Coronavirus

[Mr._Clark]

So is US. It is likely because the virus is running out "fuel" for now, i.e. those most susceptible got it and recoverd or died. Similar happened with Spanish flue pandemic.

Personally, I doubt that the virus has run out of fuel (that's not to say we can't beat it by being smart). To my mind, the situation in Manaus, Brazil is instructive when it comes to supposed herd immunity.

In Manaus Brazil an estimated 76% of the population had been infected in October, but the virus is spreading quickly there right now. It's not entirely clear why this is, but there's no doubt Manaus was hit hard during the first wave.

A recent Lancet article (link below) below suggests four non-mutually exclusive explanations:

>>>First, the SARS-CoV-2 attack rate could have been overestimated during the first wave . . .

Second, immunity against infection might have already begun to wane by December, 2020, because of a general decrease in immune protection against SARS-CoV-2 after a first exposure. . . .

Third, SARS-CoV-2 lineages might evade immunity generated in response to previous infection. . . .

Fourth, SARS-CoV-2 lineages circulating in the second wave might have higher inherent transmissibility than pre-existing lineages circulating in Manaus. . . .<<

Resurgence of COVID-19 in Manaus, Brazil, despite high seroprevalence

After initially containing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many European and Asian countries had a resurgence of COVID-19 consistent with a large proportion of the population remaining susceptible to the virus after the first epidemic wave.1 By contrast, in Manaus...

www.thelancet.com

 

[Mr._Clark]

This is a very general question for TLS Guy, Swerd, or others who know more about this topic. I wish I could bring more insight to the table, but this is well outside my technical background.

I've been trying to figure out, roughly speaking, how many viable mutations of the coronavirus receptor binding domain (RBD) are possible, and of these which are likely to escape existing vaccines.

If I understand it correctly, the cell article (link below) says that in order to propagate a mutation must, at a minimum, retain (or enhance) both ACE2 binding and protein folding. There are apparently a fairly large number of mutations that are predicted to meet both criteria, but it's unclear to me how many of these mutations are likely to result in escape from vaccine protection. The answer seems to be in the maps, but I will readily concede that my understanding of this is modest at best, and the maps do not therefore directly inform me:

>>>RBD-based antigens represent a promising vaccine approach. Our sequence-phenotype maps can directly inform efforts to engineer such vaccines in several ways. First, we identify many mutations that enhance RBD expression and thermal stability, a desirable property in vaccine immunogens. Second, our maps show which mutations can be introduced into the RBD without disrupting key biochemical phenotypes, thereby opening the door to resurfacing immunogens to focus antibodies on specific epitopes. Finally, our maps show which surfaces of the RBD are under strong constraint and might thereby be targeted by structure-guided vaccines to stimulate immunity with breadth across the sarbecovirus clade: in addition to the ACE2 interface itself, these surfaces include several core-RBD patches targeted by currently described antibodies and a previously undescribed core-RBD patch surrounding residue E465.<<< (internal citations omitted)

Basically, I'm wondering if it would be feasible to develop a "killer" vaccine that would target all likely/viable mutations before they occur (focusing of course on the mutations that are likely to escape existing vaccines).

Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding

Starr et al. systematically change every amino acid in the receptor binding domain (RBD) of the SARS-CoV-2 spike protein and determine the effects of the substitutions on RBD expression, folding, and ACE2 binding. The work identifies structurally constrained regions of the spike RBD that would...

www.cell.com

 

[Verdinut]

I can't view that video here. No idea what it is.

If you were using a VPN, you would be able to view it by putting your position in the US for instance. Apart from protecting you from scams and phishing, you would get that advantage.

I am using a VPN but I don't use it on sites I do business or payments on. This creates problems, the business or bank site is programmed to figure that you are a hacker, and you might have to change your password. That happened to me with NordVPN.

 

[TLS Guy]

Personally, I doubt that the virus has run out of fuel (that's not to say we can't beat it by being smart). To my mind, the situation in Manaus, Brazil is instructive when it comes to supposed herd immunity.

In Manaus Brazil an estimated 76% of the population had been infected in October, but the virus is spreading quickly there right now. It's not entirely clear why this is, but there's no doubt Manaus was hit hard during the first wave.

