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  • Sato Lab Preprint: Virological Characteristics of KP.3, LB.1 and KP.2.3 variants

    Sato Lab Preprint: Transmissibility, Infectivity, and Immune Resistance of the SARS-CoV-2 BA.2.86 Variant







    #17,663

    With a new, and largely enigmatic BA.2.86 variant spreading globally, researchers around the world are feverishly working to quantify its risks, including the Kei Seto Lab at the University of Tokyo. Over the past few years we've looked at a number of their assessments of emerging variants (see here, here, and here).

    While their findings were telegraphed yesterday by the authors on Twitter/X, the full preprint was published overnight.



    They find that BA.2.86 appears substantially less infectious (in vitro, using surrogate pseudoviruses) than currently circulating XBB strains and EG.5, but that it seems to make up for this deficit by ramping up its immune evasion; stating that `. . . results suggest that BA.2.86 is one of the most highly immune evasive variants ever.'

    Based on very limited data, they calculate its Effective Reproduction number (Re) to 1.29-fold greater than that of XBB.1.5 and comparable to or even greater than that of EG.5.1.



    How all of this plays out in the real world, where BA.2.86 is in direct competition of literally dozens of other well-established variants, remains to be seen.

    But between this report, and the UK's announcement earlier today of community transmission of BA.2.86 within the UK, this variant deserves our continued attention.



    Follow the PDF Link to read this brief report in its entirety.

    Transmissibility, infectivity, and immune resistance of the SARS-CoV-2 BA.2.86 variant

    Keiya Uriu, Jumpei Ito, Yusuke Kosugi, Yuri L Tanaka, Yuka Mugita, Ziyi Guo, Alfredo A Hinay Jr., Olivia Putri, Yoonjin Kim, Ryo Shimizu, MST Monira Begum, Michael Jonathan, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Akatsuki Saito, Terumasa Ikeda, Kei Sato
    doi: https://doi.org/10.1101/2023.09.07.556636



    PDF LINK

    Abstract

    In September 2023, the SARS-CoV-2 XBB descendants, such as XBB.1.5 and EG.5.1 (originally XBB.1.9.2.5.1), are predominantly circulating worldwide. Unexpectedly, however, a lineage distinct from XBB was identified and named BA.2.86 on August 14, 2023. Notably, BA.2.86 bears more than 30 mutations in the spike (S) protein when compared to XBB and the parental BA.2, and many of them are assumed to be associated with immune evasion.


    Although the number of reported cases is low (68 sequences have been reported as of 7 September 2023), BA.2.86 has been detected in several continents (Europe, North America and Africa), suggesting that this variant may be spreading silently worldwide.


    On 17 August 2023, the WHO designated BA.2.86 as a variant under monitoring. Here we show evidence suggesting that BA.2.86 potentially has greater fitness than current circulating XBB variants including EG.5.1. The pseudovirus assay showed that the infectivity of BA.2.86 was significantly lower than that of B.1.1 and EG.5.1, suggesting that the increased fitness of BA.2.86 is not due to the increased infectivity.

    We then performed a neutralization assay using XBB breakthrough infection sera to address whether BA.2.86 evades the antiviral effect of the humoral immunity induced XBB subvariants. The 50% neutralization titer of XBB BTI sera against BA.2.86 was significantly (1.4-fold) lower than those against EG.5.1. The sera obtained from individuals vaccinated with 3rd-dose monovalent, 4th-dose monovalent, 4th-dose BA.1 bivalent, and 4th-dose BA.5 bivalent mRNA vaccines exhibited very little or no antiviral effects against BA.2.86.

    Moreover, the three monoclonal antibodies (Bebtelovimab, Sotrovimab and Tixagevimab), which worked against the parental BA.2, did not exhibit antiviral effects against BA.2.86. These results suggest that BA.2.86 is one of the most highly immune evasive variants ever.



    (Continue . . . )

    .

      #17,663 With a new, and largely enigmatic BA.2.86 variant spreading globally, researchers around the world are feverishly working to quant...

    Last edited by Michael Coston; June 11, 2024, 06:24 AM.
    All medical discussions are for educational purposes. I am not a doctor, just a retired paramedic. Nothing I post should be construed as specific medical advice. If you have a medical problem, see your physician.

  • #2
    Sato Lab Preprint: Virological characteristics of the SARS-CoV-2 JN.1 variant





    #17,812

    Last August a new, and heavily mutated, BA.2.86 SARS-CoV-2 variant appeared in the UK and parts of Europe which raised concerns that it might out-perform previous Omicron variants (see UKHSA To Move COVID/Flu Jabs Forward Due To Concerns Over BA.2.86).

