Yunlong Richard Cao
@yunlong_cao
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Biochemistry & Immunology | Host Immune Response, Antibody Drug & Vaccine Design | PhD @Harvard | Assistant Professor at Peking University BIOPIC
China
Joined May 2019
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KP.3 is starting to outcompete KP.2. Its unique Q493E mutation brings some critical features:
1) KP.3 has higher ACE2 binding affinity than KP.2.
2) KP.3 is more immune evasive. KP.3 +31del (KP.3.1.1) is the most.
3) KP.3 is especially good at evading Class 1 antibodies.
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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/
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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)
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)
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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)
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A short update on how waning immunity and immune evasion by convergent mutants BQ.1.1 and XBB stack together. Data suggest that most serum obtained ~7.5 months after BA.1 breakthrough infection would hardly neutralize BQ.1.1 and XBB. (NT50 of 20 is the lower limit of our assay)
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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)
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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.
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As expected, BQ.1.1 escapes Evusheld and bebtelovimab, making all clinically available antibody drugs ineffective. BQ.1.1 and BA.2.75.2 both displayed sufficient hACE2 binding capability. (3/4)
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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.
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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).
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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.
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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.
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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.
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Together, our results suggest natural infection or vaccine boosters using BA.5 may not provide sufficiently broad protection. Broad-spectrum vaccines and NAb drugs should be developed and our constructed convergent mutants could help examine their effectiveness in advance. (20/n)
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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!
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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.
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@CorneliusRoemer
@EricTopol
@chrischirp
@TheLancetInfDis
@BenjMurrell
@PeacockFlu
@DannySheward
BA.2.75.2 is currently the most immune evasive strain we have tested so far. True for plasma isolated from all Omicon breakthrough infections, including BA.5.
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Updates on several concerning variants, JN.1 (BA.2.86+L455S), JD.1.1(FLip+A475V), HV.1(EG.5+L452R).
1) L455S on BA.2.86 (JN.1) greatly increases antibody evasion at the cost of ACE2 binding.
2) HV.1 and JD.1.1 are more evasive than FLip but display lower ACE2 binding as well. 1/3
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Sharing some preliminary results just obtained regarding the new Omicron variants BA.2.75. In short, BA.2.75 is more neutralization evasive than BA.2.12.1, but less compared to BA.4/5. BA.2.75 also exhibits higher ACE2 affinity than BA.4/5. (1/n)
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Another important observation is that XBB.1.5's hACE2 binding affinity is almost comparable to that of BA.2.75, which may enable XBB.1.5 to gain more mutations, similar to what BA.2.75 had. It's just XBB.1.5 haven't felt much immune pressure yet. 5/
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We should be able to update information on BU.1, BR.2, BM.1.1.1, CA.1, and XBB within two weeks. I agree with
@CorneliusRoemer
that XBB will be the most immune-evasive convergent variant for now, since it should be able to escape the majority of both NTD/RBD NAbs. (4/4)
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@dgurdasani1
I don't think the current WT/BA.1 or WT/BA.5 bivalent vaccines would be very effective against those convergent variants, based on the released mouse vaccination data.
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XBB is significantly more immune evasive than BA.2.75.2 and BQ.1.1 against plasma from all breakthrough infections, comparable to or even exceeding SARS-CoV-1 level escaping capability. BR.2, BM.1.1.1 and CA.1 also exhibit very strong immune evasion, but less compared to XBB.
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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)
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The fact that XBB.1.5 showed a much superior growth advantage than XBB.1 suggests that hACE2 binding affinity does play a heavy role in SARS-CoV-2 spreading. XBB.1 truly suffered from low-hACE2 binding, despite XBB.1’s highest immune evasion capability. 4/
Chart of effective Reproductive Number from Trevor Bedford
@trvrb
(annotations added).
Do you all see where BQ was even at its growth peak?
Do yall see where XBB.1.5 is?
@CDCDirector
@CDCgov
@nytimes
@washingtonpost
@CNN
@mvankerkhove
@WHO
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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)
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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/
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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
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In sum, we found that BA.2.86 is antigenically distinct from XBB.1.5 and can escape XBB-induced neutralizing antibodies. The updated vaccine's efficacy against BA.2.86 should be closely monitored; however, BA.2.86 may not prevail very fast due to its lower infectivity. (7/n)
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These observation means that due to immune imprinting, BA.5 breakthrough infection mainly recalls previous memory and rarely produces mAbs with new epitopes. This causes a significant reduction of NAb epitope diversity and an increased proportion of non-neutralizing mAbs. (10/n)
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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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We will update information on BA.2.3.20,BN.1,BA.4.6.1,BQ.1,BQ.1.1,BA.2.10.4, BN.2.1 next week. This work is greatly inspired by
@jbloom_lab
, and we will share all the DMS and neutralization data so everyone could play with it using Jessi’s
@jbloom_lab
calculator. (21/n)
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Our findings also suggest the WT component should be abandoned when updating COVID-19 vaccine antigen compositions to XBB lineages, and those who haven't been exposed to Omicron yet should receive two updated vaccine boosters. 31/n
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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)
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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
Updates on several concerning variants, JN.1 (BA.2.86+L455S), JD.1.1(FLip+A475V), HV.1(EG.5+L452R).
