Coronavirus

[bkp_duke]

My biggest concern about the vaccination issue is the careful ruling out of pathological enhancement. This refers to how re-presentation of and challenge with exposure to the pathogen after inoculation causes a significantly enhanced and self-destructive inflammatory reaction. This has been demonstrated in relationship to other coronaviruses particularly in relationship to lung involvement. Russia is pushing ahead pell-mell into widespread vaccination without any attempt to ensure that this is not a hidden risk. The second concern is just how do you rule out rapidly fading immunity if your phase 3 trial lasts a couple of months and then the stuff is on the market. People are all focused on antibodies these days which are fairly quickly declining after covid-19 infection is cleared, but T Cell immunity should be long-lasting but we don't have any data on antibody levels length of time for the various vaccines and type of T-cell responses – that's a lot of basic science to fill in. The third and maybe biggest concern is with the likelihood that this vaccine will be distributed in a distinctly inequitable fashion. At risk vulnerable populations should get it first, but if we don't have really adequate trials to ensure safety that's lining them up to be guinea pigs. There's so much pressure on the various leaders to cross the line first here I just worry about the potential for highly motivated shortcuts that could have some disastrous results. And if a vaccine proved to be either ineffective or dangerous or both think of what kind of fuel that's going to pour on the fire of anti-vaccine conspiracy theories and the like. Could set back the cause of Public Health and specifically covid-19 Public Health badly.

I'm not worried about "pathological enhancement" in the major vaccines that have undergone Phase 1 trials. Both the Moderna and Oxford vaccines are multi-dose vaccines, and we should have seen that problem with the 2nd and (if used) 3rd doses in the Phase 1 data for both of those.

Rapidly fading immunity . . . that could be a problem. Only time will be able to answer that question.

Invariably, this will be a vaccine that confers partial immunity, akin to the seasonal influenza vaccine. So something like 30% of people that get vaccinated will still be able to contract COVID-19. This will result in the morons with no scientific training saying "I got the vaccine, but I still got COVID-19" (true statement), and then saying "so the vaccine is worthless" (very FALSE statement).




Then of course . . . mother nature may have other plans and SARS-CoV-2 mutates and the vaccine(s) put into mass production are minimally effective. That's my biggest nightmare scenario. The mutation rate of this virus is lower than influenza, so hopefully we get something that lasts most people at least 2 years. If that works, we could suppress the virus back into reservoirs (non-human carriers) and not see it again in our lifetimes (probably wishful thinking).

 

[madodel]

I'm not worried about "pathological enhancement" in the major vaccines that have undergone Phase 1 trials. Both the Moderna and Oxford vaccines are multi-dose vaccines, and we should have seen that problem with the 2nd and (if used) 3rd doses in the Phase 1 data for both of those.

Rapidly fading immunity . . . that could be a problem. Only time will be able to answer that question.

Invariably, this will be a vaccine that confers partial immunity, akin to the seasonal influenza vaccine. So something like 30% of people that get vaccinated will still be able to contract COVID-19. This will result in the morons with no scientific training saying "I got the vaccine, but I still got COVID-19" (true statement), and then saying "so the vaccine is worthless" (very FALSE statement).




Then of course . . . mother nature may have other plans and SARS-CoV-2 mutates and the vaccine(s) put into mass production are minimally effective. That's my biggest nightmare scenario. The mutation rate of this virus is lower than influenza, so hopefully we get something that lasts most people at least 2 years. If that works, we could suppress the virus back into reservoirs (non-human carriers) and not see it again in our lifetimes (probably wishful thinking).

But thanks to some immunity the morons will live to moron another day. Let's hope this freak of a virus doesn't decide to get worse.

 

[bkp_duke]

But thanks to some immunity the morons will live to moron another day. Let's hope this freak of a virus doesn't decide to get worse.

Probably. That and sheer numbers.

 

[SageBrush]

My biggest concern

Enumerating potential risks is always a worthwhile exercise but decisions have to be a risk to benefit analysis.

