SARS-CoV-2 Evolution: Examining the Concordance Between Actual Evolution and Experiments

Updated SARS-CoV-2 RBD antibody escape calculator at (https://t.co/dr4oGW03G0) now shows escape from antibodies that neutralize XBB & BQ.1.1

(Previously it only showed escape relative to earlier variants).

Here I'll briefly recap some of the most interesting insights. pic.twitter.com/ipsiSncbJi

— Bloom Lab (@jbloom_lab) March 9, 2023

As reminder, escape calculator (https://t.co/h7TEjQeQ8R) visualizes deep mutational scanning measurements to show key sites of escape.

All new data come from excellent recent study by @yunlong_cao et al that makes measurements for 1000s of antibodies (https://t.co/iShFOOEwc2)

— Bloom Lab (@jbloom_lab) March 9, 2023

If we look at escape calculator over progressively newer variants, we can see SARS-CoV-2 is increasingly evolving to change sites most potently targeted by neutralizing antibodies.

In other words, there is incredible concordance between actual evolution and experiments.

— Bloom Lab (@jbloom_lab) March 9, 2023

First let's look at evolution from Wuhan-Hu-1 to BA.2. Gray line is sites targeted by antibodies that neutralize Wuhan-Hu-1; blue line shows BA.2 escaped many of them.

However, in BA.2 only some mutations (eg E484A, K417N) strongly antigenic, suggesting other pressures too. pic.twitter.com/U1KtKRsYck

— Bloom Lab (@jbloom_lab) March 9, 2023

After BA.2, we had BA.5.

Below gray is sites most targeted by antibodies that neutralize BA.2, and BA.5 has escaped some of them via L452R and F486V. pic.twitter.com/Yiw8WlBr4g

— Bloom Lab (@jbloom_lab) March 9, 2023

Then BA.5 begat BQ.1.1. Note how BQ.1.1 acquired mutations at the two sites (K444 and R346) that best escaped antibodies that neutralized BA.5, demonstrating strong antigenic selection. pic.twitter.com/IkzMVujK2I

— Bloom Lab (@jbloom_lab) March 9, 2023

In parallel, XBB.1.5 evolved from BA.2. You can see how XBB.1.5 acquired mutations at many of the specific sites that most strongly escaped antibodies that neutralized BA.2. pic.twitter.com/mPjUIj2yst

— Bloom Lab (@jbloom_lab) March 9, 2023

This fact that XBB.* has mostly escaped the major RBD specificities is why it is neutralized very poorly as compared to other variants.

This has been shown by many studies, below is one by @veeslerlab: https://t.co/BOYy3Cib0e

— Bloom Lab (@jbloom_lab) March 9, 2023

So what are the next escape mutations in XBB with respect to neutralizing antibodies elicited by current vaccine strains and earlier Omicron breakthroughs?

The sites of biggest escape from XBB neutralizing antibodies are shown below: pic.twitter.com/qG0QBfd9ah

— Bloom Lab (@jbloom_lab) March 9, 2023

One of the obvious things is that there are many more peaks in the above XBB escape map.

The reason is that XBB has actually already escaped most RBD neutralizing antibodies, so the remaining peaks are smaller magnitude escape from the residual RBD neutralization.

— Bloom Lab (@jbloom_lab) March 9, 2023

At least w respect to serum from current vaccine strains and earlier Omicron breakthroughs, there are no longer huge-effect RBD escape mutations in XBB like we saw previously for site 484, 486, or 444---simply because XBB has already acquired all such mutations!

— Bloom Lab (@jbloom_lab) March 9, 2023

But this does not mean that the antibody-RBD evolutionary arms race will stop. It just means that the next steps will largely be shaped by the specificities boosted by infections with more recent strains, like BQ.1.1 and especially XBB.*.

— Bloom Lab (@jbloom_lab) March 9, 2023

Right now there is not good data on the neutralizing antibody specificities elicited by breakthrough infection with those newest variants, and acquiring those data is an important experimental next step if we want to continue to interpret SARS-CoV-2 RBD evolution.

— Bloom Lab (@jbloom_lab) March 9, 2023