I am thrilled to coauthor an editorial piece for
@SciImmunology
with
@EricTopol
highlighting the need for Operation Nasal Vaccine—Lightning ⚡️ speed to counter COVID-19. Nasal spray boosters can induce local immunity to ⬇️ infection & transmission.
We are happy to share our data on neutralization, infectivity, fusion, spike processing and antigenic mapping of BA.2.86 and FLip. Similar to
@BarouchLab
, we find that BA.2.86 is less nAb evasive compared to XBB.1.5, EG.5.1, and FLip, with FLip the worst.
We find that BA.2.86 has low infectivity in 293T-ACE2 cells, similar to
@yunlong_cao
results, but high infectivity in CaLu-3 cells - actually the highest among all Omicron variants tested.
New data: bivalent better than monovalent in inducing nAb against XBB.1.5; XBB.1.5 less than BQ.1.1 in nAb resistance, CH.1.1 the best; Fusogenicity and infectivity higher for XBB.1.5; distinct structural roles for F486S and F486P. Results support and complement
@yunlong_cao
Our latest results raise new concerns: new subvariants particularly BQ.1, BQ.1.1 and BA.2.75.2 are better evading nAb and more fusogenic driven by N460K, F486S, R346T, and K444T - consistent with
@yunlong_cao
.
Our new work: EG.5.1 more nAb evasive than XBB.1.5 driven by F456L mutation; XBB.2.3 comparable to XBB. Syncytia formation and infectivity: comparable to XBB.1.5. Bivalent vaccine or XBB.1.5 infection: insufficient to neutralize both. Conclusion: XBB-containing vaccines needed.
Happy to share that my graduate student Jack Evans successfully defended his PhD dissertation today. Within 4 years in the lab, Jack has published 23 papers, with 12 being the first author or cofirst authors in NEJM, CHM, STM, and mBio. Congratulations Jack!
The fusion activity of BA.2.86 is low in 293T/ACE2 cells, almost comparable to BA.2/BA.1, yet this is rescued in CaLu-3 cells, consistent with the increased infectivity in CaLu-3. The spike of BA.2.86 is more conformational stable compared to XBB variants?
BA.2.86 appears more antigenically similar to early Omicorn variants BA.1, BA.2 and BA.4/5, and antigenically distinct from the XBB variants, especially FLip.
The Spike processing of BA.2.86 is less efficient compared to XBB variants, though higher than BA.2/BA.1, partly contributing to its low fusion and surface expression.
Happy to share our new work: booster-induced nAb is far more stable than the 2-dose: about 12-15% drop per month for all variants; prior infection has ~5-10 fold higher nAb titers than those boosted alone. 2nd booster fully recovered loss of nAb titer from 1st booster.
@SolidEvidence
Looking forward to working with Marc and solving this mystery. Indeed I talked to a colleague yesterday who is working at OSU and traveling between Columbus and Washington Court House. Indeed very interesting!
The first paper to report the pathogenesis of BA.2.75 among recent 4 studies on nAb evasion in
@cellhostmicrobe
by
@yunlong_cao
@SystemsVirology
and
@ShanLuLiu1
- Virological characteristics of the SARS-CoV-2 Omicron BA.2.75 variant: Cell Host & Microbe
One interesting finding of our study is that N460K drives enhanced fusion whereas G446S dominates immune evasion. Does N460K increase spike interaction with ACE2 via N90? Most likely, but glycan interaction may not be easily seen in structure due to protein overexpression.
Ab evasion by BA.2.75.
@PankeQu
@ShanLuLiu1
& Evans examine Ab escape & fusogenicity of
#Omicron
BA.2.75. BA.2.75 exhibits stronger neutralization resistance than BA.2 but weaker than BA.4/5 as well as enhanced fusogenicity-- largely due to G446S & N460K
Now peer reviewed and published, working to make it open accessible. Thanks to all colleagues
@PankeQu
@EugeneOltz
@Gumina_Lab
@CarlinDcarlin
Enhanced Neutralization Resistance of SARS-CoV-2 Omicron Subvariants BQ.1, BQ.1.1, BA.4.6, BF.7 and BA.2.75.2
Indeed! Our data in SIV-infected primates receiving solely two doses of BA4/5 bivalent vaccine (with no priming or booster by the WT) supports the same conclusion. A second bivalent booster increases the nAb titer, but none of the current XBB variants is efficiently neutralized.
Why the updated, monovalent XBB.1.5 booster is needed
2 doses of the bivalent BA.5 doesn't cut it
"A second dose of the BA.5 bivalent booster is not sufficient to broaden antibody responses and to overcome immunological imprinting."
Our new data: T547K and H655Y likely stabilize the spike trimer conformation by increasing molecular interactions, resulting in reduced S1 shedding. H655Y mutation also determines the low fusogenicity and high dependence on the endosomal entry pathway of BA.4/5 and BA.2.75.
BA.2.86 appears more antigenically similar to early Omicorn variants BA.1, BA.2 and BA.4/5, and antigenically distinct from the XBB variants, especially FLip.