I realize that the political gyrations and media will make hay of the former and be blind to the latter. Such is the USA circa 2020.

 

[wdolson]

My biggest concern about the vaccination issue is the careful ruling out of pathological enhancement. This refers to how re-presentation of and challenge with exposure to the pathogen after inoculation causes a significantly enhanced and self-destructive inflammatory reaction. This has been demonstrated in relationship to other coronaviruses particularly in relationship to lung involvement. Russia is pushing ahead pell-mell into widespread vaccination without any attempt to ensure that this is not a hidden risk. The second concern is just how do you rule out rapidly fading immunity if your phase 3 trial lasts a couple of months and then the stuff is on the market. People are all focused on antibodies these days which are fairly quickly declining after covid-19 infection is cleared, but T Cell immunity should be long-lasting but we don't have any data on antibody levels length of time for the various vaccines and type of T-cell responses – that's a lot of basic science to fill in. The third and maybe biggest concern is with the likelihood that this vaccine will be distributed in a distinctly inequitable fashion. At risk vulnerable populations should get it first, but if we don't have really adequate trials to ensure safety that's lining them up to be guinea pigs. There's so much pressure on the various leaders to cross the line first here I just worry about the potential for highly motivated shortcuts that could have some disastrous results. And if a vaccine proved to be either ineffective or dangerous or both think of what kind of fuel that's going to pour on the fire of anti-vaccine conspiracy theories and the like. Could set back the cause of Public Health and specifically covid-19 Public Health badly.

It looks to me that T-cell immunity is where the focus should be right now. If we had a T-cell immunity test that the public could get, we might find fairly high levels of it and from studies of SARS victims, it looks like it might be permanent. It appears some people had some degree of it before COVID-19 existed. It might be a contributing factor why some people get very mild or asymptomatic cases.

Why some people who haven't had Covid-19 might already have some immunity - CNN

I also agree with you regarding the roll out of the vaccine and the anti-vaxer movement. If there are any problems with the vaccine once it is approved, the anti-vaxers will go nuts and it will fuel their movement. If, on the other hand, the roll out is smooth and nobody gets unanticipated side effects, then it will take the wind out of the anti-vaxer sails.

 

[renim]

At best, Victoria's mandated masks did not help, they may even have contributed to the worsening state down there.

So now Victoria is implementing their version of stage 4 lockdown. Which is quite a severe step beyond their prior 3+ lockdown.

Some business are closed
Some business are reduced manning/output
Some business are left open.


https://www.dhhs.vic.gov.au/guide-business– stage-4-restrictions-doc

 

[renim]

'
Under Stage 4 ‘Stay at Home’ Restrictions the default is that workplaces in metropolitan Melbourne are closed unless the workplace is part of a permitted industry as set out below. All Victorians are required to work from home, except where this is not practicable. Sole operators can continue to operate, if they do not have contact with the public, or with people other than those persons living in their primary household. '

 

[renim]

....
I also agree with you regarding the roll out of the vaccine and the anti-vaxer movement. If there are any problems with the vaccine once it is approved, the anti-vaxers will go nuts and it will fuel their movement. If, on the other hand, the roll out is smooth and nobody gets unanticipated side effects, then it will take the wind out of the anti-vaxer sails.

FWIW, the antagonism against anti-vax feeds the anti-vax movement. And that is really simple to significantly deal with, just acknowledge that sometimes vacinnes have bad effects and pay up in those cases without making an adversarial fuss.

For instance the UK has a Vacinne Damage Payment.
Vaccine Damage Payment

'
Vaccine Damage Payment Scheme (VDPS) is not a compensation scheme. A VDP is a payment to help ease the financial burden for those individuals where, on very rare occasions, vaccination has caused severe disablement. The Scheme does not prejudice the right of the disabled person to pursue a claim for damages through the courts. It should be considered in context with the range of support, financial and otherwise, that is available to disabled people in the UK, for example, free healthcare, social care support and disability benefits.'

