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Andre Watson 🧬💊🌎🎹 Profile picture
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16 Apr, 17 tweets, 4 min read
Compiling some research on risk of antibody-dependent enhancement (#ADE)...

It's important to emphasize that this does not reflect support of vaccine hesitance, and that the data on vaccine efficacy is extremely good.

[Thread on recent scientific articles to keep in mind...]
It would be good to include broader antibody panels separating "good" neutralizing antibodies from potentially deleterious antibodies and correlating this to strain emergence... the concern is not just the neutralizing sites at the ACE2-binding interface and "good" antibodies.
While the public health benefit of vaccines is huge, and COVID is orders of several magnitude more dangerous to older populations than vaccination, we should remain vigilant about these potential issues emerging over time, and preempt the problem with better immunomodulators.
More antibodies, when you also generate more antibodies that are potentially deleterious against the "sides" of the spike protein, will not necessarily mean that the virus mutates to be less pathogenic. I have posted more about this the last few days.
We must gather better data on the balance of antibodies and whether rare events / individuals with autoimmunity / individuals with more side effects to vaccination have greater activity of Class IV antibodies against the spike protein RBD in particular.
frontiersin.org/articles/10.33…
nature.com/articles/s4156…
nature.com/articles/s4158…
ncbi.nlm.nih.gov/pmc/articles/P…
osf.io/hqtnp
swprs.org/israel-why-is-…

All-cause mortality in Israel for 65+ appears to be increasing in the first two weeks of March. Are we missing data on side effects and rare events, or are new strains evading immune responses? These data are early and only just emerging.
several orders of magnitude*
For 65+, risk of dying of COVID is a double digit percentage, versus risk of dying from vaccine is ~1 in a million... so it is more about the side effects and rare events that are sub-lethal, not overall lethality that is the subject of concern here...
Ideally outlining these concerns and encouraging a broader discourse about sub-lethal effects should inform drug and vaccine development going forward. We must look at all of the edge cases and trends, not just overall lethality.
Group IV* antibodies

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More from @nanogenomic

Andre Watson 🧬💊🌎🎹 Profile picture
15 Apr
Phenomenal paper from the @jbloom_lab exploring neutralization by antibodies from recovered versus vaccinated individuals and examining all possible mutations at the receptor binding motifa—the portion that binds to ACE2–of the virus.
Using yeast display technology, where the yeast fluoresces, they expressed a few thousand mutant versions of the spike protein receptor binding domain and exposed each mutant to serum from convalescent vs. vaccinated individuals.
They then took key mutants and infected ACE2-expressing cells with pseudotyped lentiviruses producing each key receptor binding domain.
Read 13 tweets
Andre Watson 🧬💊🌎🎹 Profile picture
6 Jan
THREAD
“Most people who recover from COVID-19 develop immune memory that lasts for at least six to eight months, a NIAID-funded study suggests. The findings, published today in Science, are based on analysis of blood samples from 188 people who recovered from infection.” - NIAID
“Neutralizing antibodies have generally not correlated with lessened COVID-19 disease severity... Instead, neutralizing antibodies are associated with protective immunity against secondary infection with SARS-CoV-2.”

science.sciencemag.org/content/early/…
“While sterilizing immunity against viruses can only be accomplished by high-titer neutralizing antibodies, successful protection against clinical disease or death can be accomplished by several other immune memory scenarios.”
Read 20 tweets
Andre Watson 🧬💊🌎🎹 Profile picture
30 Dec 20
1/4 SARS-CoV-2 Orf6 appears to hijack nuclear import machinery, inhibiting nuclear translocation of key signaling and cell proliferation molecules such as STAT1 and STAT2. This is another way that SARS-CoV-2 downregulates intracellular immune responses such (e.g. interferon --).
2/4 These findings also meld with prior data demonstrating nuclear translocation of SARS-CoV-2. Coupled, these data suggest that the virus has evolved multiple mechanisms for avoiding both extracellular adaptive immune responses, as well as intracellular immunity / host defenses.
3/4 These findings could also lead to future discoveries about the genesis and pathogenesis of "long COVID" and repeat infections, coupled to the discovery of SARS-CoV-2 building up deep in tissues that are not as accessible to the immune system.
Read 4 tweets
Andre Watson 🧬💊🌎🎹 Profile picture
29 Dec 20
After hours at the DMV, at closing, a DMV employee comes out and says “All hope is lost, there is no point, everyone should go home.” I said that’s the most earnest, honest depressing thing I’ve heard all day.

“Well, it could be worse. You could have my job,” she says.
“Sorry, we are at full capacity.” (4:30 PM)
This is the sixth time I’ve tried to go to the DMV to renew my license.
Read 4 tweets
Andre Watson 🧬💊🌎🎹 Profile picture
21 Jul 20
We took this image of CRISPR-Cas9 (green) being delivered to a T cell using our targeting peptide tech, which was the first demonstration of CRISPR delivery to a primary human T cell with a non-viral nanocarrier as of 2018, AFAIK. We achieved 34% editing.

Credit: @Ligandal
Green: CRISPR-Cas9 ribonucleoprotein delivered via peptide nanocarriers
Blue: nucleus
Red: cytosol
Scale bar: 500 nanometers
Imaging: super-resolution microscopy
Using this sort of tech, you can target and manipulate specific cell types with arbitrary genetic code, both in permanent (e.g. CRISPR-Cas9) and temporary (e.g. mRNA) ways. T cell editing is particularly relevant in the fields of immuno-oncology and autoimmune diseases.
Read 4 tweets
Andre Watson 🧬💊🌎🎹 Profile picture
20 Jul 20
VACCINES AND IMMUNITY

My ACE2 cloak hypothesis is shifting a bit. Soluble and membrane-bound ACE2 is clearly not fully saturating all exposed neutralizing antibody sites, and some B cells are binding. Still, ACE2 cloaking suggests that small numbers of virus get fully cloaked.
Alternatively to the ACE2 cloaking, the virus still has some shielding mechanisms alternative to that including glycosylation and going from closed to open conformations. In “open” state, ACE2 would bias the thermodynamics of B cell binding to the spike protein...
...and the subsequent antibody-generating response, to be preferential to other sites. Doesn’t mean that B cells won’t stick to neutralizing site at all.

This is in a large part driven by ACE2 existing both as a soluble and membrane-bound protein.
Read 17 tweets

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