totm april 2020 Coronavirus

[Lisias]

Do you want to see something stupid?

Spoiler

Source (pt-br)

Our magnificent Mayor, with all his Wisdom, had determined a very harsh car rotation regime: cars with license plates ending on even numbers can travel on Mondays, Wednesdays and Fridays. Odd ones in Tuesdays and Thursdays.

After math? People in essential activities that could use their own car are now disputing spaces with carless essential workers (as health professionals, usually badly paid here) on a reduced public transportation system.

Go figure out, Forum Policies prevent me to properly publish my opinions about the subject and the Mayor.

[Superfluous J]

On 5/12/2020 at 4:33 PM, Dragon01 said:

Sending 230V ventilators to US wasn't exactly the hottest idea they've had

I see what you did there.

[DDE]

"Bob, I want you to cause a scandal with the Russian authorities"

Edited May 14, 2020 by DDE
Better image

[DDE]

Meanwhile in other headlines, the Ministry of Information of Belarus kindly asks a Kazakhstan-hosted satire website to drop the article claiming the Belarus Ministry of Health has defined 38°C as the new normal body temperature.

Spoiler

That's a major fever, for all the Fahrenheit fans.

[mikegarrison]

So there are now 13 sailors on the USS Roosevelt who tested positive, then tested negative after two weeks of quarantine, and now have tested positive again.

False positives? False negatives? Re-infection? Yet to be determined.

[Superfluous J]

2 hours ago, mikegarrison said:

False positives? False negatives? Re-infection?

I'm thinking (hoping?) different strains.

[AHHans]

1 hour ago, Superfluous J said:

I'm thinking (hoping?) different strains.

That would be horrible! It would mean that you don't actually get immunity to this. But with a sensitive test for RNA/DNA fragments I wouldn't be too surprised if that reacts to "trash" that took a while leaving your body. (Or, well, I just hope it is that.)

[KerikBalm]

On 5/10/2020 at 10:27 PM, Dragon01 said:

with the revelation that very mild cases don't get immunity,

Citation? 

I've seen reports that mild cases seem to lend to lower antibody responses, but there are still no good studies on the risk of reinfection or duration of immunity, as far as I've seen.

[Guest]

5 minutes ago, KerikBalm said:

Citation? 

I've seen reports that mild cases seem to lend to lower antibody responses, but there are still no good studies on the risk of reinfection or duration of immunity, as far as I've seen.

https://www.medrxiv.org/content/10.1101/2020.03.30.20047365v2

There you go. Note that this is not, strictly speaking, a study on the risk of reinfection. It's a study of antibody response in convalescent patients. It would seem that the nonspecific immune response is, in some cases, sufficient to contain the virus, and that doesn't confer lasting immunity. As an added bonus, severity of infection seems to depend on initial viral load (albeit that comes from animal model studies, so they may not be as reliable), which would mean that even if someone had an asymptomatic infection once, they'd have no guarantee that all other infections will be like that, too.

This study is one of the reasons I'm all for the hardline approach for dealing with the pandemic. This is not going to fix itself on its own, not with results like these. That's also bad news for inactivated virus vaccines, but one can hope that giving the patient a whole lot of these, even if they don't do much, is gonna give the immune system the kick it needs.

On 5/17/2020 at 1:38 PM, AHHans said:

That would be horrible! It would mean that you don't actually get immunity to this. But with a sensitive test for RNA/DNA fragments I wouldn't be too surprised if that reacts to "trash" that took a while leaving your body. (Or, well, I just hope it is that.)

What we mostly think about as "COVID tests" is an RNA test (coronaviruses have no DNA), and it is inherently incapable of telling live and dead viruses apart. It's good at confirming if a sick patient has the disease, or if someone is very definitely not infectious, but beyond that, care must be taken when interpreting the results.