Right now the USA is set up in a far more polarised binary vacinne environment, where acknowledgement that of the grey between is not rewarded.

 

[SMAlset]

At best, Victoria's mandated masks did not help, they may even have contributed to the worsening state down there.

So now Victoria is implementing their version of stage 4 lockdown. Which is quite a severe step beyond their prior 3+ lockdown.

Some business are closed
Some business are reduced manning/output
Some business are left open.


https://www.dhhs.vic.gov.au/guide-business– stage-4-restrictions-doc

I fail to understand how masks properly worn could contribute to the worsening state. They filter out more particles that would otherwise reach your nose or mouth. Honestly sounds like a Trumper stance from up here in the States. The crowds of people congretating without masks, asymptomatic, just has made things worse for everyone on a personal level and economically on a personal and State level.

Sorry your area is experiencing this surge now. I know for sometime Australia was holding itself up to how great a job they were doing keeping it at bay. From your description the current situation is very much like what we here in the SF Bay area have been living under. We were doing pretty well with hospitalizations/deaths until the restrictions were somewhat lifted and people went outside and in closer quarters and refused to wear masks.

 

[HenryFarkas]

I didn’t find a tread suitable for this topic, so here I go. I found this page that claims to have a real time update on the Corona Virus. It shows nubers of infected, deaths, and recovered from the virus. It also include a realtime view of the building of the Wuhan hospital. Anyone here familiar with the sours of this live stream? I think this virus might might be a matter to consider as a TSLA shareholder.
Coronavirus Map

Oddly, people seem to be buying Teslas even though they can't go anywhere. I did.

 

[renim]

I fail to understand how masks properly worn could contribute to the worsening state. They filter out more particles that would otherwise reach your nose or mouth. Honestly sounds like a Trumper stance from up here in the States. ...

Its simple, masks are intended as a complementary step, but interpreted as a supplementary step.

And the stronger the message is focuses on masks being beneficial, the less benefical they are due to the same compensatory actions.


'You can't pretend you don't have it': One in four Victorians with COVID-19 not at home

More than a quarter of Victoria coronavirus patients not at home when doorknocked by ADF.

PPE is always the lowest level of hazard control, and should never be considered as a replacement for higher levels of hazard control. Physical distancing (social distancing) should never be presented as tradeable with mask wearing.

 

[renim]

'
While a mask can be used as an extra precaution, you must continue to:

• stay at home if unwell
• maintain physical distance (more than 1.5m) from other people, when out
• avoid large gatherings and crowded indoor spaces
• practise hand and respiratory hygiene

'
Should I wear a face mask in public?

 

[renim]

Sorry your area is experiencing this surge now. I know for sometime Australia was holding itself up to how great a job they were doing keeping it at bay. From your description the current situation is very much like what we here in the SF Bay area have been living under. We were doing pretty well with hospitalizations/deaths until the restrictions were somewhat lifted and people went outside and in closer quarters and refused to wear masks.

My ancestors were Victorian but I'm in Qld, it is different up here, there is a subconscious competency regarding quarantine that permeates their response.

Fwiw, health care in Victoria is superior to Qld, the cancer statistics demonstrate that.

 

[EVCollies]

Timeout is a goid use of mod power when you don't want members to hate each other after a debate. The alternative is a ban.

In any case. Can we focus on discussion of vaccine candidates? Tgere are so many out there right now I don't know which one I should take when tgey come out.

That's all, I am back to hiding.

I agree, vaccination discussion is a positive feedback loop.

Appears our system has two vaccines in trial. I expressed interest in the Moderna v placebo for high risk providers but as no call back, must not be high enough risk. Yay!?

I also volunteered to provide entry physical exams to those interested in a Astra Zeneca/Oxford vaccine trial.

Great to see some progress.

Till then, mask up.

 

[alloverx]

I am not sure mandatory masks in Victoria (AUS) have been in place long enough to judge the benefit.
I did not look at the stats but it does seem most deaths announced by the Premier are almost always 60+ years of age.
Will the potential fine of almost AUD $5000 be enough to keep people with the virus at home when they get a random visit?
i.e. they are supposed to be isolating at home.