1) L455S on BA.2.86 (JN.1) greatly increases antibody evasion at the cost of ACE2 binding.
2) HV.1 and JD.1.1 are more evasive than FLip but display lower ACE2 binding as well. 1/3
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We will keep on updating results on these emerging convergent variants, if there is more. All data will be merged into the BioRxiv preprint we previously posted.
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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.
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As many have noticed, recent evolution of Omicron has led to numerous subvariants that exhibit high growth advantages over BA.5. Interestingly, mutations on their receptor-binding domain (RBD) converge on several hotspots, including R346, R356, K444, L452, N460 and F486. (3/n)
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It can be highly expected that this winter, we will be facing XBB offspring that carry mutation combos like L455F+F456L+K478R, or even additional evasive mutations since the high ACE2 affinity could give a large buffering room for strong antibody-evading mutations to appear.
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Next, we investigated why Omicron suddenly started to evolve convergently. In short, we believe this is linked to humoral immune imprinting. Similar to BA.1 breakthrough infection, we showed BA.2/BA.5 breakthrough infection also mainly recalls previous WT-induced memory. (7/n)
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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)
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As for plasma, BA.2.75.2 exhibits the most significant reduction in NT50, even for BA.5 breakthrough-infected convalescents. Almost 10-fold difference compared to BA.5 against plasma from BA.5 convalescents. Will update results on 6~8 new variants, such as BQ.1.1 next week. (5/n)
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The above analyses suggest: due to immune imprinting, BA.5 breakthrough infection caused significant reductions of nAb epitope diversity and increased proportion of non-neutralizing mAbs, which in turn concentrated immune pressure and promoted the convergent RBD evolution. (14/n)
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XBB's superior antibody escaping capability not only comes from the convergent RBD mutations, it's NTD mutations, V83A and 144-deletion, are also extremely good at escaping NTD-targeting neutralizing antibodies.
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First, we tested the antibody evasion capability of these variants. Therapeutic antibodies are not very effective against those convergent variants. Bebtelovimab doesn't work against variants carrying K444N/M/T or V445P. Evusheld is also heavily escaped. (4/n)
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Our results on BA.2.86 are now online:
Antigenicity and infectivity characterization of SARS-CoV-2 BA.2.86 - The Lancet Infectious Diseases
BA.2.86 structural results will be on another manuscript, which will soon be posted on BioRxiv
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Results from mRNA vaccines should have overall higher neutralizing titers. But the immunity waning trend and immune evasion pattern should be highly similar, supported by recent studies by
@jbloom_lab
@LauraWa27423872
@ShanLuLiu1
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Importantly, we found that BA.2.86 exhibits lower cell infectivity compared to XBB.1.5 and EG.5, which may affect its transmission. The lower infectivity may be contributed by K356T, V483del, and E554K. Note that here the infectivity is measured through pseudovirus assays. (6/n)
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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.
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Longitudinal data of 22 individuals with a clearer trend of humoral immunity waning.
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@mryoung151
If you had an Omicron infection before and also want to have an updated booster, go get one, and it will perform well. But if you never got Omicron nor boosted with Omicron-containing vaccines, you may need two updated boosters to work well.
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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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I believe there is still room for XBB to gain more mutations, such as L452R or K356T or both. BQ.1.1 may also evolve mutations on the NTD, such as the 144-del carried by BU.1, to catch up on immune evasion capability.
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Lastly, I want to emphasize that the current convergent evolution trend can be predicted. See below, the S-series pseudoviruses were predicted/constructed in July, and check how close they are to the emerging mutants. However, I thought our prediction would last till next July😂
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These data again emphasize that high ACE2 binding affinities, such as FLip (455F+456L) variants and BA.2.86, would allow fast collections of mutations that can further boost immune evasion. 3/3
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As for monoclonal neutralizing antibody (NAb) drugs, all approved antibodies can't neutralize BA.2.86 well, but SA55 remains effective (clinical phase II-III). Interestingly, the E554K mutation carried by BA.2.86 can escape SD1-targeting NAb, represented by S3H3. (4/n)
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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.
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@ingomar_gutmann
@CorneliusRoemer
@EricTopol
@chrischirp
@TheLancetInfDis
@BenjMurrell
@PeacockFlu
@DannySheward
Evusheld does not work against BA.2.75.2. Its due to the 486S and 346T mutations.
