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The nerdy amounts of pandemic detail thread

A possible genetic link between Alzheimer's disease and severe COVID-19 outcomes (UCL and others).
Our data support a link between genetic risk for Alzheimer’s disease and susceptibility to critical illness with COVID-19 centred on [the gene] OAS1, a finding with potential implications for future treatments of Alzheimer’s disease and COVID-19, and development of biomarkers to track disease progression.
DOI: 10.1093/brain/awab337. (Alternate link).
 
Back to the S2 sub-unit again (note posts #111 and post #116) and investigations of infection and vaccine induced immunities (Fred Hutch/UWash). The epitopes and pathways of escape for spike antibodies from both convalescents and vaccinees (mRNA-1273 and BNT162b2) were profiled and potential escape mutations were identified in those epitope regions.

Recovering from severe infection or mRNA vaccination appears to elicit responses to more spike epitopes than mild infection.

They noted that the SH-H (stem-helix-HR2) epitope region in the S2 sub-unit - antibodies to which are commonly seen in mild cases (recall this tends to be preserved across HCoV genera so likely provides degrees of cross-reactive immunity from historic infections) - were also seen in non-convalescent vaccinees (cf original antigenic sin). This could potentially be a site for vaccine escape, but because this is highly conserved across HCoV (hence prior immunity cross-reactivity) - not least because it is associated with a fairly crucial part of this virus' architecture that likely helps facilitate cell entry - it might prove hard for a variant to escape here without substantially degrading fitness.

In contrast, convalescents and convalescent vaccinees exhibited strong antibody responses to four epitope regions: in the N-terminal and C-terminal domains of spike S1, in fusion peptide (FP) epitopes (adjacent to the S1/S2 furin cleavage site) and also to the S2 SH-H region.
Box plots of summed values of enrichment of wild-type peptides by serum antibodies for each sample within each of the four epitope sites considered.
Individuals with mild infection had antibodies that bound to epitopes in the S2 subunit within the fusion peptide and heptad-repeat [SH-H] regions, whereas vaccinated individuals had antibodies that additionally bound to epitopes in the N- and C-terminal domains of the S1 subunit, a pattern that was also observed in individuals with severe disease due to infection.
[...]
The finding that SARS-CoV-2 mRNA vaccination resulted in binding to additional epitopes beyond what was seen after infection suggests protection could vary depending on the route of exposure to spike antigen. The relatively conserved escape pathways to vaccine-induced antibodies relative to infection-induced antibodies suggests that if escape variants emerge, they may be readily selected for across vaccinated individuals. Given that the majority of people will be first exposed to spike via vaccination and not infection, this work has implications for predicting the selection of immune escape variants at a population level.
DOI: 10.1101/2021.10.05.463210.
 
An interesting dive (Duke) into maternal immunoresponse to SARS-CoV-2 infection and immunisation during pregnancy. In particular, an observed variation dependent on fetus gender. Might not be unrelated to gender asymmetries seen in adult cohorts.
Pregnancy and fetal sex influence the quality of antibody responses to SARS-CoV-2 infection and immunization.

Overall, the findings of this study suggest dynamic and divergent immune responses to SARS-CoV-2 in pregnant women based on fetal sex. Mothers with male fetuses had lower SARS-CoV-2 antibody titers [...] following infection and lower rates of anti-SARS-CoV-2 IgG transfer across the placenta. These observations have important implications for SARS-CoV-2 vaccination in male- versus female-expectant mothers and, following parturition, the care of at-risk male children.
DOI: 10.1126/scitranslmed.abm2070.
 
From Australia (Melbourne) an investigation comparing seroconversion in infected adults and children (non-hospitalised, mild episodes of COVID-19). Sampling was conducted May-October 2020 with all infections arising from early type virus.

Using three separate serological assays they found that (with high concordance) children were less likely to seroconvert than adults despite similar viral loads. Furthermore, evidence of cellular immunity was observed in adults who seroconverted but not in children who seroconverted.
Seropositivity rate in children and adults at convalescent period (median day 41) measured by three serological assays. Ex vivo cellular immune profile during convalescence period (median day 41). Clear box: PCR-/sero- (ie control group); dotted: PCR+/sero-; diagonal: PCR+/sero+.
Our data supports the concept that infection may not induce the robust cellular immune responses in children that are necessary for seroconversion as seen in adults.

Children are thought to have a more robust innate and/or mucosal immune response to SARS-CoV-2 than adults. This could explain why children in our study did not appear to trigger the adaptive immune system as well as adults. (*)
* Or alternatively: their immune systems are still learning/developing in their formative years.

This has implications for re-infection, future protection against disease and interpretation of serological survey results in children, for wider community transmission and the dynamics of transition to endemic state, and thus for offering vaccination to younger age cohorts.
DOI: 10.1101/2021.10.16.464660.

