ADE and SARS-CoV-2 (death, compared, status, work)

[beachGecko]

Scientists have pretended this cannot occur even though this is predicted by the classical immunological model.

This study tested ER patients for markers of ADE and found them.

FcγR-mediated uptake of antibody-coated virus into monocytes is a double-edged sword. Pyroptosis, which occurs rapidly, likely aborts viral infection before infectious virions are fully assembled. Monocyte/ macrophage infection is a dead end for the virus - it removes virions from the extracellular milieu, blocks them from producing infectious progeny and prevents them from disseminating. Pyroptosis in infected monocytes/macrophages also sounds a potent immune alarm to recruit and activate innate and adaptive immune cells to infection sites to mobi- lize immune defense. On the other hand, the inflammatory mediators spewed out from pyroptotic monocytes and macrophages can cause cytokine storm. It may not be a coincidence that clinical deteriora- tion coincides temporally with the detection of SARS-CoV-2 antibody responses8,29,40. In fact, some recent studies suggest that higher anti- body titers correlate with disease severity29,40.
Pyroptotic myeloid cells are likely a major cause of the serious inflam- matory sequelae that lead to acute lung injury, multiorgan damage, vascular leak, and respiratory distress in patients with severe disease. In particular, severe COVID-19 patients had increased plasma biomarkers of pyroptosis compared to mild or moderate patients. However, neither antibody titers nor the proportion of infected ASC speck+ monocytes at presentation correlated with severe disease, perhaps because of the small number of samples. Larger cohorts are needed to better assess the relative importance of monocyte/macrophage pyroptosis in severe COVID-19 pathogenesis. The large numbers of infected monocytes and macrophages, the fact that a quarter of lung macrophages have activated inflammasomes and that myeloid cells are the major source of IL-1 and other inflammatory cytokines make it likely that monocyte/ macrophage infection and inflammasome activation are important in severe COVID-19 pathogenesis. Although neutrophils could poten- tially be infected, infection of freshly isolated COVID-19 neutrophils or in vitro-infected HD neutrophils was not detected. Thus, neutrophil infection is unlikely to be a major contributor to pathogenesis, although neutrophil activation of GSDMD-dependent netosis or other features of neutrophil activation may well be important drivers. It will be worth- while to study other infected cells as potential sources of inflammation, and to understand what aspects of monocyte/macrophage activation enhance infection.

https://www.nature.com/articles/s415..._reference.pdf

To put it in simple terms, to develop severe disease from COVID you need to have certain antibodies. I’ll write more on this later.

[bluesjuke]

Interesting and following.
Wonder what gives some those "certain antibodies".

[beachGecko]

Originally Posted by bluesjuke

Interesting and following.
Wonder what gives some those "certain antibodies".

So, they would be from infection with SARS-CoV-2. Monoclonals as well, according to the study but it wasn’t observed with vaccine generated antibodies according to the study. But let me explain everything in detail because this study you need to understand everything.

Let’s discuss how antibodies from SARS-CoV-2 leads to severe disease in infected persons. Your first question would naturally be: people infected generally don’t have antibodies to SARS-CoV-2.

So during infection you have several stages. But you begin producing antibodies at around day 3 to the virus. By day 7, a respiratory virus is generally maximally replicated and begins “in mass” throughout your body.

Yet in the vast majority of people, severe disease was observed at day 8-10. This was purely an ADE phenomenon.

The antibodies allowed (through their FcR) infection of macrophages and monocytes by the virus. This only happens to around 6% of the monocytes who phagocytose (eat) the virus but when the virus is maximally replicated, 6% can translate into a large number of infected monocytes.

When these monocytes become infected, they pyroptosis (die and release strongly inflammatory cytokines). The study showed the endothelial and epithelial cells in the lungs was not infected and cell death was due to this mechanism. In other words, this virus does not attack your lung tissue, your immune system does.

Now, let’s look at this study. They took 22 blood samples from COVID ER patients (severe disease) and plasma from healthy donors (no infection) as well as some plasma from healthy vaccinated individuals.

They didn’t observe this effect from the plasma of vaccinated donors (their study is in vitro but uses plasma from patients). They attributed this to something called Afucosylated antibodies.

When your body makes antibodies to enveloped viruses, the antibodies are afucosylated (the FcR has missing glucose) which allows them to bind to CD16 receptors on monocytes more efficiently. When your body makes antibodies to viruses without envelopes (or antigen from vaccine) they tend to be fucosylated. They theorize this is why.

So some points on this. They used samples from severe ER patients (and they did not specify vaccinated status) but used plasma from healthy vaccinated individuals. So it could be that some people produce an antibody to a certain epitope of the virus that were present in the plasma of all the severe cases.

Either way I’m not convinced with their conclusion on vaccine generated antibodies. I think more studies need to be done, especially with varying concentrations of Ab levels as the Ab levels quickly wane from the vaccines.

They mention they observed this ADE with Monoclonals. I think there is 3 important concepts to remember:

1. Monoclonals need to be taken early to work. Taken late in the disease they can make things worse. Since roughly only 6% of monocytes become infected after phagocytosis of the virus, you need a lot of virus to see this effect. Taken inside 3 days, viral levels will be still low and the Monoclonals will mop up the virus. Taken later, and ADE begins to occur.
2. Monoclonals can be made by disabling their FcR, not sure why they weren’t in this case, but all future Monoclonals should be made as such.
3. Monoclonals we have are all anti-Spike IgG antibodies. IgA dimeric antibodies do not have the capacity to cause ADE and neither do IgM (by this mechanism). Most healthy individuals produce IgA antibodies to a respiratory virus. There is something wrong with you to produce a IgG response if you’re healthy.

So in summary
1. First study to show in vitro that ADE occurs
2. More studies need to be done on antibody responses from vaccines
3. Implications for engineering Monoclonals
4. This study corresponds nicely with an earlier study that showed people with severe disease had higher concentrations of antibodies than people with mild disease. Asymptomatic people had no antibodies or very little.