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However, BA.2.86 is evolving (BA.2.86.1 already assigned), and that's why we need to closely monitor its evolution, to see whether BA.2.86 can gain mutations or reversions (especially on Spike) that could increase its transmissibility or immune evasion. 12/n
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Even worse, NTD NAbs are enriched in individuals infected or boosted with BA.2/BA.5 compared to BA.1 and WT. Indeed, BQ.1.1+Y144del (BQ.1.1.10) has greatly boosted the immune evasion capability of BQ.1.1, and is most significant in BA.5 convalescents (~3-fold).
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Lastely, we want to know if this convergence evolution keeps on going, what would it finally lead to? We started by calculating the convergent RBD evolution trend of BA.2.75 and BA.5. The result fits very well with the emerging variants, such as BA.2.75.2, BR.1, BQ.1.1. (15/n)
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L455S mainly escapes Class 1 neutralizing antibodies, which made up for the weakness of BA.2.86 (vulnerable to Class 1 Abs). Of note, FLip + A475V could evade almost all of Class 1 Abs, which explains why we have seen so many A475V mutations on FLip variants recently. 2/3
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Such strains could survive and transmit at low levels, since their large antigenic distance to dominant strains allows them to target distinct populations and accumulate immune-evasive mutations rapidly, often at the cost of receptor binding affinity. 6/6
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So in the future, we should not only focus on the serum neutralization titers of a new variant but also care about the characteristics of the effective neutralizing antibodies, especially when their epitope distributions are dominated by one class, similar to BA.2.86. 4/6
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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.
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To better visualize the above observation, we modified the algorithm by
@jbloom_lab
and showed the immune presure elicited by BA.2/BA.5 breakthough infection. This strikingly shows the reduced NAb diversity and concentrated immune pressure for BA.5 infection than BA.2. (11/n)
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Current results do underscore the challenge posed by the continuously evolving SARS-CoV-2 JN.1 lineages and support the consideration of switching the focus of future SARS-CoV-2 vaccine updates to the JN.1 lineage.
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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)
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Also, the case of JN.1 highlights the importance of closely monitoring strains with high ACE2 binding affinity and distinct antigenicity, like BA.2.75 and BA.2.86, despite their temporarily unremarkable immune evasion capabilities. 5/6
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Proved by pseudovirus neutralization assays using soluble hACE2, we found that all of the tested variants exhibited sufficient hACE2 affinity, higher than that of D614G, indicating they all have a chance to circulate. (6/n)
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We checked whether these indicated mutations could work together. We chose ~200 BA.2-effective NAbs from distinct epitope groups and tested their neutralization against those mutations. Results suggest the mutations synergize very well and could escape almost all RBD-NAbs. (16/n)
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Note how close BA.5-S4 (BA.5+R346T+N417T+K444N+N460K) is compared to the recent BQ.1.1. They will have similiar evasion capability and the results already show how evasive BQ.1.1 would be. This also proves our prediction is on track. (19/n)
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We also tested a panel of XBB.1.5-effective NAbs against XBB.1.5-based pseudoviruses carrying single BA.2.86 RBD mutations. Results showed that N450D, K356T, L452W, A484K, V483del, V445H are the key mutations responsible for BA.2.86's enhanced immune evasion than XBB.1.5. (5/n)
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Our paper on SARS-CoV-2 “Flip” variants (L455F+F456L, a convergent mutation combo frequently observed in XBB lineages, like HK.3) is finally out
@PLOSPathogens
. In this manuscript, we studied the structural mechanism of how L455F+F456L could work synergistically to increase
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However, BA.2.75 seems to be more immune evasive than BA.4/5 in Delta-infection backgrounds, which may explain BA.2.75's growth advantage in India. Noteworthy, the sample size of Delta convalescents here is small. (2/n)
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All related information can be found on our updated Biorxiv pre-print.
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We isolated RBD-antibodies from BA.2/5 convalescent plasma, measured their neutralization, determined their epitope and escaping mutations using high-throughput DMS. Integrated with our previous data, we finally got a DMS dataset containing 3051 RBD-reactive antibodies. (8/n)
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Many labs have shown that BA.2.86 is well-neutralized. However, the absolute neutralizing titers cannot tell the full story. Since the majority of BA.2.86-neutralizing Abs are from a single epitope, huge changes in titers could happen when BA.2.86 acquires critical mutations. 3/6
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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.
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The appearance of Y144del in those BA.5 sublineages is a really bad sign since we know this mutation is extremely good at escaping NTD-neutralizing antibodies. See below, Y144 is located at the epitope center of a specific group of NTD NAbs that are potent against BA.5.