 

[bkp_duke]

The six strains of SARS-CoV-2

Good info here.

6 strains of virus circulating in the wild, and that appears to be pretty stable. It means if we are able to develop an effective vaccine, the mutation rate of the virus is unlikely to be high enough to allow it to mutate quickly enough to avoid the vaccine.

 

[dfwatt]

I'm not worried about "pathological enhancement" in the major vaccines that have undergone Phase 1 trials. Both the Moderna and Oxford vaccines are multi-dose vaccines, and we should have seen that problem with the 2nd and (if used) 3rd doses in the Phase 1 data for both of those.

Rapidly fading immunity . . . that could be a problem. Only time will be able to answer that question.

Invariably, this will be a vaccine that confers partial immunity, akin to the seasonal influenza vaccine. So something like 30% of people that get vaccinated will still be able to contract COVID-19. This will result in the morons with no scientific training saying "I got the vaccine, but I still got COVID-19" (true statement), and then saying "so the vaccine is worthless" (very FALSE statement).




Then of course . . . mother nature may have other plans and SARS-CoV-2 mutates and the vaccine(s) put into mass production are minimally effective. That's my biggest nightmare scenario. The mutation rate of this virus is lower than influenza, so hopefully we get something that lasts most people at least 2 years. If that works, we could suppress the virus back into reservoirs (non-human carriers) and not see it again in our lifetimes (probably wishful thinking).

I wish I shared your optimism about this being virtually no risk. Just to clarify, it's possible that my phrasing of this which is nonstandard may have been misleading. By 'pathological enhancement' I mean antibody dependent enhancement, which cannot be excluded until people are re-challenged with live virus which is unethical (and simply did not happen in phase 1 safety studies to my knowledge), and won't happen until naturalistic effects of phase 3 trials can be integrated into data sets. In other words, a certain percentage of individuals will, simply in the normal course of their lives, be re-exposed to the virus in a large phase 3, and then we will see whether or not pathological enhancement or antibody dependent enhancement is taking place. It's pretty clear that this is a significant risk in relationship to viral inoculation, With several interesting variables increasing the risk of this apparently in relationship to functionality emerging from the Fc gamma receptor system.

Here's one of the best reviews in my opinion on this problem. Here is the summary conclusion from that paper:

"Virus pathogenesis and host immunity relationship is controlled by multiple factors. ADE is a complex disorder that may lead to extreme virulence for many viruses. Considering the involvement of wide number of viruses in ADE, various mechanisms were proposed to explain this phenomenon. Current observations suggest that ADE is primarily induced by non-neutralizing antibodies, via FcγR (Taylor et al., 2015), or complement dependent pathway (Takada and Kawaoka, 2003). During the course of infection, different types of antibodies are produced representing mixture of neutralizing, enhancing, and non-neutralizing antibodies (Takada et al., 2007). Virus enhancement or neutralization depend on multiple factors, including antibodies type and class, antibodies titers, strain of the virus, as well as the presence of certain complement molecules. Surface proteins are the main antigenic determinants of antibody enhancing response, such as the HA of influenza (Ramakrishnan et al., 2016), G protein of RSV, spike S protein in SARS (Kam et al., 2007), E glycoprotein of flaviviruses (Bardina et al., 2017), transmembrane GP of HIV (Robinson et al., 1990a), GP of Ebola virus (Takada et al., 2001), and E2 glycoprotein of HCV (Meyer et al., 2008).

Numerous studies have characterized the host factors (B and T cellular responses) and viral factors (targeted epitopes) responsible for disease protection/enhancement. In the context of vaccine design, it is important to ensure that all vaccine are tested at different doses to ensure the elicitation of optimal titers of neutralizing antibodies. Better understanding of viral-host interplay in the context of enhanced disease illness would greatly improve the development of highly safe and effective vaccine and therapeutics."