A recent Lancet article (link below) below suggests four non-mutually exclusive explanations:

>>>First, the SARS-CoV-2 attack rate could have been overestimated during the first wave . . .

Second, immunity against infection might have already begun to wane by December, 2020, because of a general decrease in immune protection against SARS-CoV-2 after a first exposure. . . .

Third, SARS-CoV-2 lineages might evade immunity generated in response to previous infection. . . .

Fourth, SARS-CoV-2 lineages circulating in the second wave might have higher inherent transmissibility than pre-existing lineages circulating in Manaus. . . .<<

Resurgence of COVID-19 in Manaus, Brazil, despite high seroprevalence

After initially containing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many European and Asian countries had a resurgence of COVID-19 consistent with a large proportion of the population remaining susceptible to the virus after the first epidemic wave.1 By contrast, in Manaus...

www.thelancet.com

The number of possibilities is almost infinite. There are numerous strands of nucleic acid material made up of a huge number of amino acids. So just a couple of amino acid substitutions can have a dramatic effect.

So making a vaccine to pre empt these substitutions is not feasible. However having said that, these novel vaccines direct the vaccine recipients to make antibodies to multiple antigens to the part of the virus that attaches itself to the angiotensin II receptors. That is why the vaccines are not totally ineffective against these recent mutations, just less effective. So far the mRNA and mDNA vaccines have not been rendered useless. The same should apply to the Novavax system, but it appears that may be more affected. However that is hard to know as with that vaccine trial was ongoing after these recent mutations occurred, that is especially true of the large UK trial. So at this stage panic is not called for, just cencern and the gathering of data.

 

[TLS Guy]

So, more good news. We have another two good vaccine candidates, one that uses a viral vector and one that does not.

The issue of immunity to a viral vector is a big problem. Prof. Gilbert has proposed giving those that had the Oxford vaccine for the first immunization series, be given the Sputnik vaccine for the next round. Now the J & J would allow for three rounds.

The reason for proceeding down the viral vector route, is that many, including myself, where very skeptical that injecting a large does of mRNA intramuscularly would work. They fact that it works so well is really good news. However their fragility requires urgent improvement.

I think it is for this reason that the new Oxford facility is being designed to produce mRNA and mDNA vaccines.

Meanwhile the UK is now injecting nearly half a million doses a day. If that can be kept up the the UK should get vaccine herd immunity by September 1. In addition the UK has now signed enough contracts to vaccinate the whole UK population twice over. The UK government says that when the UK population is vaccinated it will give the surplus away, to where it is needed. That is likely to end up being the EU.

The Belgians allowed their police to be used by the EU commission to raid the Astrazeneca factory yesterday. The Germans as usual are resorting to form, and getting increasingly "mouth and trousers" about it.

The EU commission has now threatened to invoke article 122 of their war powers act and take over the factory by force. Apparently the Belgians say they will not allow their police or security forces to be used further by the EU against the plant. Remember the Belgians have suffered mightily twice under the German Jackboot.

The UK government has wisely been pretty silent on it all, and made vague noises of assistance when able, while hoovering up vaccine supplies which the EU commission seem incapable of. I think though that if article 122 was invoked and carried out, a very serious incident would come about. I suspect the UK would defend its interests, especially so, if the Belgians asked for assistance. If that happened I would expect a swift and severe visit from the SAS, who are about the most fierce fighting group of cut throats on the planet when provoked. There is just too much past history with Germans invading Belgium to let that pass. It was that act by Germany that lead to the first WW. They also disrespected Belgian neutrality in the second WW, to get round the back of the Maginot line.

From what I can tell from the comment columns in all UK newspapers, the UK population is in a more Bellicose mood than I have ever known in my lifetime. So if push came to shove, it would be impossible for a British prime minister not to bring the hammer down forcefully.

In addition the EU have today abrogated the terms of the Brexit agreement in Northern Ireland. The border between the Irish Republic and Northern Ireland was a huge bone of contention, between the UK and EU. The Good Friday agreement that brought peace to NI, specified there be no hard border between the two nations. This has lead to a border in the Irish Sea, whereby NI operates largely under EU rules. It is complex and awkward in the extreme. However today, the EU has imposed a hard border for vaccines between the Republic of Ireland and Northern Ireland in contravention of the Brexit agreement that is only just over a month old. This is because they are paranoid about vaccines in the R of I getting into NI.