(Note: memory B cell observations in PCR-negative/seronegatives are not inconsistent with previous studies of cross-reactive immunity conferred by prior exposures to other betacoronaviridae).
 
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I didnt immediately find an obvious thread to put this one in so I'll stick it here for now:


The study found that patients who were very unwell with coronavirus had a significantly greater chance of dying over the next year, a trend that was particularly notable among those aged under 65. As these deaths frequently occurred long after the initial infection had passed, they may never have been linked to Covid-19 by the patients’ families or doctors, the study found.

Most of the deaths that occurred in severe Covid-19 survivors were not linked with common complications from the disease – 80% of such deaths occurred for a wide variety of reasons that are not typically associated with the virus.
 
From Italy, a potential explanation for severity of COVID-19 in the elderly.

During ageing, telomere dysfunction accumulates and activates a DNA damage response (DDR), leading to increase of ACE2, the human SARS-CoV-2 receptor. This mechanism may explain the higher susceptibility of elderly to COVID-19.
  • ACE2 expression increases with ageing in human and mouse lungs.
  • DNA damage response activation, including when triggered by telomere dysfunction, increases ACE2 expression levels.
  • Telomere-specific antisense oligonucleotide (ASO)-mediated telomeric DNA damage response inhibition prevents the increase of ACE2 levels in mice.
Age-related DNA damage response leads to increasing expression of ACE2.

DOI: 10.15252/embr.202153658.
 
The UK stats regulator get understandably snotty (Eds got the hump!) about both ONS and UKHSA publications which involved data on vaccines, and ended up with the potential to mislead in various tediously technical ways.

I'm sticking them here in case I need to reference them again in future. The criticisms probably dont affect my own use of such stats here. I've mostly used UKHSA ones as the ONS one didnt impress me due to the absurdly wide time period it covered. And I've tended to focus on absolute numbers in UKHSA reports rather than population rate estimates. Mostly because I've been trying to make a point about the burden on health care from the vaccinated, since so much of others peoples focus has been on the unvaccinated. Which also means I've not been undermining peoples impression of the effectiveness of vaccines, just that they cannot be expected to carry all of thepandemic burden alone.


 
Ex vivo pathology study (HKU) suggests that omicron/B.1.1.529 infects faster than delta/B.1.617.2 in the bronchus but less so in the lung. This might paint a picture of less severity of disease but higher overall transmission.
50% tissue culture infectious dose for early-type, delta and omicron measured ex vivo in bronchus and lung samples.
No preprint yet.
 
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Initially for individuals, but not subsequently for healthcare systems.

I saw an estimate of 29% reduced severity but didn't catch all the context (maybe the number will ring a bell for you). Obviously can still lead to a lot of serious problems (including direct and indirect deaths) with the ramped up transmission.
 
I saw an estimate of 29% reduced severity but didn't catch all the context (maybe the number will ring a bell for you). Obviously can still lead to a lot of serious problems (including direct and indirect deaths) with the ramped up transmission.

What would x% of relative severity mean? More/less likely to be fatal or based on some other metric/effect?
 
I saw an estimate of 29% reduced severity but didn't catch all the context (maybe the number will ring a bell for you). Obviously can still lead to a lot of serious problems (including direct and indirect deaths) with the ramped up transmission.
#582
 
What would x% of relative severity mean? More/less likely to be fatal or based on some other metric/effect?

Indeed - like I said, I don't know the context. I was half-listening to the news at the time.
And they didn't mention the obvious point about a big increase in numbers making it very much not a good news story.
 
Ex vivo pathology study (HKU) suggests that omicron/B.1.1.529 infects faster than delta/B.1.617.2 in the bronchus but less so in the lung. This might paint a picture of less severity of disease but higher overall transmission.
Point raised by biophysical chemist specialising in aerosols that this may increase transmission further through simply talking (as oppose to singing, coughing).
 
Am going to drop this one here as it is worth noting - an addendum to the MIT/Harvard study reported in the vaccine/treatments thread.

They also investigated the neutralisation patterns of two-dose and three-dose vaccinees between early wild-type, delta and omicron.
Cross-reactivity of neutralising antibody response is increased by mRNA vaccine booster relative to primary vaccination series - aggregate data from study participants for wild-type versus delta (left) and wild-type versus omicron (right). Third-doses administered at 6 months or later; sera collected within 3 months of last dose. (Two-dose primary series=white circles ; three-dose primary plus booster = grey squares).

Notably, before boosting (two-dose wild-type spike) delta neutralisation was poor-moderate and omicron neutralisation near non-existant (dashed line fit). After boosting (three-dose wild-type spike) much stronger and homogenous delta and omicron neutralisation patterns were seen (solid line fit), clearly hinting at SHM/AM.

The lab lead comments.
 