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Based on the results, KP.3 lineages would eventually dominate. It might be beneficial to consider a KP.3 booster, or at least a KP.2 booster, against future variants since KP.3 stimulation could induce broader Class 1 NAbs, just like how JN.1 exposure outperforms XBB exposure.
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Importantly, BA.5 breakthrough infection exhibited further enrichment of non-neutralizing epitopes (E2.2/E3/F1, 63%) and less diversified NAb epitopes (less B/D1/E2.2 and more D2). The reduced B/D1/E2.2 antibodies is due to the F486V and L452R mutations. (9/n)
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Our preprint studying the antibody immune evasion and receptor-binding features of BA.2.75 is out on
@biorxivpreprint
.
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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.
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We previously predicted that BQ.1.1* may soon gain Y144del because of the huge transmission advantage it would give, but we didn't foresee the speed.
I believe there is still room for XBB to gain more mutations, such as L452R or K356T or both. BQ.1.1 may also evolve mutations on the NTD, such as the 144-del carried by BU.1, to catch up on immune evasion capability.
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In BA.2.75 derivatives, F486V confers the most striking drop in NT50 for WT/BA.1/BA.2 plasma but R346T for BA.5 plasma. We also found BA.2.75-S4 is enough to eliminate the neutralization of most plasma samples, and NTD mutations are necessary to escape BA.2/5 plasma. (18/n)
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This paper has been updated 4 times on bioRxiv in the past three months, each time adding analyses of newly emerged convergent variants. This fresh experience of pre-publication Twitter-review is fascinating, and I'm deeply thankful to all those who have been following our work.
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By integrating data of neutralization, ACE2-binding, RBD-stability, and codon-usage (method detailed described in the manuscript), we can accurately identify sites conferring high immune pressure and infer mutations preferred to appear. (12/n)
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CH.1.1 is currently the most RBD-NAbs evasive strain tested, even higher than XBB, although the difference is small. CH.1.1 is a BA.2.75 sublineage, which means it is also good at escaping NTD NAbs. This is why CH.1.1 displays such a high relative growth advantage.
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Check how well this model aligns with the convergent mutations! R346T/S/I, K356T, K444N/T/M, N450D, L452R, N460K, F486S/V/I, and F490S. (13/n)
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Then we constructed pseudoviruses carrying stacked convergent mutations to find the destination of the convergence, and tested the neutralization of plasma and NAb drugs. NAb drugs are escaped as expected, except SA55. All of the mutants exhibit sufficient ACE2-binding. (17/n)
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Q493E enables KP.3 to escape a lot of Class 1 V3-53/66 encoded mAbs, even if elicited by JN.1 infection. Since these V3-53/66 NAbs are highly enriched in mRNA vaccine recipients, we would expect KP.3 and KP.2 to show substantial immune evasion even with JN.1 mRNA boosters.
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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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Notably, XBB.1 (XBB + G252V) has escaped all NTD NAbs we tested. These NTD NAbs were isolated from pre-Omicron infections/vaccinations, so not clear yet how XBB.1 would impact NTD NAbs elicited by BA.5 boosting/infection (Working on it, and should soon obtain data).
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KP.3 (JN.1+F456L+Q493E) is the most immune evasive variant we found and is also the fastest-growing JN.1 sublineage. The additional F456L and Q493E mutation allows KP.3 to evade a substantial proportion of JN.1-effective mAbs, especially Class 1 antibodies.
(5/7)
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Sharing our results on 346-mutated BA.4/BA.5 subvariants, such as BA.4.6, which are rapidly spreading. Major findings:
1) BA.4.6 can also evade sera from BA.5 breakthrough infections.
2) Bebtelovimab is still potent; Evusheld escaped by BA.4.6.
Sharing our rapid evaluation of humoral immune evasion emerging BA.4/5 subvariants carrying spike R346 mutations.
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Regarding the newly emerged CH.1.1 (BA.2.75 + R346T + K444T + L452R + F486S) and BA.4.6.3 (BA.4.6 + K444N + N460K + Y144del), they are both very good at escaping RBD-neutralizing antibodies. Both Evusheld and Bebtelovimab are ineffective against them.
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Most importantly, we found that BA.2.75 exhibits strong evasion in convalescent plasma from BA.5 breakthrough infection (~4-fold reduction in NT50 compared to the NT50 against BA.5). This would gave BA.2.75 huge transmission advantage after the global BA.4/5 wave. (6/n)
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Detailed information for the experiments described here can be found in the newly uploaded preprint:
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Does this mean that due to superior immunogenicity, WT mRNA vaccines induced a stronger immune imprinting and is much harder to alleviate compared to the inactivated vaccine? Shall we lower mRNA vaccine dosages in the future? A critical question we are now investigating.
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