Hopefully this will de-escalate fast. However there are are lot of EU countries making Bellicose noise, especially Germany and Spain.

All the while other EU countries are making side deal against the rules. For instance Hungary has done a deal with Russia for the Sputnik vaccine and ordered vaccine from China. Neither are approved by the European regulator. By the way, the EU regulator did approve the Astrazeneca vaccine today, but Germany says it will only give it to those under 65. I don't think they will see much of that vaccine anyway. The UK has a cast iron contract which gives them precedence, and will not be sending UK made vaccine to the EU any time soon. I understand that the human kidney cell line at the Belgian plant which is used to culture the Monkey Adenovirus is in serious trouble and may have died off. That is the reason for the two the three month delay in production there.

The UK is still owed 3.5 million doses of the Pfizer vaccine from their Belgian factory. However, it looks that the UK has a robust enough supply chain of vaccines, it would not need to make a big issue of it.

Just an evening update on this saga.

Emmanuel Macron, the French President has made the bizarre claim that the Oxford/Astrazeneca is almost ineffective. He has been accused in the UK of out Trumping Trump! He has been roundly criticized from all quarters for undermining confidence in vaccines and giving ammunition to anti vaxxers. Professor Bell who was on charge of the clinical trials is furious and set Macron straight in no uncertain terms.

Meanwhile there has been fierce backlash against the EU for construction a hard border for vaccines between the Irish Republic and Northern Ireland.
Micheal Martin, the Irish Taoiseach, expressed his alarm in tense discussions with Commission president Ursula von der Leyen, with sources indicating that neither the UK or Irish governments had been notified in advance. The EU have been forced into an embarrassing U-turn on this one.

Meanwhile there are sentiments being voiced that the UK should help out the Republic of Ireland with its vaccination program. In addition the opinion is gaining ground in the UK that when and if it is appropriate to help out the EU block, that it be done on a country by country basis, and by-pass the EU Brussels bureaucracy entirely.

Below is how the UK program compares with the EU. Malta is only the highest, as the EU made an error and sent them far more doses per population.

Country		Doses given to people		Doses given per 100 people
United Kingdom		8,369,438		12.33
Malta		24,680		5.58
Denmark		228,875		3.95
Romania		647,000		3.36
Ireland		161,500		3.27
Spain		1,474,189		3.15
Portugal		315,737		3.1
Lithuania		83,550		3.07
Italy		1,794,630		2.97
Poland		1,097,036		2.9
Finland		151,790		2.74
Germany		2,216,127		2.65
Estonia		34,019		2.56
Sweden		248,991		2.47
Greece		251,303		2.41
Czech Republic		250,964		2.34
Belgium		266,768		2.3
Slovakia		123,999		2.27
Hungary		213,010		2.21
Austria		181,419		2.01
Croatia		80,000		1.95
France		1,234,731		1.89
Luxembourg		11,373		1.82
Cyprus		17,379		1.44
Netherlands		215,498		1.26
Latvia		22,124		1.17
Bulgaria		37,636		0.54

 

[Trell]

‘It’s a mess’: Biden’s first 10 days dominated by vaccine mysteries

Biden’s team is still trying to locate upwards of 20 million vaccine doses that have been sent to states — a mystery that has hampered plans to speed up the national vaccination effort.

www.politico.com

 

[Trell]

Living Sweden this cartoon sort of sums it up.

 

[Swerd]

This is a very general question for TLS Guy, Swerd, or others who know more about this topic. I wish I could bring more insight to the table, but this is well outside my technical background …

I've been trying to figure out, roughly speaking, how many viable mutations of the coronavirus receptor binding domain (RBD) are possible, and of these which are likely to escape existing vaccines …

Basically, I'm wondering if it would be feasible to develop a "killer" vaccine that would target all likely/viable mutations before they occur (focusing of course on the mutations that are likely to escape existing vaccines) …

Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding

Starr et al. systematically change every amino acid in the receptor binding domain (RBD) of the SARS-CoV-2 spike protein and determine the effects of the substitutions on RBD expression, folding, and ACE2 binding. The work identifies structurally constrained regions of the spike RBD that would...

www.cell.com

Let's go for your last question first.

