New study. We compared the immune response of XBB and JN.1 in human infections to evaluate the necessity for #SARSCOV2 vaccine updates
Results:
JN.1 exposure induces higher neutralization against emerging mutants, including FLiRT (JN.1+346T+456L) and KP.3
biorxiv.org/content/10.110…
Since JN.1 lineages have replaced XBB lineages and JN.1 subvariants are continuously gaining immune-evasive mutations, such as R346T, F456L, R346T+F456L (FLiRT), and F456L+Q493E (KP.3), it's time to evaluate whether we need to switch SARS-CoV-2 vaccine antigen to JN.1.
(2/7)

Imagine we can identify JN.1-neutralizing mAbs at the start of the pandemic, how revolutionary it would be for COVID mAb drug development. Here we provide a strategy to select potent SARS-CoV-2 broad-spectrum mAbs when we only know the ancestral strain.
biorxiv.org/content/10.110… Many studies have claimed the discovery of “SARS-CoV-2 bnAbs” based on the efficacy against known variants at that time. However, most of these "bnAbs" were rapidly escaped by subsequent viral evolution.
This is because “neutralization against known variants” is a poor indicator for true bnAbs against fast-evolving pathogens.
Inferred from a retrospective analysis of our SARS-CoV-2 mAb collection, we found that among the potent mAbs available at the early stage of the pandemic, only 1~3% could remain effective for more than two years.
If we could rationally identify bnAbs that remain potent against future variants, it would revolutionize mAb drug development against evolving viruses.
(2/9)

Our paper on JN.1 is now online @TheLancetInfDis!
The manuscript explains how a single RBD mutation L455S could turn BA.2.86 into a heavy immune evasive variant JN.1.
Notably, JN.1 is now approaching worldwide dominance (42% two weeks ago).
thelancet.com/journals/lanin… Two months ago, we warned about JN.1 due to its extreme immune evasion. The reason why we paid attention to JN.1 so early is that we know BA.2.86 is very weak to Class 1 antibodies and L455S is one of the strongest Class 1 antibody escaping mutations. 2/6

https://twitter.com/yunlong_cao/status/1714694253530804588

Our research on how repeated Omicron exposure mitigates ancestral strain immune imprinting is finally out in @Nature!
In this paper, we found that multiple Omicron exposures can induce high proportions of Omicron-specific Abs that target new RBD epitopes.

nature.com/articles/s4158…
Detailed descriptions of this paper can be found in our previous tweets published half a year ago:

The work can not be done without the talented grad students @Ayijiang_ @jianfcpku @Ava_jingWang @Weilian71107085

https://twitter.com/yunlong_cao/status/1653804041821093889

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

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)

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.

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

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. 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.

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/

Our paper regarding Omicron convergent evolution is out on @Nature.
In this story, we analyzed the immune evasion capability of ~50 convergent variants and explained how RBD mutations suddenly emerged convergently due to a more focused immune pressure.
nature.com/articles/s4158… Moreover, in this paper, we proved that by accurately mapping the immune pressure elicited by our humoral immunity, we can predict future immune-evasive RBD mutations of the virus! This is a big step to help us better prepare new variant-specific vaccines and antibody drugs.

Latest update on some new convergent variants.
Summary:
1. XBB, XBB.1, CH.1.1, BA.4.6.3, and BQ.1.1.10 (BQ.1.1+Y144del) are currently the most immune-evasive strains to monitor.
2. BQ.1*+NTD mutations, such as Y144del, makes them much more immune evasive.
biorxiv.org/content/10.110… Like @LongDesertTrain @JosetteSchoenma @CorneliusRoemer have mentioned, recently there has been a rapid increase of Y144del proportion in the BQ.1* lineages. This NTD deletion is observed in many worrisome BA.5 sublineages such as BQ.1.1.10, BQ.1.18, as well as BA.4.6.3.

Updating results regarding convergent variants BU.1, BR.2, BM.1.1.1, CA.1, and XBB.
XBB is currently the most antibody-evasive strain tested, and BR.2, BM.1.1.1, CA.1 are more immune evasive than BA.2.75.2 and BQ.1.1.
biorxiv.org/content/10.110… Similar to BQ.1.1, XBB also escapes Evusheld and Bebtelovimab. BU.1, BR.2, BM.1.1.1, CA.1, and XBB all displayed sufficient hACE2 binding capability.

Updating information regarding convergent variants BA.2.3.20, BN.1, BA.2.10.4, BN.2.1, BA.4.6.1, BQ.1, BQ.1.1.
In short, BA.2.75.2 and BQ.1.1 are the most antibody-evasive convergent variants tested, far exceeding BA.5 and approaching SARS-CoV-1 level. (1/4)

https://twitter.com/yunlong_cao/status/1570922875590414336

BA.2.75.2 is slightly more evasive than BQ.1.1 against plasma from BA.2/BA.5 breakthrough infections. Its due to the enriched NTD-NAbs elicited by BA.2/BA.5 infections, which BQ.1.1 can't escape. Note that these varaints are approaching SARS-CoV-1 level escaping capability. (2/4)

Sharing our investigation on the unprecedented convergent RBD evolution of BA.2.75 and BA.5 on sites including 346, 356, 444-446, 450, 460, 486, which have generated highly concerning variants such as BA.2.75.2, BR.1, BJ.1, and BQ.1.1. (1/n)
biorxiv.org/content/10.110… In this paper, we tried to solve the following three questions:
1) How immune evasive could these variants be?
2) Why do they evolve mutations on these converging sites?
3) What could this convergence evolution finally lead to? (2/n)
biorxiv.org/content/10.110…

Sharing some updates on our BA.2.75 study.
In brief, BA.2.75 shows high-level neutralization resistance to BA.5 breakthrough-infection plasma, due to the distinct RBD and NTD antigenicity exhibited by BA.2.75 and BA.4/BA.5. (1/n)
biorxiv.org/content/10.110… ~25 days after our previous report on BA.2.75, its growth advantage over BA.5 in India has become clearer. The question is whether this local spread would translate into a global prevail after the BA.4/BA.5 wave. (2/n)