However, as per the link above, your concerns are correct. All evidence points out that yes, we don't get immunity to this, at least if we're not "properly" sick with COVID-19. From what I gather, these sailors found out they are infected with SARS-CoV2 at a screening, meaning they had no symptoms at that point. Seeing as sailors are generally young and healthy folk, it's likely that they didn't feel particularly sick at any point during the quarantine. 

For the record, COVID-19 is the disease, SARS-CoV2 is the virus. In a nutshell, it seems that being infected with SARS-CoV2 does not confer immunity, unless it gives you COVID-19. It doesn't do that for everyone.

[KerikBalm]

4 hours ago, Dragon01 said:

https://www.medrxiv.org/content/10.1101/2020.03.30.20047365v2

There you go. Note that this is not, strictly speaking, a study on the risk of reinfection. It's a study of antibody response in convalescent patients. It would seem that the nonspecific immune response is, in some cases, sufficient to contain the virus, and that doesn't confer lasting immunity.

I think you're reading too far into it.

#1) As you note, there's no re-infection

#2) They may still have cell mediated immunity without detectable levels of NAb in their serum

#3) They measure NAb, which is neutralizing antibody, not necessarily reactive antibody.

Reactive antibody could still possibly trigger recognition of infected cells, and have them killed before the cell releases virus.

So... it does suggest a strong possibility of a lack of immunity, but it still must be regarded as unknown.

[Guest]

6 hours ago, KerikBalm said:

I think you're reading too far into it.

Not quite. They may have resistance, but without NAb, it is highly unlikely we can talk about immunity. NAb is the most robust immune response system there is, reactive antibodies do not prevent viruses from entering the cells, and in fact, can help them (this is called antibody-dependent enhancement). This is a serious concern with antibody therapies, BTW, though thankfully, it doesn't seem to be a problem with most candidates currently being studied. Either way, I highly doubt one can gain actual immunity through other types of immune response. USS Roosevelt case is evidence for reinfection being a possibility, and this lines up with what we know about the immune system in general. In particular, people who are merely resistant can avoid the disease themselves, but still spread the virus. Also, neutralizing antibodies, by virtue of being both specific and doing the work themselves, are not affected by conditions (other viruses, bacterial infections) that occupy the more general-purpose parts of the immune system. 

If this was a purely scientific problem, I would have no problem regarding it as unknown, but it's not. The evidence at hand is sufficient to conclude, for the purposes of our decision making in handling this pandemic, that the risk of reinfection exists and needs to be accounted for. Mild and outright asymptomatic cases are a big enough part of how the pandemic spreads that even if only some of them don't get full immunity (specifically, the ability to prevent the virus from using them to spread), the implications are pretty awful.

EDIT: Here's an interesting article. One of the vaccines under development had ran into a related problem, at least in rhesus monkeys. It appears to protect the monkey that got vaccinated, but does not prevent it from spreading the virus. Of course, it'd still be better than nothing, but ultimately, the infection was not prevented. A booster shot could solve that, or it could be lived with if that was not feasible, but it's something to look out for.
https://blogs.sciencemag.org/pipeline/archives/2020/05/18/criticism-of-the-oxford-coronavirus-vaccine
Fortunately, the other vaccine efforts are looking better. This one, in particular, had some promising results, though it should be kept in mind that it's only a small phase I trail. 
https://blogs.sciencemag.org/pipeline/archives/2020/05/18/first-results-from-modernas-coronavirus-vaccine
Also, this particular vaccine would require deep refrigeration (RNA is notoriously unstable), which would complicate the already monumental logistics of vaccinating the entire world population. Still, it's an RNA vaccine that looks to be on track, which is great news all around. I'm really looking forward to more results on that one.

Edited May 18, 2020 by Guest

[Shpaget]

Peter Hadfield, aka potholer54, gives his analysis of data available and online blogosphere.

As usual for his videos, check the video description for links to sources.