    While its path to global dominance has been slower than expected, it - and its direct offshoot JN.1 - continue to gain ground, and last week JN.1 debuted in 2nd place in the CDC's Nowcast.

    According to the CDC:
    • JN.1 was first detected in the United States in September 2023. By the end of October, it made up less than 0.1% of SARS-CoV-2 viruses.
    • CDC projects that the variant JN.1 comprises an estimated 15–29% of in the United States as of December 8, 2023.
    • CDC projects that JN.1 will continue to increase as a proportion of SARS-CoV-2 genomic sequences. It is currently the fastest-growing variant in the United States.
    • Updated COVID-19 vaccines are expected to increase protection against JN.1, as they do for other variants.
    • At this time, there is no evidence that JN.1 presents an increased risk to public health relative to other currently circulating variants.There is no indication of increased severity from JN.1 at this time.
    Of course, with the global testing, surveillance, and reporting system for COVID largely dismantled, we don't have as much real-time information as we'd like about this emerging variant.
    One of the ways we can make up for those reporting gaps are laboratory studies on emerging variants, such as provided by the Kei Seto Lab at the University of Tokyo.

    Last September we looked at their initial analysis of the parental BA.2.86 variant (see Preprint: Transmissibility, Infectivity, and Immune Resistance of the SARS-CoV-2 BA.2.86 Variant), which suggested that ` . . . BA.2.86 is one of the most highly immune evasive variants ever.'

    Over the weekend the Sato Lab released their preprint on the JN.1 offshoot, which differs from BA.2.86 by only a single change (L455S) in the spike protein, and 3 others in the non-S proteins. The L455S mutation has previously been linked to increased immune evasion.

    While the analysis that follows is somewhat technical, the bottom line is that JN.1 appears to be even more immune evasive than its parental BA.2.86, which suggests that it - and its descendants - may have a growth advantage over the the older XBB Omicron lineage in the months ahead.

    First some excerpts from the preprint, after which I'll have a postscript:
    Yu Kaku, Kaho Okumura, Miguel Padilla-Blanco, Yusuke Kosugi, Keiya Uriu, Alfredo Amolong Hinay Jr., Luo Chen, Arnon Plianchaisuk, Kouji Kobiyama, Ken J Ishii, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Jiri Zahradnik, Jumpei Ito, Kei Sato
    doi: https://doi.org/10.1101/2023.12.08.570782
    Abstract

    The SARS-CoV-2 BA.2.86 lineage, first identified in August 2023, is phylogenetically distinct from the currently circulating SARS-CoV-2 Omicron XBB lineages, including EG.5.1 and HK.3. Comparing to XBB and BA.2, BA.2.86 carries more than 30 mutations in the spike (S) protein, indicating a high potential for immune evasion. BA.2.86 has evolved and its descendant, JN.1 (BA.2.86.1.1), emerged in late 2023. JN.1 harbors S:L455S and three mutations in non-S proteins. S:L455S is a hallmark mutation of JN.1: we have recently shown that HK.3 and other "FLip" variants carry S:L455F, which contributes to increased transmissibility and immune escape ability compared to the parental EG.5.1 variant. Here, we investigated the virological properties of JN.1.
    Text

    The SARS-CoV-2 BA.2.86 lineage, first identified in August 2023, is phylogenetically distinct from the currently circulating SARS-CoV-2 Omicron XBB lineages, including EG.5.1 and HK.3. Comparing to XBB and BA.2, BA.2.86 carries more than 30 mutations in the spike (S) protein, indicating a high potential for immune evasion.1-4


    BA.2.86 has evolved and its descendant, JN.1 (BA.2.86.1.1), emerged in late 2023. JN.1 harbors S:L455S and three mutations in non-S proteins (Figure 1A). S:L455S is a hallmark mutation of JN.1: we have recently shown that HK.3 and other "FLip" variants carry S:L455F, which contributes to increased transmissibility and immune escape ability compared to the parental EG.5.1 variant.5

    Here, we investigated the virological properties of JN.1. We estimated the relative effective reproductive number (Re) of JN.1 using genomic surveillance data from France, the United Kingdom and Spain, where >25 sequences of JN.1 have been reported, using a Bayesian multinomial logistic model (Figures 1B, 1C, Table S3).6

    The Re of JN.1 in these three countries was higher than that of BA.2.86.1 and HK.3, one of the XBB lineages with the highest growth advantage at the end of November 2023 (Figure 1B).5

    These results suggest that JN.1 may soon become the dominant lineage worldwide.
    Indeed, by the end of November 2023, JN.1 has already overtaken HK.3 in France and Spain (Figure 1C). The in vitro ACE2 binding assay7 showed that the dissociation constant (KD) value of the JN.1 receptor-binding domain (RBD) is significantly higher than that of the BA.2.86 RBD (Figure 1D), suggesting that S:L455S decreases the binding affinity to the human ACE2 receptor.

