Thread by @nanogenomic

Some research on changes in neutralizing antibody potency of some SARS-CoV-2 variants of concern (VOC): namely, 1) E484K, 2) N501Y, 3) ∆69/70 + N501Y + D614G, and 4) E484K + N501Y + D614G. Out of these VOCs, E484K mutants are showing greatest escape potency for vaccinated serum.

E484K:
"SARS-CoV-2 spike E484K mutation reduces antibody neutralisation"
thelancet.com/journals/lanmi…

N501Y:
"The N501Y mutation in SARS-CoV-2 spike leads to morbidity in obese and aged mice and is neutralized by convalescent and post-vaccination human sera"
medrxiv.org/content/10.110…

∆69/70, E484 and N501Y vs. ∆69/70, N501Y, D614G:
"Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K and N501Y variants by BNT162b2 vaccine-elicited sera"
nature.com/articles/s4159…

L452R:
California mutant (not in infographic)
"Transmission, infectivity, and neutralization of a spike L452R SARS-CoV-2 variant"
cell.com/cell/pdf/S0092…

In vivo, another important factor to consider will be how higher binding affinity mutants have soluble ACE2 competing with some of the neutralizing antibody binding sites, and how the soluble ACE2 may create an even stronger antibody escape through this mechanism we discovered.

We demonstrated that soluble ACE2 can potently reduce the binding of soluble neutralizing antibody to the receptor binding domain of the spike protein in our study with UCSF last year. This needs to be studied in the context of new variants.

biorxiv.org/content/10.110…

Studies claiming to study neutralization should be including soluble ACE2 along with antibodies, though this is harder to model ex vivo. In vivo, soluble ACE2 is likely preventing Fc receptor mediated degradation of the virus and should be explored for its role in "long-COVID."

I posit that in sub-acute infectious states, people may be experiencing prolonged immune evasion of small amounts of virus getting cloaked in soluble ACE2, which could explain persistent immune evasion despite the presence of neutralizing antibodies.

When you couple new mutants and strains having increased binding affinity for ACE2 while also having decreased binding affinity for antibodies, this could explain some persistent infections.

Thankfully, the neutralizing site that prevents ACE2 binding directly is not the only site where antibodies are generated, though this site is more preferentially responded to in naturally recovered individuals versus vaccinated individuals. See more:

https://twitter.com/nanogenomic/status/1382725260148043780

https://twitter.com/nanogenomic/status/1382725218926432261

https://twitter.com/nanogenomic/status/1382761155437883392

I'd love to see whether soluble ACE2-cloaked virions are penetrating deeper into organs where antibody-mediated immunity may be weaker, with less B- and T-cell penetration, and whether SARS-CoV-2 is building up in hypoxic niches with less active cellular immunity.

It will also be important to study how various HLA alleles across populations (membrane proteins that present pieces of antigens for your immune system to see) factor into potential immune evasion from T cells with new mutants.

en.wikipedia.org/wiki/Human_leu…

nature.com/articles/s1003…

Vaccines are protecting us, though there is potential for variants that will further escape both vaccinated individuals and naturally recovered individuals. The best thing we can do is to vaccinate as many people as possible, and aggressively pursue therapeutics in parallel.

threadreaderapp.com/thread/1386959…

See also for South Africa strain (501.V2):

nature.com/articles/s4158…

“Moreover, compared to wild-type SARS-CoV-2, B.1.351 is markedly more resistant to neutralization by convalescent plasma (9.4-fold) and sera from individuals who have been vaccinated (10.3–12.4-fold).”