Efficacy of Antiviral Agents against Omicron Subvariants BQ.1.1 and XBB | NEJM

In a recent study posted to the
bioRxiv* preprint server, researchers demonstrated a viral amplification procedure to isolate the astringent acute respiratory syndrome coronavirus two (SARS-CoV-ii) Omicron subvariants.













Study: Resistance of Omicron subvariants BA.ii.75.2, BA.4.6 and BQ.1.1 to neutralizing antibodies. Prototype Credit: Naeblys/Shutterstock

Additionally, they examined their sensitivity to a panel of half-dozen therapeutic monoclonal antibodies (mAbs) and sera from vaccinated individuals.

Background

Omicron BA.2, BA.iv, and BA.5 lineages have given rise to several new subvariants, including BA.2.75.2, and BA.iv.vi. and BQ.1.1. Successive sub-lineages of Omicron have infected nearly 80% of the globe population in less than a yr. Due to the increased transmissibility and allowed evasion potential of Omicron subvariants, vaccines offer inadequate protection against them, which, in turn, has increased the incidence of breakthrough infections even in triply vaccinated individuals.

The R346T spike (Southward) mutation found in Omicron sublineages, BA.2-derived BA.2.75.two, BA.4.6, and BQ.1.one, has also been associated with escape from mAbs and vaccine-induced antibodies. The convergent evolution of the SARS-CoV-ii Southward glycoprotein suggests that the different circulating Omicron subvariants experienced like selective pressure, likely exerted by preexisting or imprinted immunity. It makes the characterization of these new Omicron-derived viruses crucial.

Virtually the study

Omicron relies more on endocytic proteases and less on transmembrane protease serine, 2 (TMPRSS2) than prior SARS-CoV-ii variants. Hence, its isolates grow less efficiently in Vero E6 and Vero-TMPRSS2+ cells. Still, Omicron isolates demonstrated a high sensitivity to ovarian carcinoma-derived IGROV-1 cells, naturally expressing depression angiotensin-converting enzyme 2 (ACE2) and TMPRSS2 levels, as assessed past menstruum cytometry (FC).

Omicron BA.1 was particularly more sensitive to IGROV-ane cells. As with BA.i, numerous foci of infected cells were detected at two days mail-infection (p.i.), and supernatants were harvested at days two or three p.i., yielding loftier titers with the S-Fuse reporter cells. S-Fuse cells course syncytia and become GFP+ upon infection, assuasive overnight measurement of viral infectivity and neutralizing antibody (nAb) activity. Sequences of the variants later on one passage on IGROV-ane cells identified BA.iv.6 and BQ.1.i, indicating that no adaptative mutations were generated during this short culture period.

Syncytia were also observed in BA.2.75.two, and BA.4.6. and BQ.1.1-infected S-Fuse cells. The 3 variants generated syncytia of similar size that were smaller than those formed by the ancestral D614G strain. It will be worth farther examining whether other Omicron subvariants may display different fusogenic potentials in unlike cell types.

The squad collected 72 sera samples from a cohort of 35 healthcare workers in Orleans, France, who received three doses of the BNT162b2 vaccine. Xxx out of these 35 individuals experienced a mild symptomatic breakthrough Omicron infection 60 to 359 days afterward the third vaccination. To this end, the team analyzed 18 individuals early, i.e., one-month mail the third dose and x individuals at four months mail the third dose. They investigated whether vaccine-elicited antibodies neutralized the novel Omicron subvariants, BA.ii.75.2, and BA.4.six. and BQ.1.1. They used the D614G ancestral strain belonging to the B.1 lineage and BA.1 and BA.five as controls. Finally, the team calculated the half-maximal effective dose (ED50) for each combination of serum and virus.

Next, the researchers examined the bear on of BA.1/BA.2 breakthrough infections on the cross-neutralizing activity of serum antibodies. They analyzed xviii individuals at three months; they resampled 11 of these 18 individuals eight months afterward infection to evaluate the development of the humoral response. The distinct neutralization profile of BA.2.75.2, BA.four.6. and BQ.1.1 later on BA.1/BA.2 reinfections prompted researchers to examine the consequences of a BA.5 quantum infection on neutralization. They assessed the sera of 15 individuals nearly a month after the BA.5 infection.

Finally, the researchers assessed the sensitivity of BA.2.75.2 and BA.4.vi. and BQ.i.1 to mAbs currently authorized (cilgavimab, tixagevimab, and bebtelovimab) or withdrawn because of Omicron escape (sotrovimab, casirivimab, and imdevimab) using the S-Fuse assay.

Study findings

Neutralizing titers declined varyingly depending on the Omicron isolate. After 3 months, the researchers noted a stiff augmentation of neutralization against D614G and BA.1, with EDl
above x4. Compared to BA.1, the nAb titers were reduced past about seven-fold confronting BA.five and BA.4.half-dozen and xviii-fold confronting BA.two.75.two and BQ.1.1. Eight months afterward infection, while nAb titers remained loftier against D614G and BA.1, the reject was more confronting BA.5 and BA.4.6 and fifty-fifty more, marked confronting BA.ii.75.2 and BQ.1.1. Therefore, post-vaccination breakthrough infection by BA.one/BA.2 led to an increase in Omicron-specific nAb titers, with disparities between variants. The anti-BA.1 response was higher than confronting BA.five and BA.4.6, whereas BA.two.75.2 and BQ.i.one were less sensitive to neutralization.