    In contrast, the pseudovirus assay showed that the infectivity of JN.1 is significantly higher than that of BA.2.86 (Figure 1E). This discrepancy (Figures 1D, 1E) would be due to the difference between monomeric RBD and trimerized whole S protein (see also Supplementary Discussion).

    We then performed a neutralization assay using rodent sera infected with BA.2.86 or immunized with BA.2.86 S protein. In both cases, the 50% neutralization titer (NT50) against JN.1 was comparable to that against BA.2.86 (Figures 1F, 1G), suggesting that S:L455S does not affect the antigenicity of BA.2.86.

    On the other hand, the NT50 of breakthrough infection (BTI) sera with XBB.1.5 and EG.5.1 against JN.1 was significantly lower than that of HK.3 (2.6- to 3.1-fold) and BA.2.86 (3.8-fold) (Figures 1H, 1I). Furthermore, JN.1 shows robust resistance to monovalent XBB.1.5 vaccine sera compared to BA.2.86 (Figure 1J).

    Taken together, these results suggest that JN.1 is one of the most immune-evading variants to date. Our results suggest that S:L455S contributes to increased immune evasion, which partly explains the increased Re of JN.1

    (Continue . . . )

    None of this speaks to the severity or presentation of JN.1 compared to XBB Omicron, only its virological `fitness'.

    So far we've seen no evidence of increased morbidity or mortality from this new lineage.

    On Saturday the Sato Lab twitter/X account posted a series of explanatory tweets, including the following post which raises concerns over the amount of protection offered by the updated COVID vaccine.



    This, admittedly, appears to differ somewhat from other recent studies (see Preprint: XBB.1.5 Monovalent mRNA Vaccine Booster Elicits Robust Neutralizing Antibodies Against Emerging SARS-CoV-2 Variants) and the most recent assessment from the CDC.

    Laboratory results don't always translate into real-world results, and so we'll simply have to wait for better data.
    But even assuming reduced protection against breakthrough infection - the vaccine may still provide valuable benefits - including less severe acute infections and a lower chance of developing Long COVID.

    While it is always possible that something even more transmissible, or immune evasive, will emerge to usurp it, right now the JN.1 SARS-CoV-2 variant appears destined to ring in the new year in a big way.

    Which is why, limited protection or not, I'm glad I've got my updated vaccine and why I'll be wearing my KN95 masks whenever I'm in a crowded indoor public space.


    https://afludiary.blogspot.com/2023/...rological.html
    All medical discussions are for educational purposes. I am not a doctor, just a retired paramedic. Nothing I post should be construed as specific medical advice. If you have a medical problem, see your physician.

    Comment


    • #3
      Preprint: Virological Characteristics of the SARS-CoV-2 KP.3, LB.1 and KP.2.3 variants






      #18,115






      Regardless what H5Nx does in the months ahead, the SARS-COV-2 virus continues to circulate globally, producing new waves of infection as it evolves into new sub-variants (see above).
      Add in increased chronic health problems linked to `Long' or `Post' COVID syndrome (see CIDRAP Study reveals persistent risk of death, symptoms in COVID survivors at 3 years), and there are ample reasons to continue to follow its evolution and spread.

      Unfortunately, COVID evolves so quickly, it is impossible to know what variant will be dominant 3 or 6 months from now. Few variants have remained `on top' for longer than 6 months, and many have come and gone in half that time.

      Given the lead-time it takes to develop, produce, and distribute vaccines, this has made it difficult to select a target strain for each updated vaccine. Last week the FDA announced their intention to recommend the JN.1 strain (see below) for next fall's vaccine.

      Updated COVID-19 Vaccines for Use in the United States Beginning in Fall 2024

      FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC) met on June 5, 2024, to discuss and make recommendations on the selection of the 2024-2025 Formula for COVID-19 vaccines for use in the United States beginning in the fall of 2024.

      The committee unanimously voted to recommend a monovalent JN.1-lineage vaccine composition. Following the vote, the committee discussed considerations for the selection of a specific JN.1 lineage SARS-CoV-2 strain (e.g., JN.1 or KP.2) and expressed a strong preference for JN.1.


      The problem being, that in recent weeks the JN.1 strain has been rapidly usurped by several of its offspring (KP.3, KP.2, and LB.1). Some have recommended going with the newer KP.2 variant instead, but there are no guarantees that will be the dominant strain 5 months from now.




      The FDA appears to be gambling on the expectation that a direct descendant of JN.1 will likely be dominant next fall (and beyond), and that a JN.1 vaccine would remain cross-protective against an array of potential heirs to the viral throne.
      Be glad it isn't your decision to make.