Basically, I'm wondering if it would be feasible to develop a "killer" vaccine that would target all likely/viable mutations before they occur (focusing of course on the mutations that are likely to escape existing vaccines).

The short answer is no it isn't feasible to try and develop a "killer" vaccine that could target all likely mutations before they occur. But the good news is that such a single vaccine isn't needed.

A better way to accomplish this has already been in mind among vaccine scientists for a while. Anthony Fauci recently spoke about it.

1. Keep the original vaccines directed against the entire sequence of the Spike protein gene, as it was known a year ago in January 2020. Use these vaccines as the primary vaccinations.
   
   
2. Keep up with the various Spike protein mutations as they appear in new strains of the virus.
   
   
3. Edit the sequence of the Spike protein gene to reflect the new mutations in either the mRNA vaccines (Pfizer or Moderna) or the recombinant DNA adenovirus vaccines (AstraZeneca, J&J, or Sputinik).
   
   
4. Use these edited vaccines as booster shots for those already immunized with original vaccines directed against the January 2020 version of the Spike protein gene. That should get the job done. And it would be much easier to accomplish that than trying to develop the One Vaccine That Rules All Spike Protein Mutations.

I'll attempt to answer your broader question, but I first must know how much chemistry you know, the basic high school kind of inorganic chemistry. Next, are you familiar at all with college level organic chemistry? And similarly, what do you know, if anything, about protein 3-dimensional structure & chemistry. I find it hard to talk about immunology without also talking about protein structure. So, I have to know what you know and what you don't know.

Proteins are very large organic molecules, with numerous chemical properties. They are so large that it takes single genes, large amounts of DNA sequence, to provide a blueprint of their amino acid sequence. If it helps, we can consider the DNA sequence of a protein as a simple linear message that describes what amino acids must be assembled in what linear order to make the protein – it has a single dimension. Once made, the protein assumes a large 3-dimensional physical structure determined entirely by it's sequence of amino acids. It also has the important chemical features of numerous positive, negative, or neutral charges across it's surface, as well as numerous ways it can interact with the surrounding molecules of water or grease (phospholipids in biological membranes).

Audio can be a useful analogy: Musical signals consist of a complex mix of varying voltages. Once these multiple one-dimensional signals (DNA gene sequences) are amplified (mRNA copies) and sent to loud speakers (translated into proteins) that one-dimensional varying voltage becomes a large complex, 3-dimensional sound pressure wave that expands with time in a roughly spherical pattern.

That's the starting point. It quickly gets more complex from there.

 

[TLS Guy]

Living Sweden this cartoon sort of sums it up.

I feel very sorry for anyone living in the EU right now. As usual the EU have turned this vaccine acquisition into an omnishambles of staggering proportions.

If the UK can keep ramping up vaccinations, I'm pretty sure they will help EU countries. It will be on a country y country basis. They will under no circumstances allow the clowns in Brussels to have anything to do with it.

My eldest sister and her husband were vaccinated about 2 weeks ago. My wife's sister and brother in law, have an appointment to be vaccinated on Wednesday. So things are moving at a clip there now.

I think Frexit might be next, I note that Marie Le Pen is catching Macron fast in the polls. It would be a good job too. The French are being absolute jerks at the border, and rejecting loads because the ink is the wrong color on forms, and making up obscure rules as they go along as to what color ink is required on which form. You just can't make this stuff up!
The EU needs to go, it is an absolute menace. If not, I expect the UK to progressively disengage from Europe. Historically the UK has kept at arm's length from Europe's affairs, and only intervened to maintain balance of power in the region, and when it doubt to intervene on the side of the Protestant cause. That was basically the policy after William of Orange (William III) ascended the throne, after the abdication of James II, after he ran from London and threw the Crown Jewels in the Thames on his way out in 1688.

 

[highfigh]

I think it is far more likely that people are being much more careful. I know they are round here.