[KerikBalm]

On 5/18/2020 at 9:23 PM, Dragon01 said:

Not quite. They may have resistance, but without NAb, it is highly unlikely we can talk about immunity. NAb is the most robust immune response system there is, reactive antibodies do not prevent viruses from entering the cells, and in fact, can help them (this is called antibody-dependent enhancement).

I am well aware of this stuff, I happen to work for the virology department at a university hospital, which is also a WHO diagnostic reference lab. (Some of their papers have been cited in this thread)

One point is that immunity is not really a binary condition, its always just varying levels of resistance. Even in individuals with NAbs, if the titer is insufficient, then you get infected.

NAb activity is good, for sure - but these individuals had an infection, where viral load was increasing, so it wasn't the innate immune system that shut down the viral replication. The infection was stopped after a while, indicating some sort of adaptive immune response. If NAb isn't detected at any point during the infection, and the infection is defeated, it seems logical to conclude they had, at some point, immunity without NAb activity.

This could be a T-cell response... And without the whole response spectrum, including  NAbs, its likely not going to last as long, but its jumping the gun to say that they have none 

Our group is discussing the idea of vaccination of asymptomatic or mildly symptomatic individuals in particular, with the idea that they will have some immunity/ protection, but that it needs to be boosted for longer duration.

Also, ADE has only been demonstrated in vivo for a few viruses lik dengue as far as I know, all the demonstration of ADE in coronavirus come from in vitro studies, without confirmation in vivo.

Its a concern for sure, but lets not make the public think its hopeless.

As for the reinfection question, again, had it actually been demonstrated, or could a few simple false negatives or false positives explain the results?

Interesting article about T cell immunity

https://www.cell.com/cell/fulltext/S0092-8674(20)30610-3

[Guest]

3 hours ago, KerikBalm said:

NAb activity is good, for sure - but these individuals had an infection, where viral load was increasing, so it wasn't the innate immune system that shut down the viral replication. The infection was stopped after a while, indicating some sort of adaptive immune response. If NAb isn't detected at any point during the infection, and the infection is defeated, it seems logical to conclude they had, at some point, immunity without NAb activity.

This could be a T-cell response... And without the whole response spectrum, including  NAbs, its likely not going to last as long, but its jumping the gun to say that they have none 

Our group is discussing the idea of vaccination of asymptomatic or mildly symptomatic individuals in particular, with the idea that they will have some immunity/ protection, but that it needs to be boosted for longer duration.

True, however note that I was focusing on a slightly different question, and a somewhat more binary, namely whether the person can infect others or not. That's where trouble is, because herd immunity is, generally speaking, a feature of models that don't have an "S" at the end. The question is, can you kill a virus fast enough without NAbs that you are at no point a carrier for it? From what I know about immunology (admittedly, I do biophysics, mostly vesicles and such, so that's a bit orthogonal to my field), I don't think so. Antibodies are pretty fast binders, while other components of the immune system take time to ramp up the response. Before they do, a person infected this way is a carrier (even if asymptomatic), and that complicates things. If SIR model doesn't fit that particular pandemic, and I don't think it does, then it might be rather more difficult to get rid of than initially thought. I might be a bit pessimistic in saying that natural herd immunity is definitely not a thing with this disease, but IMO, relying on it is too much of a risk at this point. Results from the rhesus monkeys that I mentioned in the previous post show the very thing I'm concerned about (admittedly, that was a monkey given a vaccine, not a human with a mild disease).

I do think that vaccinating asymptomatic or mildly symptomatic individuals would likely be a good idea, if our logistics can handle this, for the sake of both longer duration of the immunity and faster response to an infection. Of course, it depends on the vaccine in question. With so many different approaches being tried, it's hard to tell if the one that does make it through the trails will be suited for that.

EDIT: Yes, that does mean that a low quantity of NAbs is not enough either. They do indeed need to be present in substantial enough quantities to take the virus out right as it enters the body. I think the term I should have used is "sterilizing immunity". This needs to become widespread if we are to get rid of the virus for good, and a solid vaccine is the only way we can reliably ensure that. 

