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

Planas et al., bioRxiv, doi:10.1101/2022.11.17.516888
Nov 2022  
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In Vitro study suggesting a lack of efficacy for bebtelovimab with BQ.1.1.
Study covers bebtelovimab, casirivimab/imdevimab, and tixagevimab/cilgavimab.
Planas et al., 17 Nov 2022, preprint, 25 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperBebtelovimabAll
Resistance of Omicron subvariants BA.2.75.2, BA.4.6 and BQ.1.1 to neutralizing antibodies
Delphine Planas, Timothée Bruel, Isabelle Staropoli, Florence Guivel-Benhassine, Françoise Porrot, Piet Maes, Ludivine Grzelak, Matthieu Prot, Said Mougari, Cyril Planchais, Julien Puech, Madelina Saliba, Riwan Sahraoui, Florent Fémy, Nathalie Morel, Jérémy Dufloo, Rafael Sanjuán, Hugo Mouquet, Emmanuel André, Laurent Hocqueloux, Etienne Simon-Loriere, David Veyer, Thierry Prazuck, Hélène Péré, Olivier Schwartz
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. .
Vital materials: P.M., C.P., J.P., M.S., R.S., F.F., N.M., J.D., R.S., H.M., E.A., L.H., D.V., T.P., H.P. Viral sequencing: P.M., M.P., S.M., J.P., E.S-L., D.V., H.P. Manuscript writing and editing: D.P., T.B., O.S. Methods No statistical methods were used to predetermine sample size and the experiments were not randomized. The investigators were not blinded. Our research fulfills all relevant ethical requirements. Cohorts Serum from vaccinated and BA.1/2 and BA.5 breakthrough infected individuals (Orléans cohort). A prospective, monocentric, longitudinal, interventional cohort clinical study (ABCOVID) is conducted since 27 August 2020 with the objective to study the kinetics of COVID-19 antibodies in patients with confirmed SARS-CoV-2 infection (NCT04750720). A sub-study aimed to describe the kinetic of neutralizing antibodies after vaccination. The cohort was previously described 11, 16 . This study was approved by the Ile-de-France IV ethical committee. At enrollment, written informed consent was collected and participants completed a questionnaire covering sociodemographic characteristics. Virological findings (SARS-CoV-2 RT-qPCR results, date of positive test, screening, or sequences results) and data related to SARS-CoV-2 vaccination (brand product, date of first, second, third and fourth vaccination) were also collected. Nasopharyngeal swabs from infected individuals (Hôpital Européen Georges Pompidou). 134 nasopharyngeal swabs collected for standard care between..
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