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Yunlong Richard Cao

@yunlong_cao

Sep 10

Updates on BA.2.86.
1) BA.2.86's ACE2 binding affinity is very high.
2) BA.2.86 has lower fusogenicity than XBB.1.5.
3) BA.2.86's infectivity in Vero cells is similar to BA.1, lower than XBB.1.5.
4) Structure analysis shows that BA.2.86's Spike prefers RBD "down" conformation.

BA.2.86's RBD showed a pretty high hACE2 binding affinity measured by SPR, higher than that of XBB.1.5 and EG.5 and is even comparable to "FLip" variants like HK.3. BA.2.86's V483del indeed decreases ACE2 binding, but R403K is just too powerful and makes up for the loss. 2/n

We also measured the cell-cell fusion capability using Spike-transfected 293T cells and 293T-hACE2 cells. BA.2.86 showed a lower fusogenicity than XBB.1.5, despite the fact that BA.2.86's ACE2 binding affinity is much higher. Note this assay is free of pseudoviruses. 3/n

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Yunlong Richard Cao

@yunlong_cao

Aug 31

Sharing some new experimental data on BA.2.86:
1) BA.2.86 is antigenically distinct compared to XBB.1.5.
2) BA.2.86 can significantly escape XBB-infection/vaccination induced antibodies.
3) However, the infectivity of BA.2.86 may be much lower than XBB.1.5 and EG.5. (1/n)

By using pseudovirus neutralization assay and antigenic cartography (based on mRNA immunized mouse serum), we found that BA.2.86 is antigenically distinct from WT, BA.2, BA.5, and XBB.1.5. This means that XBB-induced antibodies cannot well recognize and neutralize BA.2.86. (2/n)

Indeed, BA.2.86 can induce significant antibody evasion of plasma isolated from convalescents who experienced XBB breakthrough infection or reinfections. BA.2.86's immune evasion capability even exceeds EG.5 and is comparable to "FLip" variants (XBB.1.5 + L455F & F456L). (3/n)

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Yunlong Richard Cao

@yunlong_cao

Aug 5

F456L-carrying XBB*, like EG.5, is rapidly rising. Meanwhile, XBB*+L455F+F456L is also growing fast. Some updates explaining their advantages:
1) F456L evades serum neutralization, even after XBB infection.
2) L455F+F456L combo adds on evasion and could also boost ACE2 binding!

The L455F+F456L RBD mutation combo is a very smart move by the virus (it's actually an LF->FL shift). Note that both individual L455F or F456L actually lose ACE2 binding, but together, the LF->FL shift somehow strengthened ACE2 interaction while destroying most antibody binding.

The emergence of 455 & 456 mutations is well-predicted half-year ago by our model built on DMS. Interestingly, we recently found that F456L is much more well-tolerated on the XBB.1.5 backbone instead of BA.2, which may explain why F456L only started to rise just now.

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Yunlong Richard Cao

@yunlong_cao

May 3

Sharing our latest work on SARS-CoV-2 immune imprinting.
Main finding:
Repeated Omicron infection/boosting alleviates WT vaccine-induced immune imprinting by generating many potent XBB-neutralizing Omicron-specific antibodies that target new RBD epitopes.
biorxiv.org/content/10.110…

First, let's revisit the major concept of SARS-CoV-2 immune imprinting:
When we experience a variant-vaccine boosting or breakthrough infection, our immune system will mainly recall WT vaccination-induced memory B cells and rarely produces variant-specific antibodies. 2/n

The problem caused by this concept is that when the boosting/infecting variant has a long antigenic distance to WT, the majority of memory B cells recalled will be those that target conserved and non-neutralizing epitopes, which will greatly hinder the antibody response. 3/n

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Yunlong Richard Cao

@yunlong_cao

Apr 21

Recently, many fast-growing XBB lineages have gained RBD mutations on K478, such as VOI XBB.1.16 (K478R), XBB.2.3.5 (K478N), XBB.2.3.4 (K478Q). Also, many XBB* have independently obtained F456L, like FD.1.1, FE.1, XBB.1.5.10. In this thread I'll briefly discuss these mutations.

@SystemsVirology

Like the results by Kei @SystemsVirology, we found XBB.1.16 and XBB.1.5 have comparable immune evasion capabilities in the serum tested. The ACE2 binding affinity of XBB.1.16 and XBB.1.5 is also similar. In contrast, F456L brings additional immune evasion but lowers ACE2 binding.

F456L escapes XBB.1.5-effective class I mAbs. These mAbs are quite abundant in various immune backgrounds, such as people who experienced BA.5 breakthrough infections or repeated Omicron infections. Those that are developing RBD-targeting mAb drugs should pay attention to F456L

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Yunlong Richard Cao

@yunlong_cao

Dec 28, 2022

@JPWeiland

The superior growth advantage of XBB.1.5 has been well-documented by many colleagues @JPWeiland @LongDesertTrain @EricTopol. Here I'll add some experimental data:
1) XBB.1.5 is equally immune evasive as XBB.1, but
2) XBB.1.5 has a much higher hACE2 binding affinity. 1/

Notably, even BF.7 breakthrough infection doesn't induce high neutralization against XBB.1 and XBB.1.5. The S486P mutation only caused a slight reduction in immune evasion capability. mRNA breakthrough infection samples (n=9) here all received at least 2-dose mRNA vac. 2/

However, the S486P mutation greatly enhanced hACE2 binding, since 486S completely destroyed the local hydrophobic interaction while 486P retained it. 3/

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