Here’s a pass at my answers at present (2020/03/15)
Is this virus doing this in-vivo? What induces it?
At the moment, I’m leaning towards yes
Some other coronaviruses absolutely have it (ex: FIP, MERS)
in-vitro, they could get it to happen using SARS-1 vaccines containing S-protein
There are some white blood cell (WBC) anomalies, but what people are noticing is mostly T-cell reductions, a variety that shouldn’t be directly impacted by ADE (wrong receptors)
Possible alternative explanation for some of the white blood cell reductions: HSCs (the stem cells that make blood) or the thymus are being impacted in some way that reduces the rate of immune cell production. Some similar downstream effects, so you would probably have to test distal causes to differentiate this theory from ADE.
What exactly are the consequences of this ADE interaction? Can we pin it down to symptoms?
It’s not dengue (no hemorrhagic fevers here). So what are the symptoms of this? (Patients who previously had SARS-1 are probably the example to look at here.)
One preprint proposed that the current wide variance in severity is already caused by the presence/absence of this reaction with the antibodies an individual produces
Are there diagnostic tests that search for an ADE interaction? Are there high-specificity tests for ADE that are easier or faster than RNA-testing for SARS-2 in some cases?
Low T-cell counts are common in severe cases, but not specific to this illness and unlikely to be caused by ADE. High inflammation is even less specific.
How does this change things?
For vaccines, it probably means the most basic naiive S-protein-heavy vaccine types need to be thoroughly tested in animals and may not work as intended.
If this enters circulation as a recurring cold, ADE could leave me deeply concerned about multiple distinct subtypes evolving and existing over time. But I also find the proposal that this already is happening and is what causes variance in illness-severity pretty convincing, and in that case it may add up to the numbers we’re already seeing? Or maybe the post-SARS Chinese numbers? I’m torn.
Concrete prediction: People who had the SARS-1 or MERS vaccine previously (esp. if vs. S-protein, which most include) will tend to get a more severe case with SARS-2.
What can we do about it?
Vaccines <del>targeting just N-protein</del> (ETA: N-protein vaccines seem to still have in-vivo second-exposure issues) (or another viral protein) or antibody-based therapies might be able to route around this issue.
Here’s some of the papers I’ve looked at, and my interpretation (warning: this is messy).
Some (but not all) other coronaviruses, ex: FIP, have had vaccines that presented with this problem (imperfect antibodies against the vaccine resulted in increased severity of illness compared to baseline).
An in-vitro experiment suggesting that nCOV could use imperfect antibodies as a viable “anchor” for infecting white blood cells. Was tested using previous SARS-1 vaccines.
Interpretation: Assuming it’s the same case among SARS subtypes, antibodies against the spike-protein are a bad idea, but antibodies against other components of the virus (which don’t evolve as fast as the S-protein) seemed to work. The one N-protein vaccine didn’t have this bad effect.
Interpretation: in-vitro isn’t nearly as conclusive as in-vivo, though...
A preprint suggesting that ADE may already be part of why we have such wide variance in the severity of symptoms. Severe cases may be severe in part because of this exacerbating response to non-neutralizing antibodies.
Interpretation: Geez, this actually seems to match-up with the disease pattern well. The elderly have worse immune responses and tend to be more prone to poorly-constructed antibodies (resulting in things like ex: autoimmune responses), and the high-severity disease tends to happen late (around when the antibody-based adaptive immune response kicks in). I need to double-check, but if kids have better innate immune responses, it fits fantastically. <del>The white blood cell deficiencies which the paper mentions occur in the severe cases feels fairly conclusive to me.</del> (ETA: It’s Complicated; T-cells are unlikely to be affected by ADE, so it’s likely that something else is also going on here)
(ADE is likely to specifically affect Fc receptor bearing cells, which consist of: B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells. I need to run throgh the preprint on symptom-variance and double-check the types of WBC affected.)