      While we wait to see how this all plays out, we've a new preprint from the Kei Seto Lab at the University of Tokyo, on this new crop of COVID contenders (KP2.3 & LB.1 appear most problematic).
      Although a lot of what follows is fairly technical, the bottom line is pretty simple. SARS-CoV-2 doesn't appear anywhere near going quietly into the night.

      Follow the link to read the full report. I'll have a postscript after the break.
      Yu Kaku, Maximilian Stanley Yo, Jarel Elgin Tolentino, Keiya Uriu, Kaho Okumura, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Jumpei Ito, Kei Sato
      doi: https://doi.org/10.1101/2024.06.05.597664
      Abstract

      The SARS-CoV-2 JN.1 variant (BA.2.86.1.1), arising from BA.2.86.1 with a substitution in the spike (S) protein, S:L455S, exhibited increased fitness and outcompeted the previously predominant XBB lineages by the beginning of 2024.

      Subsequently, JN.1 subvariants including KP.2 (JN.1.11.1.2) and KP.3 (JN.1.11.1.3), which convergently acquired S protein substitutions such as S:R346T, S:F456L, and S:Q493E, have emerged concurrently.
      Furthermore, JN.1 subvariants such as LB.1 (JN.1.9.2.1) and KP.2.3 (JN.1.11.1.2.3), which convergently acquired S:S31del in addition to the above substitutions, have emerged and spread as of June 2024.
      We have recently reported the virological features of KP.2. Here we investigated the virological properties of KP.3, LB.1, and KP.2.3. We estimated the relative effective reproduction number (Re) of KP.3, LB.1, and KP.2.3 using a Bayesian multinomial logistic model based on the genome surveillance data from Canada, the UK, and the USA, where these variants have spread from March to April 2024.
      The Re of KP.3 is more than 1.2-fold higher than that of JN.1 and higher than or comparable to that of KP.2 in these countries. Importantly, the Re values of LB.1 and KP.2.3 are even higher than those of KP.2 and KP.3.

      These results suggest that the three variants we investigated herein, particularly LB.1, and KP.2.3, will become major circulating variants worldwide in addition to KP.2 and KP.3.

      We then performed virological and immunological experiments with pseudoviruses. The pseudovirus infectivity of KP.2 and KP.3 was significantly lower than that of JN.1. On the other hand, the pseudovirus infectivity of LB.1 and KP.2.3 was comparable to that of JN.1.

      Neutralization assay was conducted by using four types of breakthrough infection (BTI) sera with XBB.1.5, EG.5, HK.3 and JN.1 infections as well as monovalent XBB.1.5 vaccine sera. In all four groups of BTI sera tested, the 50% neutralization titers (NT50) against LB.1 and KP.2.3 were significantly lower than those against JN.1 (2.2-3.3-fold and 2.0-2.9-fold) and even lower than those against KP.2 (1.6-1.9-fold and 1.4-1.7 fold). Although KP.3 exhibited neutralization resistance against all BTI sera tested than JN.1 (1.6-2.2-fold) with statistical significance, there were no significant differences between KP.3 and KP.2.

      In the case of infection-naive XBB.1.5 vaccine sera, the NT50 values of JN.1 subvariants were very low. In the case of XBB.1.5 vaccine sera after natural XBB infection, the NT50 values against KP.3, LB.1 and KP.2.3 were significantly lower than those of JN.1 (2.1-2.8-fold) and even lower than KP.2 after infection (1.4-2.0-fold).

      Overall, our results suggest that the S substitutions convergently acquired in the JN.1 subvariants contribute to immune evasion, and therefore, increase their Re when compared to parental JN.1. More importantly, LB.1 and KP.2.3 exhibited higher pseudovirus infectivity and more robust immune resistance than KP.2. These data suggest that S:S31del is critical to exhibit increased infectivity, increased immune evasion, and therefore, potentially contributes to increased Re.

      Five weeks ago, it appeared as if KP.2 was the heir apparent, but now it looks as if KP.3 or LB.1 have some distinct fitness advantages. Of course, by October, we could be dealing with an entirely new group of up-and-coming variants.
      • The good news is, we haven't seen any signs that these emerging variants produce more severe illness, or increased deaths.
      Despite reassurances (4 years ago) that we were only months away from achieving `herd immunity', and predictions the virus would eventually stabilize, and become a minor `seasonal' threat, COVID shows few signs of taking early retirement.


      https://afludiary.blogspot.com/2024/...istics-of.html
      All medical discussions are for educational purposes. I am not a doctor, just a retired paramedic. Nothing I post should be construed as specific medical advice. If you have a medical problem, see your physician.

      Comment

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