Edited May 20, 2020 by Guest

[AHHans]

11 hours ago, KerikBalm said:

Also, ADE has only been demonstrated ...

Can you explain what you mean with "ADE"? It doesn't look like you are talking about Adobe Digital Editions or Atlantis Diesel Engines. (SCNR!)

10 hours ago, Dragon01 said:

That's where trouble is, because herd immunity is, generally speaking, a feature of models that don't have an "S" at the end.

What do you mean with "models that don't have an 'S' at the end"?

And while it may make it hard(er) to outright eliminate the virus, persons that are not infectious for four or more days but only one or two days will make the epidemic much more manageable.

[Start personal rant]
A similar thing can be said about the crappy face masks that we are now forced to use in Germany(*). Even if they only prevent a third or less infections that would have happened without them it will make a difference for the spread in the general population. It wouldn't do excrements(**) for a nurse or similarly exposed person, it would just mean that they get infected maybe a day later. So they need decent protective equipment.

I also don't think that eliminating the virus is that important. If we can reduce the spread to a low number of new infections per day without restricting our economy or social life, then that would be good enough for me. And, yes, that would include being able to have large parties - like a sports event - with lots of people in close contact, without spreading the disease too much. Our western society has lived with deadly and infectious diseases - like the measles - well enough that some people don't consider them enough of a threat anymore to get their kids vaccinated.

Another issue that I believe often gets overlooked is that the doctors learn more and more about the best treatment of COVID-19. So everything else being the same (i.e. no overloaded health system or so) getting sick a few month later in the early phase (say May vs. March) will give you a better chance of survival - even if only slightly. And I believe that knowledge about treatment will keep increasing for the foreseeable future. So trying to get people to not get sick now but later - if at all - has that as an additional benefit.

10 hours ago, Dragon01 said:

I might be a bit pessimistic in saying that natural herd immunity is definitely not a thing with this disease, but IMO, relying on it is too much of a risk at this point.

Well, a policy that relies on getting "herd immunity" when it is not known that this can be achieved at all is IMHO - let's say - ill advised. But that's just my opinion.

(*) If you want to go into a shop or public transportation in Germany you now have to wear something that covers your nose and mouth. Most people use a simple "self made" (I got mine from a local tailor shop) masks.
(**) Yes, I expect that will get / has been changed by the forum filters.
[End personal rant]

[Guest]

23 minutes ago, AHHans said:

What do you mean with "models that don't have an 'S' at the end"?

I was talking about the standard epidemiological models, which are generally designated by letters corresponding to the number of variables they involve. These would be familiar to someone with a background in biology and/or medicine. Basically, the variables in these models correspond to status of the population. For example, the most commonly used SIR model is "susceptible-infected-removed". The latter includes the dead and the immune, as, they can no longer spread the virus. This is what all herd immunity calculations are based on, when you hear people talk about R0 and Rt, these are some of the constants that go into the differential equations that make up the SIR model. It's not the only one, though. For example, the SIS model, means "susceptible-infected-susceptible", and models a disease that confers no lasting immunity at all. There are other models, as well, but the naming convention is the same, so in a model with "S" for "susceptible" as a possible end state, herd immunity either does not exist or is conditional, that is, it depends on the values of some or all of the constants. 

You can see a list of models here:
https://en.wikipedia.org/wiki/Compartmental_models_in_epidemiology

35 minutes ago, AHHans said:

And while it may make it hard(er) to outright eliminate the virus, persons that are not infectious for four or more days but only one or two days will make the epidemic much more manageable.

This is true, but . Also, bear in mind that outright elimination is impossible without either herd immunity, or eliminating all reservoirs of the disease. If there is a large enough population in which the virus can spread and multiply asymptomatically, without them becoming immune, that will allow the disease to resurface every time one of these people comes into contact with someone vulnerable. It's a similar situation as with an animal reservoir, which is another possible concern. These problems are part of the reason why we haven't managed to eradicate more diseases than smallpox and rinderpest.