Further Messy Scientific Interpetation: “T-predominant lymphopenia, high circulating levels of proinflammatory cytokines and chemokines, accumulation of neutrophils and macrophages in lungs, and immune dysregulation including immune supression.” T-cells are not generally Fc-binding outside of a brief window, so I wouldn’t expect them to be directly affected by ADE. This proposes that T-cell depletion may be a secondary effect, accelerated by the infection of phagocytic antigen-presenting cells (APCs, basically a major subset of Fc-receptor bearers). Their proposal of testing autophagy inhibitors as a treatment seems interesting. MERS apparently can infect T-cells (SARS-CoV-2 is not yet characterized wrt this, but I’d assume it does.), and both MERS and SARS-1 also induce T-cell depletion. Alternative theories for T-cell depletion were “sequestration of lymphocytes within the inflamed tissues, cytokine-induced cell death, as well as suppression of hematopoietic progenitor cells in bone marrow or thymus” (from a MERS-related source). My read is that cytokine-induced cell death could be an ADE consequence. But HSC (hematopoietic stem/progenitor cells) suppression is a different phenomenon that would result downstream in at least some similar consequences to ADE. Distinguishing between the two (ADE vs HSC supression) would require looking further-upstream at cause and effect. About “sequestration”, I don’t know anything.
T-cell exhaustion may have some bearing on this question, as either evidence or counter-evidence depending on whether the infected/dying immune cells are specifically Fc-bearing or not.
Interpretation: This might be evidence that something else is going on (worth at least a few points against), or it could be a secondary effect (neutral to positive). T-cells only express Fc receptor in a brief window following activation, and otherwise should be basically immune to direct ADE. In Dengue, even with mismatched antibody selection, high T-cells count is still considered quite protective (and low T-cell count dangerous). High ambient serum inflammatory cytokines and cell-death markers (PD-1) is hard for me to read a cause into, they could be released by a lot of different cells.
This proposes that China may have had a far-worse death rate in part because of exposure to previous cases of SARS-1.
Interpretation: At least a few points towards the hypothesis, but my prior was that a zoonotic disease straight-off-the-literal-bat would be more severe anyway. Update: Maybe not even that, the scenario it proposes is something I’d deem basically untestable.
Future prediction: People who had the SARS-1 or MERS vaccine previously (esp. if vs. S-protein, which most include) will tend to get more severe cases with SARS-2.
Interpretation: Observed ADE with SARS-1 in-vitro when using S-protein vaccines. ADE entry was mediated by Fcγ receptor II . Level of ADE effects varied by the specific vaccine.
I’m generally skeptical of the theory in that paper being provable at all unless they’re very careful. There are just so many possible confounders.
(I had actually only skimmed it until now. Its theory seems to be that some low-symptom coronavirus cold did the priming? Ugh, given our current viral monitoring habits (bad), that sounds like a hopeless non-starter for study.)
I haven’t compared the exact death-rates. Off the top of my head, I remember Italy generating the impression that hospital overflow can make a difference that changes 0.5% to 4% in death rates, but I didn’t question or dissect it.
About the death rates I feel pretty informed (unlike with ADE), and I think there’s nothing that needs to be explained that isn’t already likely covered by varying degrees of hospital crowding and (in Italy’s case) demographics such as the early outbreak starting primarily in hospitals (as opposed to Germany where it started disproportionally in travellers who visited affected places).
Edit: It would be concerning to see unusually high death rates in countries that don’t seem to have hospital crowding yet, but I’m not aware of any such examples. The difference between death rates in France and Italy (high) and Germany (very low) are possibly worth looking into, but even that seem to me like it can be explained well through other factors (Germany had really good testing, and again demographics – it just makes a huge difference if the virus ever hits an entire hospital or nursing home or Church with elderly demographic).
Even though I don’t know enough biology to understand what you two are discussing, it sounds pretty concerning! :/
I’m just commenting because I have a suggestion about a possible data point to check (and maybe it’s a total non-starter). Singapore doctors seem to have noticed that quick tests for Dengue virus test “positive” (for Dengue) on some Covid-19 patients. The doctors say it’s because the viruses are similar also biologically. Maybe looking at what these tests target could be useful here?
And personally I’d be curious about more context on the implications of the above hypothesis – whether there’s anything you can say about risk factors for a particularly severe disease runout. For instance, is it good or bad if someone had especially many or especially few colds in the last 2 years? Or lifetime? Etc. (Of course, no need to reply, esp. because my questions may not make much sense..)
Flipped through the article, my guess is that it was a case of “Person X was infected with both (or used to have Dengue), and they tested Dengue first so they dismissed them without even considering that they had both!”
(Antibody-tests are usually highly-specific, and Dengue and Coronavirus are pretty different viruses, so I’m inclined to trust that the “Dengue +” result was correct and just how they handled that information was wrong.)
The idea of “if you’ve had a wide variety of other colds in a past, maybe you’ll get it worse” actually sounds like a fairly good one! But also, there’s probably some other reason they are getting more and worse illnesses in the first place? Would be hard to separate out the causes.
