Incidentally, also strong evidence against it being a lab-strain. It’s a wild strain.
Closest related viruses: bats and Malayan pangolins
Mutation Descriptions
Polybasic Cleavage Sites (PCS): They seem to have something to do with increased rates of cell-cell fusion (increased rate of virus-induced XL multi-nucleated cells). Mutations generating PCS have been seen in Influenza strains to increase their pathogenicity, and they had similar effects in a few other viruses. So it’s not exactly increasing virus-cell fusion, it’s actually… increasing the rate at which infected cells glom into nearby cells. Fused cells are called syncytia.
O-linked glycans : Are theorized (with uncertainty) to help the virions masquerade as mucin, so hiding from the immune system. (Mutation unlikely to evolve in a lab on a petri dish)
Arguments strongly in favor of it being a wild strain
It’s not that similar to one of the known lab-strains, so it probably was wild
The “polybasic cleavage site” and “O-linked glycans” mutations would have required a very human-like ACE-protein binding site, so basically only human or ferret cells
O-linked glycans are usually evolved as an immune defense, which isn’t something cell cultures do.
(I’ve repeatedly had to update in the direction of it being plausible, and I currently think it’s more-likely-than-not to be a factor that will complicate vaccine development.)
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. The white blood cell deficiencies which the paper mentions occur in the severe cases feels fairly conclusive to me.
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.
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.
(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.)
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.
I am under the impression from a few case-studies that people have high-virus-titer a day before, and at least a few days after symptoms appear. Including mild symptoms.
It was hard to find conclusive studies on how long after symptoms the mild cases retain a high virus titer, but a German mild case still had high titer 2 days post-symptoms. Probably longer than that.
Additional impressions: Fever is pretty common and incriminating (but case-studies elsewhere suggest it isn’t always the first symptom to show up!), runny nose is rare (although I’ve heard it’s more common in mild child cases).
CIDRAP seems to confirm my impression that “6ft distance from people” came from assuming that the only relevant transmission method was distance-of-large-droplets-from-cough/sneeze. Aerosols describe transmission via fine droplets over much larger distances, and are exemplified in Influenza transmission.
This CIDRAP article suggests that SARS-CoV-2 aerosol transmission is at least plausible since it had been demonstrated in MERS.
(Quick side sanity-checks: The SARS virion is 1.2x the size of Influenza’s, the R0 is higher than Influenza’s but over a longer time-period. Aerosol transmission feels plausible to me.)
My nCOV/SARS-CoV-2 research head until I figure out exactly where to post things.
Things to post next: Link and summary of the research into the nCOV spike-protein mutations.
Paper on some of nCOV’s mutations
Incidentally, also strong evidence against it being a lab-strain. It’s a wild strain.
Closest related viruses: bats and Malayan pangolins
Mutation Descriptions
Polybasic Cleavage Sites (PCS): They seem to have something to do with increased rates of cell-cell fusion (increased rate of virus-induced XL multi-nucleated cells). Mutations generating PCS have been seen in Influenza strains to increase their pathogenicity, and they had similar effects in a few other viruses. So it’s not exactly increasing virus-cell fusion, it’s actually… increasing the rate at which infected cells glom into nearby cells. Fused cells are called syncytia.
O-linked glycans : Are theorized (with uncertainty) to help the virions masquerade as mucin, so hiding from the immune system. (Mutation unlikely to evolve in a lab on a petri dish)
Arguments strongly in favor of it being a wild strain
It’s not that similar to one of the known lab-strains, so it probably was wild
The “polybasic cleavage site” and “O-linked glycans” mutations would have required a very human-like ACE-protein binding site, so basically only human or ferret cells
O-linked glycans are usually evolved as an immune defense, which isn’t something cell cultures do.
The possibility of Antibody-Dependent Enhancement looks very real, to me.
(I’ve repeatedly had to update in the direction of it being plausible, and I currently think it’s more-likely-than-not to be a factor that will complicate vaccine development.)
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. The white blood cell deficiencies which the paper mentions occur in the severe cases feels fairly conclusive to me.
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.
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.
(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.)
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.
I know FIP as feline infectious peritonitis
Is that what you are referring to?
I am under the impression from a few case-studies that people have high-virus-titer a day before, and at least a few days after symptoms appear. Including mild symptoms.
It was hard to find conclusive studies on how long after symptoms the mild cases retain a high virus titer, but a German mild case still had high titer 2 days post-symptoms. Probably longer than that.
Symptom frequency chart via ourworldindata
Additional impressions: Fever is pretty common and incriminating (but case-studies elsewhere suggest it isn’t always the first symptom to show up!), runny nose is rare (although I’ve heard it’s more common in mild child cases).
CIDRAP seems to confirm my impression that “6ft distance from people” came from assuming that the only relevant transmission method was distance-of-large-droplets-from-cough/sneeze. Aerosols describe transmission via fine droplets over much larger distances, and are exemplified in Influenza transmission.
This CIDRAP article suggests that SARS-CoV-2 aerosol transmission is at least plausible since it had been demonstrated in MERS.
More recently, this aerosol and surface stability preprint says the SARS-CoV-2 virions remained viable as an aerosol for 3 hours.
(Quick side sanity-checks: The SARS virion is 1.2x the size of Influenza’s, the R0 is higher than Influenza’s but over a longer time-period. Aerosol transmission feels plausible to me.)