The graphic below looks at the functionality off of the Fc gamma receptor, which can be both immune enhancing and paradoxically immuno-suppressing (via effects on T helper 1 cells), and additionally that recruitment of the complement system looks like it promotes host cell damage.

Figure 1
Mechanisms of ADE of viral infections. (A) Enhancement on FcγR bearing cells: (1) Viruses-antibody complexes are internalized to cells after antibody Fc-region binding to FcγR on the immune cells. (2) Subversion of the immune system response by reducing Th1 cytokines IL2, TNF-α and IFN-γ, increasing Th2 cytokines IL-10, IL-6, PGE-2 and INF-α, and inhibiting STAT pathway leading to decreased levels IRF and subsequent decrease in the antiviral iNOS. (3) Increased viral replication as a result of suppression of the antiviral response. (B) Enhancement on CR-bearing cells: (1) Formation of virus-antibody complexes. (2) This complex will activate the complement pathway by binding to C1q. Following activation, C2a and C4b proteins are recruited to produce C3 convertase, which in turn hydrolyses C3, to produce C3b. (3) C3b binds to the virus and to complement receptor (CR) on CR bearing cells. (4) Cell lysis and enhanced disease pathology.


I respect your far greater knowledge of virology – I'm sure you have forgotten more than I've ever learned, but I think this material makes it clear that surface protein antigens (which are much more likely to generate ADE), and lack of careful follow-up once large numbers of patients have been inoculated increases the risk of this problem. To my knowledge, and this is reassuring, everybody is going after the S protein as an epitope, which expert opinion suggests is both safer and possibly/probably more effective - but this review still lists the S protein target as capable of eliciting ADE.

My bottom line is that rushing through this process makes it more likely that this kind of serious side effect may not be appreciated until it's out there in significant numbers. Perhaps I'm just chronically suspicious that the Trump administration can blow up almost anything, even things that are normally pretty responsibly managed.

 

[bkp_duke]

I wish I shared your optimism about this being ritually no risk. Just to clarify, it's possible that my phrasing of this which is nonstandard may have been misleading. By 'pathological enhancement' I mean antibody dependent enhancement, which cannot be excluded until people are re-challenged with live virus which is unethical (and simply did not happen in phase 1 safety studies to my knowledge), and won't happen until naturalistic effects of phase 3 trials can be integrated into data sets. In other words, a certain percentage of individuals will, simply in the normal course of their lives, be re-exposed to the virus in a large phase 3, and then we will see whether or not pathological enhancement or antibody dependent enhancement is taking place. It's pretty clear that this is a significant risk in relationship to viral inoculation, With several interesting variables increasing the risk of this apparently in relationship to functionality emerging from the Fc gamma receptor system.

Here's one of the best reviews in my opinion on this problem. Here is the summary conclusion from that paper:

"Virus pathogenesis and host immunity relationship is controlled by multiple factors. ADE is a complex disorder that may lead to extreme virulence for many viruses. Considering the involvement of wide number of viruses in ADE, various mechanisms were proposed to explain this phenomenon. Current observations suggest that ADE is primarily induced by non-neutralizing antibodies, via FcγR (Taylor et al., 2015), or complement dependent pathway (Takada and Kawaoka, 2003). During the course of infection, different types of antibodies are produced representing mixture of neutralizing, enhancing, and non-neutralizing antibodies (Takada et al., 2007). Virus enhancement or neutralization depend on multiple factors, including antibodies type and class, antibodies titers, strain of the virus, as well as the presence of certain complement molecules. Surface proteins are the main antigenic determinants of antibody enhancing response, such as the HA of influenza (Ramakrishnan et al., 2016), G protein of RSV, spike S protein in SARS (Kam et al., 2007), E glycoprotein of flaviviruses (Bardina et al., 2017), transmembrane GP of HIV (Robinson et al., 1990a), GP of Ebola virus (Takada et al., 2001), and E2 glycoprotein of HCV (Meyer et al., 2008).