Update 2020/04/02 : See second answer
V1.3
Here’s a pass at my answers at present (2020/03/15)
Is this virus doing this in-vivo? What induces it?
At the moment, I’m leaning towards yes
Some other coronaviruses absolutely have it (ex: FIP, MERS)
in-vitro, they could get it to happen using SARS-1 vaccines containing S-protein
There are some white blood cell (WBC) anomalies, but what people are noticing is mostly T-cell reductions, a variety that shouldn’t be directly impacted by ADE (wrong receptors)
Possible alternative explanation for some of the white blood cell reductions: HSCs (the stem cells that make blood) or the thymus are being impacted in some way that reduces the rate of immune cell production. Some similar downstream effects, so you would probably have to test distal causes to differentiate this theory from ADE.
What exactly are the consequences of this ADE interaction? Can we pin it down to symptoms?
It’s not dengue (no hemorrhagic fevers here). So what are the symptoms of this? (Patients who previously had SARS-1 are probably the example to look at here.)
One preprint proposed that the current wide variance in severity is already caused by the presence/absence of this reaction with the antibodies an individual produces
Are there diagnostic tests that search for an ADE interaction? Are there high-specificity tests for ADE that are easier or faster than RNA-testing for SARS-2 in some cases?
Low T-cell counts are common in severe cases, but not specific to this illness and unlikely to be caused by ADE. High inflammation is even less specific.
How does this change things?
For vaccines, it probably means the most basic naiive S-protein-heavy vaccine types need to be thoroughly tested in animals and may not work as intended.
If this enters circulation as a recurring cold, ADE could leave me deeply concerned about multiple distinct subtypes evolving and existing over time. But I also find the proposal that this already is happening and is what causes variance in illness-severity pretty convincing, and in that case it may add up to the numbers we’re already seeing? Or maybe the post-SARS Chinese numbers? I’m torn.
Concrete prediction: People who had the SARS-1 or MERS vaccine previously (esp. if vs. S-protein, which most include) will tend to get a more severe case with SARS-2.
What can we do about it?
Vaccines <del>targeting just N-protein</del> (ETA: N-protein vaccines seem to still have in-vivo second-exposure issues) (or another viral protein) or antibody-based therapies might be able to route around this issue.
Here’s some of the papers I’ve looked at, and my interpretation (warning: this is messy).
Some (but not all) other coronaviruses, ex: FIP, have had vaccines that presented with this problem (imperfect antibodies against the vaccine resulted in increased severity of illness compared to baseline).
An in-vitro experiment suggesting that nCOV could use imperfect antibodies as a viable “anchor” for infecting white blood cells. Was tested using previous SARS-1 vaccines.
Interpretation: Assuming it’s the same case among SARS subtypes, antibodies against the spike-protein are a bad idea, but antibodies against other components of the virus (which don’t evolve as fast as the S-protein) seemed to work. The one N-protein vaccine didn’t have this bad effect.
Interpretation: in-vitro isn’t nearly as conclusive as in-vivo, though...
A preprint suggesting that ADE may already be part of why we have such wide variance in the severity of symptoms. Severe cases may be severe in part because of this exacerbating response to non-neutralizing antibodies.
Interpretation: Geez, this actually seems to match-up with the disease pattern well. The elderly have worse immune responses and tend to be more prone to poorly-constructed antibodies (resulting in things like ex: autoimmune responses), and the high-severity disease tends to happen late (around when the antibody-based adaptive immune response kicks in). I need to double-check, but if kids have better innate immune responses, it fits fantastically. <del>The white blood cell deficiencies which the paper mentions occur in the severe cases feels fairly conclusive to me.</del> (ETA: It’s Complicated; T-cells are unlikely to be affected by ADE, so it’s likely that something else is also going on here)
(ADE is likely to specifically affect Fc receptor bearing cells, which consist of: B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells. I need to run throgh the preprint on symptom-variance and double-check the types of WBC affected.)
Further Messy Scientific Interpetation: “T-predominant lymphopenia, high circulating levels of proinflammatory cytokines and chemokines, accumulation of neutrophils and macrophages in lungs, and immune dysregulation including immune supression.” T-cells are not generally Fc-binding outside of a brief window, so I wouldn’t expect them to be directly affected by ADE. This proposes that T-cell depletion may be a secondary effect, accelerated by the infection of phagocytic antigen-presenting cells (APCs, basically a major subset of Fc-receptor bearers). Their proposal of testing autophagy inhibitors as a treatment seems interesting. MERS apparently can infect T-cells (SARS-CoV-2 is not yet characterized wrt this, but I’d assume it does.), and both MERS and SARS-1 also induce T-cell depletion. Alternative theories for T-cell depletion were “sequestration of lymphocytes within the inflamed tissues, cytokine-induced cell death, as well as suppression of hematopoietic progenitor cells in bone marrow or thymus” (from a MERS-related source). My read is that cytokine-induced cell death could be an ADE consequence. But HSC (hematopoietic stem/progenitor cells) suppression is a different phenomenon that would result downstream in at least some similar consequences to ADE. Distinguishing between the two (ADE vs HSC supression) would require looking further-upstream at cause and effect. About “sequestration”, I don’t know anything.