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Ex vivo pathology study (HKU) suggests that omicron/B.1.1.529 infects faster than delta/B.1.617.2 in the bronchus but less so in the lung. This might paint a picture of less severity of disease but higher overall transmission.
View attachment 300932
No preprint yet.
Building on this, an early report of work from Ravi Gupta's lab (Cambridge) which underscores some of the findings in vitro.

Omicron/B.1.1.529 spike expressed in a pseudovirus found to be less efficient at cell entry in alveolar organoids than delta/B.1.617.2 or early-type spike, with consequent implications for reduced syncitia formation and thus some severe disease outcomes.
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They also reproduced vaccine sera neutralisation results seen by others with significant reductions in both mRNA and viral vector vaccine efficacy after only two doses, but rescued by a third dose.

No preprint yet. Thread.
 
Am going to drop this one here as it is worth noting - an addendum to the MIT/Harvard study reported in the vaccine/treatments thread.

They also investigated the neutralisation patterns of two-dose and three-dose vaccinees between early wild-type, delta and omicron.
Cross-reactivity of neutralising antibody response is increased by mRNA vaccine booster relative to primary vaccination series - aggregate data from study participants for wild-type versus delta (left) and wild-type versus omicron (right). Third-doses administered at 6 months or later; sera collected within 3 months of last dose. (Two-dose primary series=white circles ; three-dose primary plus booster = grey squares).

Notably, before boosting (two-dose wild-type spike) delta neutralisation was poor-moderate and omicron neutralisation near non-existant (dashed line fit). After boosting (three-dose wild-type spike) much stronger and homogenous delta and omicron neutralisation patterns were seen (solid line fit), clearly hinting at HSM/AM.

The lab lead comments.

Sorry, what is HSM (immunology isn’t one of my strong points)?
 
Building on this, an early report of work from Ravi Gupta's lab (Cambridge) which underscores some of the findings in vitro.
Ravi has already extended this study and has noted a tropism shift in omicron/B.1.1.529 - they appear to have a mechanistic explanation for the apparent observed change in pathogenesis associated with this variant.

Whereas previous variants have made use of ACE2 for cell entry and then TMPRSS2 for cell-cell fusion, omicron appears to have a greatly reduced ability to take advantage of TMPRSS2 (probably has to rely largely on cathepsin L), most likely arising from the large number of changes at/around the S1/S2 furin cleavage site.
Fold change in TMPRSS2 mRNA between lower and upper respiratory tract cells.
TMPRSS2 expression in various respiratory tract cell types.
Entry of pseudovirus expressing omicron spike in cells transduced to overexpress ACE2 and either depleted for TMPRSS2 (A2▵T2) or overexpressing TMPRSS2 (A2T2).

Notably TMPRSS2 expression is significantly greater in the lower respiratory tract.
These in vitro data indicate that suboptimal Omicron S1/S2 cleavage reduces efficient infection of lower airway cells expressing TMPRSS2, but not TMPRSS2 negative cells such as those found in the upper airway.

Omicron has gained immune evasion properties whilst compromising cell entry in lung cells and ability to form syncytia.
DOI: 10.1101/2021.12.17.473248.
 
Delving into the replication kinetics of omicron/B.1.1.529 a little further...

Very preliminary work from a preprint of a live and pseudovirus study (Imperial, Pirbright) that indicates that omicron replicates much faster than delta/B.1.617.2 (and AY.4.2), and indeed outcompetes it in human nasal epithelial cells (upper respiratory tract), but omicron entry/replication is otherwise relatively attenuated in other cell line types (lung, ie lower respiratory tract).

Through flow cytometry they determined that (as shown in other studies) omicron continues to use ACE2 for cell entry rather than other receptors, and indeed it binds to human ACE2 to a greater extent than delta or alpha/B.1.1.7 spike.
Comparative replication kinetics of SARS-CoV-2 omicron and delta variants in vitro and ex vivo (URT and LRT cell lines). Competition assays between SARS-CoV-2 omicron (purple) and delta (green) isolates in vitro and ex vivo.
They reproduced results from other recent studies suggesting cell surface fusion of omicron, and thus syncytia formation, is greatly reduced compared to previous variants. Quite possibly this reduction in fusogenicity is down to epistatic interactions elsewhere in spike (ie how all the changes in spike play together) as similar S1/S2 adjacent 'point mutations' (notably N679K and P681H) in other variants have heretofore enhanced cleavage.

Using a pseudovirus assay they determined that omicron spike is more able to enter cells expressing ACE2 from a wider range of species than reported for previous SARS-CoV-2 variants. In particular, rat, horseshoe bat, mice and some birds. This could suggest an increased propensity for reverse zoonosis and likelihood of establishing animal reservoirs in those species (though undoubtably there are additional complicating factors associated with the biology, behavioural and environmental circumstances of each species that could either hinder or promote this being realised in each case).
Viral entry screening using pseudoviruses with indicated spike proteins for cell lines expressing various species' ACE2 receptors.

