients with SLE had anti-RNA antibodies. And I think only 70% of SLE patients have antibodies against DNA. Still if I was the FDA, I would specifically look at the clinical trials and see if there was any uptick in Lupus among mRNA vaccine recipients. I could easily see something like this being missed in an expedited review process. Even without an uptick, I think it is possible that the more times exposed to mRNA vaccines, the greater the chance of developing SLE. This is just a random thought though and studies would have to be done to see if there is any correlation. I just figured I would add a caveat since I earlier stated that I wouldn't hesitate to get an mRNA vaccine. And as another disclaimer, I have never studied Lupus so this is just a random thought and not meant to scare anybody: It is just food for thought.

Edited by Bevo
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34 minutes ago, Bevo said:

I had a dream last night regarding mRNA vaccines and Lupus. I think I read that only 9.2% of patients with SLE had anti-RNA antibodies. And I think only 70% of SLE patients have antibodies against DNA. Still if I was the FDA, I would specifically look at the clinical trials and see if there was any uptick in Lupus among mRNA vaccine recipients. I could easily see something like this being missed in an expedited review process. Even without an uptick, I think it is possible that the more times exposed to mRNA vaccines, the greater the chance of developing SLE. This is just a random thought though and studies would have to be done to see if there is any correlation. I just figured I would add a caveat since I earlier stated that I wouldn't hesitate to get an mRNA vaccine. And as another disclaimer, I have never studied Lupus so this is just a random thought and not meant to scare anybody: It is just food for thought.

63463450.jpg

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On 11/9/2020 at 9:36 AM, Bevo said:

I like traditional approaches but the mRNA vaccine is interesting. mRNA surprisingly enters cells readily without a vector or lipid transfection agent. Designing is a little difficult in that it needs extra stuff like CAPS that effect translation and half-life/longevity of the mRNA. Otherwise, it looks pretty safe so I wouldn't hesitate to get vaccinated.

I completely understood this post

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13 minutes ago, Txzen said:

Cancer drug development. Immunology background.

That makes sense. I remember you were very familiar with Regeneron. Do you work with mAbs, immunomodulators (biologics), or small molecules? Academia or start-up? PM if you don't want it out there. I assume that it is applied science and not basic science. Just curious anyway.

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I've done a little of all of those at different stops in industry. More years than I'd like to admit to at this point. 

For Moderna, I'm really curious about the 'special sauce' with regard to their formation which they claim allows them to store at 4C for up to 7 days. Something to do with their nanoparticle formulation, though that explanation doesn't quite do it for me (sounds like some other alternations to the mRNA itself?). I think storage and distribution for the Pfizer one is a logistical nightmare. I'd be concerned that you'd need to re-train all the staff handling it as their normal SOP is so different. 

 

Why Does Pfizer's COVID-19 Vaccine Need To Be Kept Colder Than Antarctica?

Moderna Announces Longer Shelf Life for its COVID-19 Vaccine Candidate at Refrigerated Temperatures

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5 minutes ago, Txzen said:

I've done a little of all of those at different stops in industry. More years than I'd like to admit to at this point. 

For Moderna, I'm really curious about the 'special sauce' with regard to their formation which they claim allows them to store at 4C for up to 7 days. Something to do with their nanoparticle formulation, though that explanation doesn't quite do it for me (sounds like some other alternations to the mRNA itself?). I think storage and distribution for the Pfizer one is a logistical nightmare. I'd be concerned that you'd need to re-train all the staff handling it as their normal SOP is so different. 

 

Why Does Pfizer's COVID-19 Vaccine Need To Be Kept Colder Than Antarctica?

Moderna Announces Longer Shelf Life for its COVID-19 Vaccine Candidate at Refrigerated Temperatures

That sounds about right with regard to Pfizer. Although, many hospitals would have -70 so maybe you can use those sites as vaccine centers and avoid trying to distribute through CVS, Walgreens and other normal channels. Obviously, Pfizer has thought this through and plan on giving it to healthcare workers first and maybe this will buy them time to figure out the distribution to everyone else. As long as there isn't panic in the streets with a slow rollout, I'm not too worried.

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2 minutes ago, Bevo said:

That sounds about right with regard to Pfizer. Although, many hospitals would have -70 so maybe you can use those sites as vaccine centers and avoid trying to distribute through CVS, Walgreens and other normal channels. Obviously, Pfizer has thought this through and plan on giving it to healthcare workers first and maybe this will buy them time to figure out the distribution to everyone else. As long as there isn't panic in the streets with a slow rollout, I'm not too worried.

On the national news, there was an interview with someone (didn't catch if she was an actual representative from CVS or just some random yahoo - perhaps the latter) who stated that they'd have to resort to dry ice for the Pfizer vaccine, which I think is not going to work. Sounds like Moderna has it figured out, though it would be great to learn more. 

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1 minute ago, Txzen said:

On the national news, there was an interview with someone (didn't catch if she was an actual representative from CVS or just some random yahoo - perhaps the latter) who stated that they'd have to resort to dry ice for the Pfizer vaccine, which I think is not going to work. Sounds like Moderna has it figured out, though it would be great to learn more. 

I'm suspecting that Pfizer's vaccine can be focused on medical professionals, and/or administered in a hospital setting, which can get a lot of people covered, and then Moderna (and others) can be used for general population.  Let the logistics drive the administration, to some degree.

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It sounds like Moderna uses lipid nanoparticles (LNPs). LNPs are composed of an ionizable lipid, cholesterol, PEGylated lipid, and a helper lipid such as distearoylphosphatidylcholine (DSPC). The most clinically advanced LNP contains the ionizable lipid MC3. I don't know what Moderna used but I assume it was MC3 or possibly DOTAP (1,2-dioleoyl-3-trimethylammonium-propane).

 
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3 hours ago, Liquor and Poker said:

Looks like an antidepressant (fluvoxamine) might help in preventing patients from going downhill:

https://jamanetwork.com/journals/jama/fullarticle/2773108

Interesting, but way too small of a sample size. In the conclusions, they did a pretty good job of summarizing the shortcomings of their own study.

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