ED50 attained values of 3×104
against D614G, similar to what the researchers observed for BA.1/BA.2 quantum infections. The neutralization of BA.five and BA.5-derived variants BQ.one.i was high but lower for the BA.ii-derived BA.2.75.two strain. Notably, the neutralization activity confronting BA.ane was less potent after a BA.v infection than later a BA.i/BA.2 infection. Conversely, a BA.1/BA.ii breakthrough infection favored neutralizing BA.1, and BA.2 derived strains relative to the BA.5 lineage.

ED50 were high for D614G simply decreased by viii- and fifteen-fold for BA.1 and BA.5, respectively, after a month of boosting, confirming the antibiotic escape properties of these previous sublineages. For BA.four.vi. and BQ.1.1, the EDl
was low but inside the range as observed with the parental BA.5 strain. BA.2.75.2 neutralization titers were 11-fold lower than BA.1. The researchers noted a similar trend four months after the third vaccination, indicating that vaccinees’ sera either poorly neutralized or could non neutralize BA.two.75.2, BA.four.6. and BQ.1.1 subvariants.

All mAbs used as pre- or post-exposure prophylaxis (PrEP) vest to the 4 anti-RBD antibody classes defined past their bounden site. Prophylaxis based on ronapreve and evusheld cocktails provided ~fourscore% protection against symptomatic infection, while post-therapy with sotrovimab prevented COVID-19-related hospitalization or decease with 85% efficacy. Cilgavimab and tixagevimab, fifty-fifty in combination, and casirivimab, lost all neutralization activity against the iii Omicron variants. Imdevinab inhibited BA.4.6, with one-half maximal inhibitory concentration (ICl) of 220 ng/ml but was inactive against BA.two.75.two and BQ.ane.ane. Bebtelovimab was efficient confronting BA.4.half dozen and BA.ii.75.two merely did not neutralize BQ.1.1. Sotrovimab was weakly active against BA.ii.75.two, BA.4.6. and BQ.1.1, with IC50s ranging from two,874 to xix,391 ng/ml, representing a 45-to-300-fold increase compared to D641G.

Cocktail mAbs, ronapreve (casirivimab and imdevimab), and evusheld (cilgavimab and tixagevimab) lost antiviral efficacy against BA.two.75.two and BQ.one.ane, whereas sotrovimab remained weakly active. BQ.i.i was besides resistant to Bebtelovimab. The evolutionary trajectory of novel Omicron subvariants facilitated their spread in immunized populations and raised concerns about the efficacy of most currently bachelor mAbs. Together, these results demonstrated that the prevalent BA.two.75.two and BQ.ane.1 strains are resistant or weakly sensitive to currently approved mAbs.

Conclusions

The IGROV-i cells recapitulated the permissibility of primary human nasal or alveolar cells to Omicron subvariants. They allowed rapid infectivity assessments using samples from infected individuals and ane-passage amplification of Omicron subvariants. Time to come work will aid understand viral entry pathways and replication in IGROV-1 cells and their underlying cellular mechanisms. Combining viral isolation in IGROV-1 cells with the S-Fuse neutralization assay provided a rapid method to evaluate the backdrop of novel yet-to-emerge SARS-CoV-2 variants of concern (VOCs).

Furthermore, the study demonstrated that the currently approved or withdrawn coronavirus disease 2019 (COVID-19) therapeutic mAbs lost about of their neutralization potential against these Omicron subvariants. Only sotrovimab retained a relatively low neutralization activity against all strains, with ICfifty
ranging from three to more than nine µg/ml. It as well displayed non-neutralizing antiviral activities, including antibody-dependent cellular cytotoxicity (ADCC). The current findings could aid accost the debate on the need to reassess the World Health Organization (WHO) therapeutics and COVID-19 guidelines on mAbs.

The college neutralization titers against D614G highlighted the role of allowed imprinting in anamnestic responses. However, the neutralizing response afterwards BA.1/BA.2 or BA.5 breakthrough infection in vaccinated individuals was dichotomous. Quantum infections in triply vaccinated individuals stimulated cross-neutralizing responses with distinct efficacies depending on the infecting Omicron variant. The development trajectory of the novel Omicron subvariants likely reflects their continuous apportionment in immunized populations. In summary, the study findings showed that a few convergent mutations in the BA.2 or BA.5 S led to resistance to about of the clinically used mAbs and strongly dumb the efficacy of vaccine-elicited antibodies.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/wellness-related behavior, or treated as established information.

Journal reference:

  • Delphine Planas, Timothee Bruel, Isabelle Staropoli, et al. (2022). Resistance of Omicron subvariants BA.ii.75.2, BA.four.6, and BQ.1.i to neutralizing antibodies.bioRxiv.
    doi:
    https://doi.org/10.1101/2022.xi.17.516888 https://www.biorxiv.org/content/10.1101/2022.xi.17.516888v1

Source: https://www.news-medical.net/news/20221121/New-method-for-isolating-Omicron-subvariant-and-evaluating-resistance-to-therapeutic-and-vaccine-elicited-antibodies.aspx

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