Numerous studies have characterized the host factors (B and T cellular responses) and viral factors (targeted epitopes) responsible for disease protection/enhancement. In the context of vaccine design, it is important to ensure that all vaccine are tested at different doses to ensure the elicitation of optimal titers of neutralizing antibodies. Better understanding of viral-host interplay in the context of enhanced disease illness would greatly improve the development of highly safe and effective vaccine and therapeutics."

View attachment 572295

I respect your far greater knowledge of virology – I'm sure you have forgotten more than I've ever learned, but I think this material makes it clear that surface protein antigens (which are much more likely to generate ADE), and lack of careful follow-up once large numbers of patients have been inoculated increases the risk of this problem. To my knowledge, and this is reassuring, everybody is going after the S protein as an epitope, which expert opinion suggests is both safer and possibly/probably more effective - but this review lists the S protein target as capable of eliciting ADE.

My bottom line is that rushing through this process makes it more likely that this kind of serious side effect may not be appreciated until it's out there in significant numbers. Perhaps I'm just chronically suspicious that the Trump administration can blow up almost anything, even things that are normally pretty responsibly managed.

Well, respectfully, I disagree. While you can never "fully exclude" a vaccine reaction due to antibody dependent enhancement, the molecular mechanism of that reaction is due to re-exposure of antigen epitopes. That would happen, and in a perfect manner, with 2nd and if needed 3rd doses of the vaccine. You are re-exposing someone to the same antigen epitopes they were sensitized to during the first innoculation. And those epitopes are only a subset of the total epitopes that the virus carries with a full viral exposure.


EDIT - the Moderna vaccine would be very unlikely to cause ADE, since it is only expressing a subset of the S protein.

The Oxford vaccine, if memory serves, is an inactivated vaccine that uses a different viral vector. The extra antigens in this would make it more likely to cause ADE.

 

[dfwatt]

Well, respectfully, I disagree. While you can never "fully exclude" a vaccine reaction due to antibody dependent enhancement, the molecular mechanism of that reaction is due to re-exposure of antigen epitopes. That would happen, and in a perfect manner, with 2nd and if needed 3rd doses of the vaccine. You are re-exposing someone to the same antigen epitopes they were sensitized to during the first innoculation. And those epitopes are only a subset of the total epitopes that the virus carries with a full viral exposure.


EDIT - the Moderna vaccine would be very unlikely to cause ADE, since it is only expressing a subset of the S protein.

The Oxford vaccine, if memory serves, is an inactivated vaccine that uses a different viral vector. The extra antigens in this would make it more likely to cause ADE.

I know you're probably very busy but I'd love to get your reaction to the whole paper. One of the clear implications is that dosage titration as well as epitopes are variables in whether or not this phenomena is elicited or not. Again that suggests that rushing a vaccine to Market increases the risk of this problem. That's my only point.

 

[bkp_duke]

I know you're probably very busy but I'd love to get your reaction to the whole paper. One of the clear implications is that dosage titration as well as epitopes are variables in whether or not this phenomena is elicited or not. Again that suggests that rushing a vaccine to Market increases the risk of this problem. That's my only point.

I read the paper, with a focus on the Coronavirus section. I believe that while there is some data to support ADE, the authors make logical leaps, specifically from animal studies, that there is simply not data in humans to support at this time. Having worked in animal models, I have had the unfortunate experience of having fantastic data not translate from animal cells to provide the same effect in human cells (and forget human studies).

In theory, based upon that review article, a vaccine based upon specific epitopes (the Moderna vaccine, or a more traditional antigen-based vaccine) should result in far less likelihood for ADE than a vaccine based upon live-attenuated or inactivated virus particles (i.e. whole-virus based vaccines).

This is another theoretical-based paper that looks at ADE in the context of COVID-19, but I cannot get anything but the first page to load. If you get a copy (and it has NOT been peer reviewed, so take it with a grain of salt), please send it my way.
https://www.nature.com/articles/s41586-020-2538-8_reference.pdf