Next, using an assay to measure pseudovirus entry into different cell lines they investigated cell entry pathways. Omicron pseudovirus most efficiently entered cells lacking TMPRSS2 expression and, compared to previous VOCs, was less dependent on cells that express abundant TMPRSS2. They demonstrated that omicron spike is sensitive to innate inhibitors of endosomal entry, suggesting this is a preferred route for this particular variant.

Finally, using live virus in primary human airway cells they saw omicron replicate more rapidly than delta. Additionally, a TMPRSS2 inhibitor blocked delta replication but had no effect on omicron. They suggest that omicron can avoid the anti-viral effects of interferon-induced restriction factors which are features of innate immunity, which would otherwise disadvantage endosomal entry (a cell entry pathway not exploited by previous VOC).
Comparative replication kinetics of SARS-CoV-2 omicron and delta live virus variants in primary human nasal epithelial cultures (hNECs). Vehicle=no treatment; Camostat=TMPRSS2 inhibitor; AmphoB=Amphotericin B, an innate response enhancing anti-viral.
The study authors propose that omicron has become more generalised, being able to infect a larger number of upper airway cells, and suggest that perhaps it requires a lower infectious dose as a consequence.
Omicron is capable of efficiently entering cells in a TMPRSS2-independent manner, via the endosomal route. We posit this enables Omicron to infect a greater number of cells in the respiratory epithelium, allowing it to be more infectious at lower exposure doses, and resulting in enhanced intrinsic transmissibility.
DOI: 10.1101/2021.12.31.474653.
 
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Delving into the replication kinetics of omicron/B.1.1.529 a little further...

Very preliminary work from a preprint of a live and pseudovirus study (Imperial, Pirbright) that indicates that omicron replicates much faster than delta/B.1.617.2 (and AY.4.2), and indeed outcompetes it in human nasal epithelial cells (upper respiratory tract), but omicron entry/replication is otherwise relatively attenuated in other cell line types (lung, ie lower respiratory tract).

Through flow cytometry they determined that (as shown in other studies) omicron continues to use ACE2 for cell entry rather than other receptors, and indeed it binds to human ACE2 to a greater extent than delta or alpha/B.1.1.7 spike.
View attachment 304247 View attachment 304248
They reproduced results from other recent studies suggesting cell surface fusion of omicron, and thus syncytia formation, is greatly reduced compared to previous variants. Quite possibly this reduction in fusogenicity is down to epistatic interactions elsewhere in spike (ie how all the changes in spike play together) as similar S1/S2 adjacent 'point mutations' (notably N679K and P681H) in other variants have heretofore enhanced cleavage.

Using a pseudovirus assay they determined that omicron spike is more able to enter cells expressing ACE2 from a wider range of species than reported for previous SARS-CoV-2 variants. In particular, rat, horseshoe bat, mice and some birds. This could suggest an increased propensity for reverse zoonosis and likelihood of establishing animal reservoirs in those species (though undoubtably there are additional complicating factors associated with the biology, behavioural and environmental circumstances of each species that could either hinder or promote this being realised in each case).
View attachment 304250

Next, using an assay to measure pseudovirus entry into different cell lines they investigated cell entry pathways. Omicron pseudovirus most efficiently entered cells lacking TMPRSS2 expression and, compared to previous VOCs, was less dependent on cells that express abundant TMPRSS2. They demonstrated that omicron spike is sensitive to innate inhibitors of endosomal entry, suggesting this is a preferred route for this particular variant.

Finally, using live virus in primary human airway cells they saw omicron replicate more rapidly than delta. Additionally, a TMPRSS2 inhibitor blocked delta replication but had no effect on omicron. They suggest that omicron can avoid the anti-viral effects of interferon-induced restriction factors which are features of innate immunity, which would otherwise disadvantage endosomal entry (a cell entry pathway not exploited by previous VOC).
View attachment 304249
The study authors propose that omicron has become more generalised, being able to infect a larger number of upper airway cells, and suggest that perhaps it requires a lower infectious dose as a consequence.

Preprint pending.

Bold use of green and purple, but I think you have pulled it off. :thumbs:
 
Far from just the Irish government.
It’s totally cynical, though. You know there’s someone in the background who could explain it adequately to them.

I think that there is someone explaining it. Our CMO has resorted to Twitter to post warnjngs to the people of Ireland. The government tried to muzzle NPHET and stop them releasing statements before meeting with government but CMO wont be silenced. He has consistently been telling it like it is about the lack of beds and begging people to not meet up indoors over Christmas and new year. He even warned about shopping at sales. To do as much shipping as possinle online and avoid crowds indoors even if all are masked.
 
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