T-cell exhaustion may have some bearing on this question, as either evidence or counter-evidence depending on whether the infected/dying immune cells are specifically Fc-bearing or not.
Interpretation: This might be evidence that something else is going on (worth at least a few points against), or it could be a secondary effect (neutral to positive). T-cells only express Fc receptor in a brief window following activation, and otherwise should be basically immune to direct ADE. In Dengue, even with mismatched antibody selection, high T-cells count is still considered quite protective (and low T-cell count dangerous). High ambient serum inflammatory cytokines and cell-death markers (PD-1) is hard for me to read a cause into, they could be released by a lot of different cells.
This proposes that China may have had a far-worse death rate in part because of exposure to previous cases of SARS-1.
Interpretation: At least a few points towards the hypothesis, but my prior was that a zoonotic disease straight-off-the-literal-bat would be more severe anyway. Update: Maybe not even that, the scenario it proposes is something I’d deem basically untestable.
Future prediction: People who had the SARS-1 or MERS vaccine previously (esp. if vs. S-protein, which most include) will tend to get more severe cases with SARS-2.
SARS-1 ADE
Interpretation: Observed ADE with SARS-1 in-vitro when using S-protein vaccines. ADE entry was mediated by Fcγ receptor II . Level of ADE effects varied by the specific vaccine.
Does Italy fit that line of thought?
I’m generally skeptical of the theory in that paper being provable at all unless they’re very careful. There are just so many possible confounders.
(I had actually only skimmed it until now. Its theory seems to be that some low-symptom coronavirus cold did the priming? Ugh, given our current viral monitoring habits (bad), that sounds like a hopeless non-starter for study.)
I haven’t compared the exact death-rates. Off the top of my head, I remember Italy generating the impression that hospital overflow can make a difference that changes 0.5% to 4% in death rates, but I didn’t question or dissect it.
I don’t think Italy has ever seen SARS before.
About the death rates I feel pretty informed (unlike with ADE), and I think there’s nothing that needs to be explained that isn’t already likely covered by varying degrees of hospital crowding and (in Italy’s case) demographics such as the early outbreak starting primarily in hospitals (as opposed to Germany where it started disproportionally in travellers who visited affected places).
Edit: It would be concerning to see unusually high death rates in countries that don’t seem to have hospital crowding yet, but I’m not aware of any such examples. The difference between death rates in France and Italy (high) and Germany (very low) are possibly worth looking into, but even that seem to me like it can be explained well through other factors (Germany had really good testing, and again demographics – it just makes a huge difference if the virus ever hits an entire hospital or nursing home or Church with elderly demographic).
Even though I don’t know enough biology to understand what you two are discussing, it sounds pretty concerning! :/
I’m just commenting because I have a suggestion about a possible data point to check (and maybe it’s a total non-starter). Singapore doctors seem to have noticed that quick tests for Dengue virus test “positive” (for Dengue) on some Covid-19 patients. The doctors say it’s because the viruses are similar also biologically. Maybe looking at what these tests target could be useful here?
And personally I’d be curious about more context on the implications of the above hypothesis – whether there’s anything you can say about risk factors for a particularly severe disease runout. For instance, is it good or bad if someone had especially many or especially few colds in the last 2 years? Or lifetime? Etc. (Of course, no need to reply, esp. because my questions may not make much sense..)
Flipped through the article, my guess is that it was a case of “Person X was infected with both (or used to have Dengue), and they tested Dengue first so they dismissed them without even considering that they had both!”
(Antibody-tests are usually highly-specific, and Dengue and Coronavirus are pretty different viruses, so I’m inclined to trust that the “Dengue +” result was correct and just how they handled that information was wrong.)
The idea of “if you’ve had a wide variety of other colds in a past, maybe you’ll get it worse” actually sounds like a fairly good one! But also, there’s probably some other reason they are getting more and worse illnesses in the first place? Would be hard to separate out the causes.