The other thing is that we have a fairly low incidence, I think, of the more infectious strains. So data shows it takes these variants about two months to become absolutely catastrophic. If we can not roll out the vaccine fast, we will have the worst part of the crisis in most states, March April time frame.

Some friends went to Florida and returned last Sunday- both had mild cases before the trip and said that almost nobody wore a mask- they went to restaurants several times and it seems that people in Florida decided to stop wearing masks before the 'Biden is POTUS, so we can re-open the economy' move. California has lifted the mask mandate, too.

I look forward to the negative comments that I expect.

 

[Old Onkyo]

I look forward to the negative comments that I expect.

A vaccination site meant to serve a hard-hit Latino neighborhood in New York instead serviced more Whites from other areas | CNN

A Covid-19 vaccination site in a Latino neighborhood in New York City hard hit by the pandemic saw an overwhelming number of White people from outside the community show up to get the shot this month, city leaders say, laying bare a national disparity that shows people of color are being...

www.cnn.com

 

[highfigh]

A vaccination site meant to serve a hard-hit Latino neighborhood in New York instead serviced more Whites from other areas | CNN

A Covid-19 vaccination site in a Latino neighborhood in New York City hard hit by the pandemic saw an overwhelming number of White people from outside the community show up to get the shot this month, city leaders say, laying bare a national disparity that shows people of color are being...

www.cnn.com

That's just stupidity on parade.

 

[trochetier]

Some friends went to Florida and returned last Sunday- both had mild cases before the trip and said that almost nobody wore a mask- they went to restaurants several times and it seems that people in Florida decided to stop wearing masks before the 'Biden is POTUS, so we can re-open the economy' move. California has lifted the mask mandate, too.

I look forward to the negative comments that I expect.

They are likely all pro-life Floridians too. Sooner they get the virus and don't make it faster the State better it is..

 

[trochetier]

If you were using a VPN, you would be able to view it by putting your position in the US for instance. Apart from protecting you from scams and phishing, you would get that advantage.

I am using a VPN but I don't use it on sites I do business or payments on. This creates problems, the business or bank site is programmed to figure that you are a hacker, and you might have to change your password. That happened to me with NordVPN.

Not sure it will work, in TOR browser setting the country to US may be an option.

 

[mtrycrafts]

.... California has lifted the mask mandate, too.

...

When and where did that happen?

 

[Mr._Clark]

Let's go for your last question first.
The short answer is no it isn't feasible to try and develop a "killer" vaccine that could target all likely mutations before they occur. But the good news is that such a single vaccine isn't needed.

A better way to accomplish this has already been in mind among vaccine scientists for a while. Anthony Fauci recently spoke about it.

1. Keep the original vaccines directed against the entire sequence of the Spike protein gene, as it was known a year ago in January 2020. Use these vaccines as the primary vaccinations.
   
   
2. Keep up with the various Spike protein mutations as they appear in new strains of the virus.
   
   
3. Edit the sequence of the Spike protein gene to reflect the new mutations in either the mRNA vaccines (Pfizer or Moderna) or the recombinant DNA adenovirus vaccines (AstraZeneca, J&J, or Sputinik).
   
   
4. Use these edited vaccines as booster shots for those already immunized with original vaccines directed against the January 2020 version of the Spike protein gene. That should get the job done. And it would be much easier to accomplish that than trying to develop the One Vaccine That Rules All Spike Protein Mutations.

I'll attempt to answer your broader question, but I first must know how much chemistry you know, the basic high school kind of inorganic chemistry. Next, are you familiar at all with college level organic chemistry? And similarly, what do you know, if anything, about protein 3-dimensional structure & chemistry. I find it hard to talk about immunology without also talking about protein structure. So, I have to know what you know and what you don't know.

Proteins are very large organic molecules, with numerous chemical properties. They are so large that it takes single genes, large amounts of DNA sequence, to provide a blueprint of their amino acid sequence. If it helps, we can consider the DNA sequence of a protein as a simple linear message that describes what amino acids must be assembled in what linear order to make the protein – it has a single dimension. Once made, the protein assumes a large 3-dimensional physical structure determined entirely by it's sequence of amino acids. It also has the important chemical features of numerous positive, negative, or neutral charges across it's surface, as well as numerous ways it can interact with the surrounding molecules of water or grease (phospholipids in biological membranes).