Our new work demonstrated that nAb levels against omicron variants in vaccinated adults decline by at least 15% per month after a single booster shot; titers are recovered by a second booster. Thanks to coworkers and collaborators
@Gumina_Lab
@PankeQu
@CarlinDcarlin
@EugeneOltz
.
After a 3rd (booster) dose of SARS-CoV-2 vaccine, immunity wanes slower than after just 2 doses and decays even more slowly in those with breakthrough Covid-19. Neutralization of omicron variant BA.4/5 is particularly resistant to vaccine-induced immunity.
@EricTopol
@JPWeiland
Indeed concerning! BQ.1.1, BQ.1, along with BA.2.75.2, are more capable of nAb evasion as well as causing cell-cell fusion based on our new work
Virus has no border, and control of global pandemic requires international cooperation including scientific collaboration between the US and China
@WHO
@JVirology
@theNAMedicine
🤝Protecting the well-being of humanity: Acclaimed
@Columbia
virologist Prof David Ho and
@hkumed
microbiologist Prof Yuen Kwok-yung are teaming up to create the "Pandemic Research Alliance" for conducting research in emerging infectious diseases. More at:
Our new results on BA.2.75: enhanced neutralization resistance over BA.2, but less than BA.4/5 - G446S and N460K primarily responsible, yet R493Q mutation reduces it; enhanced cell-cell fusion over BA.2, driven largely by the N460K mutation, which enhances S processing.
Work by Wenhui Hu showed that Exin21 increases CoV-2 E expression by 34-fold and also boosts the production of SARS-CoV-2 S, M, and N, accessory proteins (NSP2, NSP16, and ORF3), and host cellular gene products such as IL-2, IFNγ, ACE2, and NIBP.
@mvankerkhove
In my letter to Nature published on Jan 19, 2020, I stated “Controlling the spread of emerging and re-emerging viruses calls for international efforts. China’s research collaborations and data-sharing must continue”
Happy to share our new work. We keep seeing increased fusion of newly emerged Omicron variants since the birth of BA. 2, but none of those has reached to the level of D614G. A turning point could happen, either forward or reverse.
Pleased to share our collaborative work with
@QianbenWang
and
@yizhoudonglab
on Cas13d nanoparticle-mediated lung-specific COVID therapy and prevention in mice.
@TRyanGregory
Cocirculation of XBB variants makes generation of recombinant variants more likely and unpredictable. Would trivalent vaccines containing XBB.1.5, XBB.1.16 and XBB.2.3 or even EG.5.1 that can induce mucosal immunity be more appropriate and the way to go for this fall and winter?
@florian_krammer
@SutharLab
In our hands, two types of assay are very consistent. I think results from more labs with larger sample sizes shall clarify the differences.
>90% of awardees are white vs. less than 7% of Asian descent, despite that people of Asian descent make up more than 21% of biomedical faculty, according to a study by HHMI investigator Yuh Nung Jan, who called the numbers “pretty appalling.”
“Working hard and having all kinds of accomplishments may get you ... a faculty appointment, but it doesn’t get you into the C-suite,” said one Asian American doctor.
Excited to share our new work: L452 mutation does it! Differential Evasion of Delta and Omicron Immunity and Enhanced Fusogenicity of SARS-CoV-2 Omicron BA.4/5 and BA.2.12.1 Subvariants
@kallmemeg
@yunlong_cao
CH.1.1, along with CA.3.1, are so far the most capable of evading nAb induced by bivalent/monovalent mRNA vaccines and BA4/5 infection, worse than BQ.1.1. And XBB lineages including XBB.1.5 have comparable nAb resistance, all less than BQ.1.1. and BA.2.75.2
@EricTopol
@LongDesertTrain
@StuartTurville
Yes, we have shown that BA.2.86 infectivity and fusogenicity in CaLu-3 cells is higher than all other Omicron subvariants
@LongDesertTrain
@GuptaR_lab
@veeslerlab
@sigallab
@SystemsVirology
We did a series of reversion mutation based on BA.1 through BA.2.75 and identified some key mutations responsible, including N460K, H655Y in S1 and some more in S2. A clear trend is an increased syncytia formation from BA.1 to FLip. BA.2.86 is distinct, seems cell type dependent.
@LongDesertTrain
In vitro, we showed that the fusogenicity of recently emerged Omicron subvariants has been increasing since BA.2, including BQ.1.1 and XBB lineages.
@EricTopol
@OhioState
CH.1.1 and CA.3.1 appear to be more capable of evading nAb induced by bivalent/monovalent mRNA vaccines and BA4/5 infection than the recently dominant BQ.1.1. XBB lineages including XBB.1.5 have comparable nAb resistance, all less than BQ.1.1. and BA.2.75.2
@yunlong_cao
@ACasadevall1
@MayoClinic
@US_FDA
In the panel discussion of a COVID workshop yesterday, we discussed about reconsidering the high-titer CP treatment for those immune compromised individuals who do not respond to vaccines. I believe this is important, and new clinical trials should be done.
Immune imprinting or original antigenic sin continues to be a serious issue for the current COVID vaccine development, check out our recent review in Journal of Immunology and a preview in Cell Reps Med
@RajlabN
@CDCgov
CH.1.1, the most nAb evasive subvariant we have seen so far, is on the rise in US and could become predominant in the months to come as having been seen in UK and other countries.