[KerikBalm]

12 hours ago, Dragon01 said:

True, however note that I was focusing on a slightly different question, and a somewhat more binary, namely whether the person can infect others or not. That's where trouble is, because herd immunity is, generally speaking, a feature of models that don't have an "S" at the end. The question is, can you kill a virus fast enough without NAbs that you are at no point a carrier for it? From what I know about immunology (admittedly, I do biophysics, mostly vesicles and such, so that's a bit orthogonal to my field), I don't think so.

Can they? if they could kill the active infection fast enough in the individual, then they certainly can. The question is... how long does it last? Certainly 1 femtosecond minute after the last virus particle/infected cell is killed... 1 minute./hour/day... pretty safe bet... weeks, months? Its also a false premise to say its somewhat more binary whether a person can infect others or not.

When talking about herd immunity, we must look at the average number of individuals that will be infected by an infected individual. If this number falls below 1, the infection will go away in the populatiom. If its >1, then the outbreak grows in size, and if it hovers around 1, you get a pretty stable infection in your population. Of course, its not a fixed number, and it often varies with seasons, and the intensity of the last outbreak.

Anyway....

If an individual gets infected, but the duration of viral shedding is shorter, and the viral titers are lower, then its follows that they are less infectious. Its not binary: infectious or not, but a question of: how infectious are they? If they are asymptomatic, this means they are unlikely to be sneezing and spreading the virus much by aerosol, but it also means they are likely to still be going out, meeting people, and taking no precautions, so the net effect is... hard to say. However, an asymptomatic individual with no prior exposure to SARS-CoV-2, vs. an asymptomatic individual with exposure to SARS-CoV-2, is likely to be shedding more virus, and for longer periods of time, making them more of a spreading risk.

[KerikBalm]

1 hour ago, AHHans said:

Can you explain what you mean with "ADE"? 

Antibody-Dependent-enhancement, as mentioned by Dragon 01:

On 5/18/2020 at 9:23 PM, Dragon01 said:

reactive antibodies do not prevent viruses from entering the cells, and in fact, can help them (this is called antibody-dependent enhancement). This is a serious concern with antibody therapies,

*with the caveat that he means reactive antibodies that don't have neutralizing activity... since the neutralizing antibodies that he mentioned are also reactive antibodies. Basically, antibodies that react to a virus, without neutralizing a virus (either they aren't binding and blocking a crucial site on a viral surface protein, which can often happen with antibodies to coronavirus spike proteins, or bind too weakly), have the possibility of being "bad"- now the "enhancement" part is rather vague. It may be the binding causes more of a host reaction that is not beneficial (the "cytokine storm" and inflammation of the lungs in SARS-CoV-2 patients could be an example of such a host reaction, but I am not saying that is due to ADE)... and then there's another mechanism, which also can use the acronym ADE

Anti-body Dependent-Entry-  this has been demonstrated in vitro for coronaviruses. They have this "spike" protein that in some cases will get cleaved after binding its target, which causes a conformational change, and it will extend one of its domains to "try" and insert into a cell membrane and then fuse the viral membrane with the host cell membrane to gain entry. 

In the case of SARS-CoV-2, it will normally fuse with cells after binding to ACE-2. If an Antibody binds to the ACE-2 binding site, it may cause the same conformational change as if the spike protein bound ACE-2, and the virus would then be primed to fuse with the next cell it comes into contact with... Since the cell is coated in antibodies, and immune cells will recognize and bind to the Fc portion of those antibodies infecting the virus, the immune cells themselves may get infected.

Its been shown in vitro that addition of some antibodies that don't neutralize the fusion domain of Spike protein can cause the virus to stop infecting its normal targets, and start infecting immune cells.... at even higher levels in vitro (which I dont know if its even close to physiological conditions), then infection is again hindered, as all the viral receptors are bound by Ab, and the immune cells are saturated by Ab, and the virus just floats around not infecting anything until its no longer viable.