Audio can be a useful analogy: Musical signals consist of a complex mix of varying voltages. Once these multiple one-dimensional signals (DNA gene sequences) are amplified (mRNA copies) and sent to loud speakers (translated into proteins) that one-dimensional varying voltage becomes a large complex, 3-dimensional sound pressure wave that expands with time in a roughly spherical pattern.

That's the starting point. It quickly gets more complex from there.

Thanks, I had a year of chemistry and materials science undergrad but no organic chemistry. As a practical matter, protein chemistry is not the type of thing that can be taught in a few posts here.

At work, if I get an invention disclosure that's heavily chemical I hand it off to one of our PhDs.

Somewhat off topic, when I first read about prions it was a surprise to me that such a thing was possible (not so much that a protein could fold incorrectly, but that it could spread).

 

[TLS Guy]

Thanks, I had a year of chemistry and materials science undergrad but no organic chemistry. As a practical matter, protein chemistry is not the type of thing that can be taught in a few posts here.

At work, if I get an invention disclosure that's heavily chemical I hand it off to one of our PhDs.

Somewhat off topic, when I first read about prions it was a surprise to me that such a thing was possible (not so much that a protein could fold incorrectly, but that it could spread).

Surprize to you, it was an enormous surprize to me also. When I read the original paper, in Scientific American from the UK veterinary researchers studying Swayback in sheep, I was absolutely incredulous. However they showed that these small protein molecules of the amyloid class were in fact infectious transmissible agents, and had fulfilled all of Koch's postulates. As a class though they only cause central nervous system infection.

 

[highfigh]

When and where did that happen?

NY and CA did it last week. From what I hear, Newsom is still likely to be recalled, so if he did this as a parachute for his term in office, I don't think it will work, especially if the infections rise (which I expect).

 

[highfigh]

They are likely all pro-life Floridians too. Sooner they get the virus and don't make it faster the State better it is..

Actually, my friends are kind of centrist, but they absolutely hate Trump. They have swung a bit left, but not batcrap crazy about any of what's happening. Haven' heard that any of the others they met with have had any problems, though. I have been seeing that case counts are declining- that would be a good thing, but with mutations, I'm not sure this thing will go away. If it becomes manageable, fine, but it seems to be here to stay.

 

[GO-NAD!]

Actually, my friends are kind of centrist, but they absolutely hate Trump. They have swung a bit left, but not batcrap crazy about any of what's happening. Haven' heard that any of the others they met with have had any problems, though. I have been seeing that case counts are declining- that would be a good thing, but with mutations, I'm not sure this thing will go away. If it becomes manageable, fine, but it seems to be here to stay.

I really don't understand how people can justify unnecessary travel now. If you're going from one low-case area to another nearby low-case area, that's OK. But, crossing the country for some time in the sun is irresponsible.

Maybe my view is shaped by of our fairly unique circumstances. We had a spike in cases last Fall, in Nova Scotia, reaching an average of about 15 cases per day at one point. With an increase in restrictions, we have wrestled that caseload down. Even with some restrictions eased at the start of the year, we are averaging about one case per day and as of yesterday, we have 11 (known) active cases. When cases are reported daily, they are invariably linked directly to out-of-province travel, or a close contact with a traveler. These cases generally involve university students returning from the holidays (we have eleven universities, with a high proportion from out-of-province) and rotational workers (eg. truck drivers and remote northern oil/mining site workers returning from high caseload areas). All returning students were required to self-isolate for two weeks upon arrival and be tested for the virus. Rotational workers are required to self-isolate and be tested every time they return to the province.

Discretionary out-of-province travel is otherwise highly discouraged and everyone else* entering the province is also required to self-isolate for two weeks. This requirement has pretty much dried up travel into the province and several small airports have shutdown, as a result. Of course, the restrictions are having a significant economic impact, but right now, they are our best defence (along with masking, social distancing, hand-washing, etc.). With our vaccine supply drying up, we don't have a lot of choice. If we can't vaccinate our people, we have to keep the virus out.

*There are exceptions, such as temporary essential workers, who must be tested before entry and are very restricted in their movements.