Yunlong Richard Cao Profile picture
Apr 23 8 tweets 3 min read Read on X
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…
Image
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) Image
We first compared the antibody response of XBB and JN.1 infection in SARS-CoV-2 naive individuals (people who weren't vaccinated and haven't been infected). Similar to naive mice, we found that XBB and JN.1 lineages are also antigenic distinct in naive humans.
(3/7) Image
We then compared the immunogenicity of XBB and JN.1 infections in those who had been vaccinated and exposed to Omicron before (Major population). As expected, JN.1 exposure clearly induces higher neutralization titers against emerging mutants, such as FLiRT and KP.3.
(4/7) Image
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) Image
Additionally, we found that JN.1+F456L and FLiRT showed equal ACE2 binding affinity compared to JN.1, and JN.1.23, which carries a Y453F mutation, exhibits greatly enhanced ACE2 binding. Acquisition of more immune-evasive mutations should be closely monitored for JN.1.23.
(6/7) Image
We have also isolated and expressed mAbs from these cohorts to compare the humoral immune response landscape at the monoclonal antibody level of XBB and JN.1 exposure. Subsequent studies regarding the mAbs' epitope distribution and escaping mutations will soon be updated.
(7/7)
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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More from @yunlong_cao

Apr 19
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)Image
Previously, we showed the possibility of accurately predicting SARS-CoV-2 RBD evolution by aggregating high-throughput antibody DMS results.

Therefore, we hypothesize that if we use constructed pseudoviruses carrying predicted mutations as filters, we could screen for those "true" bnAbs as drug candidates, even when no knowledge of real-world viral evolution was available.
To demonstrate whether this strategy would work, we used the DMS profiles of mAbs elicited by SARS-CoV-2 WT infection/vaccination, which were the only data available early in the pandemic, and constructed pseudoviruses (B.1-S1~S5) harboring mutations on the identified hotspots.
(3/9)nature.com/articles/s4158…Image
Read 9 tweets
Dec 17, 2023
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
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
Read 6 tweets
Nov 22, 2023
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…
Image
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
There is an additional burning question following this study. In this paper, we showed that 3 doses of inactivated vaccination + 2 Omicron infection could override immune imprinting. However, multiple studies using mRNA vaccine cohorts did not see this phenomenon.
Read 5 tweets
Sep 10, 2023
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. Image
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 Image
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 Image
Read 12 tweets
Aug 31, 2023
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) Image
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) Image
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) Image
Read 7 tweets
Aug 5, 2023
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! Image
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. Image
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. Image
Read 4 tweets

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