@LongDesertTrain
@siamosolocani
@Canakiwi2
BA.2 acquired mutations that make it more fit than BA.1, especially with increased fusogenicity. This is similar to D614G vs. the ancestral SARS-CoV-2, and BA.2.86 decedents vs BA.2.86. Hints of this repeated pattern for the origins of parental Omicron and current BA. 2.86?
@FabrizioChiodo
@EricTopol
@OhioState
Correct. The point is that bivalent mRNA vaccines on top of the 3-dose booster can provide enhanced immunity against XBB lineages, especially given the loss of ~17-20% nAb per 30 days, based on our
@NEJM
paper -
@wanderer_jasnah
FAST is probably the most fusogenic viral protein ever seen in our experiments, and it may not have the hemifusion step which is common to all fusion processes, including cellular fusion. Truly amazing.
@EricTopol
It’s intriguing to see exactly the same titer between XBB.1.5 and XBB.1.16 in no breakthrough infection, which has a relatively low number. We will post our results soon on titers and also interesting biology of BA.2.86 in comparison with other variants.
@JosetteSchoenma
@EricTopol
@OhioState
The bivalent mRNA vaccine contains half of BA.4/5 but not BA.1, which in part explains the higher resistance of CH.1.1. From our NEJM paper below, we know that L452 mutations are critical determinants of differential nAb resistance.
@MCoteLab
@EricTopol
@JPWeiland
The cell-cell fusion assay was originally developed for JSRV and ENTV actually by you in our lab at McGill. And the extremely cold temperatures in Montreal made the fusion much less efficient and later we figured out it’s THE temperature in our TC room!” to blame.
@dfocosi
@ColumbiaMed
Our data in SIV-infected primate monkeys receiving solely two doses of BA4/5 bivalent vaccine (with no priming or booster by WT) supports the conclusion. The second bivalent booster dramatically increase the nAb titer but still does not neutralize sufficiently the XBBs variants.
@yunlong_cao
Great work! Low infectivity is interesting and seems marking sense. We also saw one of the Ohio cryptic spikes also shows much reduced infectivity.
@ejustin46
@lasradoN
The live virus data on BA.2.86, CH.1.1, and others are very consistent with pseudoviral results, with CH.1.1 (along with CA.3.1 etc) the worst in nAb neutralization and BA.2.86 not as evasive as XBB.1.5 and FLip. See our previous paper on
@vipintukur
@siamosolocani
The titer of XBB.1.5 monovalent vaccine against XBB.1.5 itself is lower than that of B.1 and BA.5, why? Immune imprinting from prior infection or vaccination?
@veeslerlab
In our newly published paper, we reported that one mutation H655Y present in all Omicron subvariants is critical for their predominant endosomal entry pathway.
@Marc_Veld
I would speculate that the so-called ACE2 independent infection of T cells is a non-productive cell-to-cell transmission, as we had shown in our Dec’2021 PNAS paper for human PBMC
@PNASNews
@mvankerkhove
I also stated “ The authorities have been understandably cautious after the early misidentification of the SARS pathogen in 2003. However, the results of animal testing from a seafood market in Wuhan…must be released as soon as possible”.
@LongDesertTrain
@GuptaR_lab
@veeslerlab
@sigallab
@SystemsVirology
However, our new work shows that XBB.1.16 has reduced fusion compared to XBB.1.5. In fact, fusion assay measures solely the intrinsic capability of spike conformational changes, i.e. 6HB formation, and it does not always correlate with entry.
@LubanLab
@MassCPR
Jeremy, a very nice article. Our results showing that Omicron has reduced fusion but increased cell-to-cell transmission is consistent with the notion that Omicron is likely a result of chronic infection and its potential impacts on chronic COVID cannot be ignored.
@LongDesertTrain
The highly primed Delta spike due to its enhanced furin cleavage would intrinsically restrict other critical mutations that would increase binding to ACE2 so as to avoid possible premature inactivation.
Can MLV infect nondividing cells? For a long time, no; but new results from Susan Ross’s lab indicate yes: MLV can infect non-dividing primary DCs and requires the viral p12 protein. MLV capsid also associates with the nuclear pore proteins NUP358 and NUP62 during infection.
@LongDesertTrain
That is true, but BA.2.75 also picks up a reversion mutation R493Q that reduces the neutralization resistance. In the end, it comes to a balance for the spike - as we show in the CHM paper.
@ejustin46
Excellent work! Previously we have shown that PBMCs and other low- or no-ACE2 cells can be trans-infected via cell-to-cell transmission but may not lead to productive infection
@Mira_24_
@GuptaR_lab
@C_A_Gustave
Yes, we found that it is target-cell dependent. In CaLu-3 cells, BA.2.86 is the highest among Omicron variants tested so far. Delta is the highest in fusion among all SARS-CoV-2 strains.
@laura_ungar
Thanks for the opportunity. The new preprint from Japan and online yesterday shows that BA.2.12.1 is more pathogenic and more transmissible than the original Omicron, supporting our results.