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Preprint: Resistance of Omicron Subvariants BA.2.75.2, BA.4.6 and BQ.1.1 to Neutralizing Antibodies

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  • Preprint: Resistance of Omicron Subvariants BA.2.75.2, BA.4.6 and BQ.1.1 to Neutralizing Antibodies

    Preprint: Resistance of Omicron Subvariants BA.2.75.2, BA.4.6 and BQ.1.1 to Neutralizing Antibodies

    A Radically Different COVID - Antigenic Diversity of SARS-CoV-2

    Next week will mark 1 year since the original announcement by South Africa's NICD on the spread of an emerging, and radically different COVID B.1.1.529 variant (dubbed VOC Omicron) - which, while `milder' than Delta - has proven itself to be far more transmissible.

    Much of its transmission advantage comes from Omicron's ability to evade prior immunity; acquired either from previous infection, from vaccination, or a combination of both.

    Vaccine `breakthrough' infections - which were once thought rare - are now quite common. Although newer bivalent boosters appear to provide better protection (see Preprint: mRNA Bivalent Booster Enhances Neutralization Against 2 BA.2.75.2 and BQ.1.1), it is too soon to know how long that added protection will last. Nearly as concerning, we've seen a steady erosion in the number of monoclonal treatment options since the emergence of Omicron.
    The Centers for Disease Control and Prevention (CDC) has reported a rapid increase in the circulation of certain SARS-CoV-2 Omicron subvariants in the United States that are likely to be resistant to currently used anti-SARS-CoV-2 monoclonal antibodies (mAbs).1

    The subvariants BQ.1 and BQ.1.1 are likely to be resistant to bebtelovimab,2 and the subvariants BA.4.6, BA.2.75.2, BA.5.2.6, BF.7, BQ.1, and BQ.1.1 are likely to be
    resistant to tixagevimab plus cilgavimab (Evusheld).

    The anticipated loss of susceptibility is based on knowledge about amino acid mutations that confer resistance to anti-SARS-CoV-2 antibodies and on data from in vitro neutralization studies.3

    While the antiviral Paxlovid remains available, it is not appropriate for all patients (see CIDRAP report Many hospital COVID patients have factors that rule out Paxlovid), making the continued loss of monoclonal treatment options a concern.

    This loss of treatment options was among the possible scenarios discussed by the UK's SAGE (Scientific Advisory Group for Emergencies) on COVID, which released a series of reports over the summer of 2021.

    With BQ.1.1 rising rapidly in the United States (we'll get a CDC Nowcast update later today), the following preprint - posted yesterday on the bioRxiv server - is particularly timely.

    Resistance of Omicron subvariants BA.2.75.2, BA.4.6 and BQ.1.1 to neutralizing antibodies

    Delphine Planas, Timothee Bruel, Isabelle Staropoli, Florence Guivel-Benhassine, Francoise Porrot, Piet Maes, Ludivine Grzelak, Matthieu Prot, Said Mougari, Cyril Planchais, Julien Puech, Madelina Saliba, Riwan Sahraoui, Florent Femy, Nathalie Morel, Jeremy Dufloo, Rafael Sanjuan, Hugo Mouquet, Emmanuel Andre, Laurent Hocqueloux, Etienne Simon-Loriere, David Veyer, Thierry Prazuck, Helene Pere, Olivier Schwartz
    Preview PDF


    Convergent evolution of SARS-CoV-2 Omicron BA.2, BA.4 and BA.5 lineages has led to the emergence of several new subvariants, including BA.2.75.2, BA.4.6. and BQ.1.1. The subvariants BA.2.75.2 and BQ.1.1 are expected to become predominant in many countries in November 2022. They carry an additional and often redundant set of mutations in the spike, likely responsible for increased transmissibility and immune evasion.

    Here, we established a viral amplification procedure to easily isolate Omicron strains. We examined their sensitivity to 6 therapeutic monoclonal antibodies (mAbs) and to 72 sera from Pfizer BNT162b2-vaccinated individuals, with or without BA.1/BA.2 or BA.5 breakthrough infection.

    Ronapreve (Casirivimab and Imdevimab) and Evusheld (Cilgavimab and Tixagevimab) lost any antiviral efficacy against BA.2.75.2 and BQ.1.1, whereas Xevudy (Sotrovimab) remained weakly active. BQ.1.1 was also resistant to Bebtelovimab.

    Neutralizing titers in triply vaccinated individuals were low to undetectable against BQ.1.1 and BA.2.75.2, 4 months after boosting. A BA.1/BA.2 breakthrough infection increased these titers, which remained about 18-fold lower against BA.2.75.2 and BQ.1.1, than against BA.1. Reciprocally, a BA.5 breakthrough infection increased more efficiently neutralization against BA.5 and BQ.1.1 than against BA.2.75.2. Thus, the evolution trajectory of novel Omicron subvariants facilitated their spread in immunized populations and raises concerns about the efficacy of most currently available mAbs.


    In summary, we show here that the few convergent mutations present in the spike of BA.2 or BA.5 subvariants led to resistance to most of available therapeutic mAbs and strongly impaired the efficacy of vaccine-elicited antibodies. Breakthrough infections in triply vaccinated individuals stimulate cross-neutralizing responses with distinct efficacy depending on the variant responsible for the infection. The evolution trajectory of the novel Omicron subvariants likely reflects their continuous circulation in immunized populations.

    (Continue . . . )

    While the future course and impact of COVID are unpredictable, two weeks ago we saw another preprint out of China, warning that a new batch of Omicron subvariants (including BQ.1.1.10, BA.4.6.3, XBB, and CH.1.1) may possess even higher levels of immune escape.

    They wrote:

    Together, our results suggest current herd immunity and BA.5 vaccine boosters may not provide good protection against infection. Broad-spectrum SARS-CoV-2 vaccines and NAb drugs development should be highly prioritized, and the constructed mutants could help to examine their effectiveness in advance.

    As long as this rapid-replacement cycle continues, it is going to be very difficult for vaccines and therapeutic development to keep up.
    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.