Thread by @nanogenomic

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.

https://twitter.com/jbloom_lab/status/1382475939678855169

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.

They found that vaccinated serum was more potent at abolishing infection in the pseudotyped lentivirus infections than convalescent serum with the new spike mutation variants out there.

I think further studies examining how ACE2 and potentially disease-enhancing antibodies and their titers play a role in pathogenesis as strains evolve will be necessary going forward, and in the interim these are encouraging findings for new strains.

Will also be good to explore infection-enhancing antibodies being of very high titer and playing a role in potential disease enhancement with ACE2 shielding the neutralizing sites. I have not seen this studied enough.

Group IV antibodies against the RBD can show neutralizing activity while also acting as Fc-dependent infection-enhancing antibodies via antibody-dependent enhancement, and that mutations in these sites can yield enhanced binding.

sciencedirect.com/science/articl…

In the above "Enhancement versus neutralization by SARS-CoV-2 antibodies...", some mutants in the ~370-385 range, as well as 342 and 339 AA positions of the RBD, can lead to enhanced binding of these neutralizing Class IV antibodies that can potentially be disease enhancing.

It will be important to factor in the increased KD (binding affinity) of some of the new strains against the ACE2 receptor and therefore the reduced neutralization potential of antibodies against these sites. Couple this to Class IV antibody infection-enhancement.

In the paper referenced in the original post from the Bloom lab, 2/14 of the vaccine recipients had greatest sensitivity to mutations at these Class IV sites... what does this mean? We will need to look at how this affects emerging strain immunity.

Producing extremely high titers of antibodies against all sites of the RBD, in a way that is greater than the more RBM-focused antibody generation against actual infection, could yield disease enhancement down the line.

More focus on the immune evasive, potential infection-enhancing, and ACE2 competition with antibody binding is warranted. Certainly, immunity is not binary — and there are many very good antibodies produced by vaccination, which is why we are seeing such strong clinical results.

It's important to emphasize that the vaccine efficacy is extremely high, and that clinical results are currently showing that all vaccines are extremely protective against severe and lethal COVID. This is something to keep in the back of our minds, though.