Now, if this is occurring in vivo, its nothing like what HIV does (before you start draing any comparisons). In a study of common coronavirus done back in 85 or 90 (forget which paper it was right now), people (who were intentionally infected for the study) that developed symptoms (as many volunteers had recent exposure anyway, and some level of protection), had up to a 25% drop in their leukocyte count.

In severe cases of SARS-CoV-2, they notice large drops of leukocyte counts (around 80% if I recall of the top of my head)... so... I don't know, maybe its going on...

BUT!

The study Dragon01 mentioned was measuring neutralizing antibodies, and not all recovered patients had them. They could still have had reactive antibodies which enhance their cellular immune response, without having antibodies that cause ADE, as the particular mechanism studied in vitro requires a specific sort of reactivity that mimics the spike protein binding to its ligand.

NAbs may be the best defense, but they aren't the only defense, and just because you didn't find neutralizing activity in vitro, doesn't mean the individual is just as vulnerable as before exposure (and will shed just as much virus for just as long if reinfected)

[AHHans]

@Dragon01 and @KerikBalm: Thanks for the explanations!

[DDE]

Moscow serological study reports 12,5% of the population has antibodies, random normalized sample, n = 70000, will push for 3-6 mln.

https://amp.rbc.ru/rbcnews/society/23/05/2020/5ec8cc1c9a7947213bff4b6a

This is insanely high, and means barely a tenth of all cases have been identified.

...there's also strong evidence that whoever tests positive to antibodies is immediately sent into the standard 14-day quarantine.

[mikegarrison]

56 minutes ago, DDE said:

whoever tests positive to antibodies is immediately sent into the standard 14-day quarantine.

This makes no sense at all.

[GearsNSuch]

30 minutes ago, mikegarrison said:

This makes no sense at all.

That only makes it more likely that the report is true.

 

Though maybe the thinking is that there is a time where a patient has antibodies but is still infectious.

Edited May 24, 2020 by GearsNSuch

[Guest]

1 hour ago, DDE said:

Moscow serological study reports 12,5% of the population has antibodies, random normalized sample, n = 70000, will push for 3-6 mln.

My university recently did a similar study in my city, and found something like 2% of the population to have antibodies. How accurate this is, I don't know, but that would mean that the virus is both far more infectious than we assumed (probably not in the same league as measles, but higher than even the Los Alamos R0) and far more benign than we thought. We definitely need more of these studies, of course assuming the tests aren't set off by some random common cold coronavirus antibodies in addition to SARS-CoV2 specific ones. I've heard about false positive problems with early serological tests.

Also, we might have another way of dealing with it: interferon therapy. It turns out one of the ways it bypasses the immune system is not triggering interferon production, a key step in its operation. It's somewhat akin to what Dengue does, and injecting interferons (something we already know how to do) could improve early stage immune response. This, incidentally, is connected as to why it causes cytokine storms, too, immune system first underreacts, then overreacts to compensate. Good writeup here:
https://blogs.sciencemag.org/pipeline/archives/2020/05/21/there-may-be-a-unique-coronavirus-immune-response
This needs more investigation, and won't be of help to those already in cytokine storm stage nor as a prophylactic therapy, but if given early in the infection it could help prevent it from getting too serious.

[kerbiloid]

4 hours ago, DDE said:

is immediately sent into the standard 14-day quarantine.

At home, afaik.

Also they try to have them signed the paper about their informed agreement, etc, and install a mobile application to control their location by periodic SMS asking to make a selfie. A delay of answer causes/may cause a 4 000 RUR (~50 USD) fine.
And, if internet tells the truth, it gets access to the contacts and the phone memory.

Afaik, they also bring some medicines for free.

Edited May 24, 2020 by kerbiloid

[Guest]

Every damn app these days tries to get access to contacts and phone memory. Most work fine if you deny them these permissions, too.