Lack of effectiveness of Bebtelovimab monoclonal antibody among high-risk patients with SARS-Cov-2 Omicron during BA.2, BA.2.12.1 and BA.5 subvariants dominated era

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants are expected to be resistant to Bebtelovimab (BEB) monoclonal antibody (MAb) and the real-world experience regarding its effectiveness is scarce. This retrospective cohort study reports a data analysis in Banner Healthcare System (a large not-for-profit organization) between 4/5/2022 and 8/1/2022 and included 19,778 Coronavirus disease-19 (COVID-19) positive (by PCR or direct antigen testing) patients who were selected from Cerner-Electronic Health Record after the exclusions criteria were met. The study index date for cohort was determined as the date of BEB MAb administration or the date of the first positive COVID-19 testing. The cohort consist of COVID-19 infected patients who received BEB MAb (N = 1,091) compared to propensity score (PS) matched control (N = 1,091). The primary composite outcome was the incidence of 30-day all-cause hospitalization and/or mortality. All statistical analyses were conducted on the paired (matched) dataset. For the primary composite outcome, the event counts and percentages were reported. Ninety-five percent Clopper-Pearson confidence intervals for percentages were computed. The study cohorts were 1:1 propensity matched without replacement across 26 covariates using an optimal matching algorithm that minimizes the sum of absolute pairwise distance across the matched sample after fitting and using logistic regression as the distance function. The pairs were matched exactly on patient vaccination status, BMI group, age group and diabetes status. Compared to the PS matched control group (2.6%; 95% confidence interval [CI]: 1.7%, 3.7%), BEB MAb use (2.2%; 95% CI: 1.4%, 3.3%) did not significantly reduce the incidence of the primary outcome (p = 0.67). In the subgroup analysis, we observed similar no-difference trends regarding the primary outcomes for the propensity rematched BEB MAb treated and untreated groups, stratified by patient vaccination status, age (<65 years or ≥65), and immunocompromised status (patients with HIV/AIDS or solid organ transplants or malignancy including lymphoproliferative disorder). The number needed to treat (1/0.026–0.022) with BEB MAb was 250 to avoid one hospitalization and/or death over 30 days. The BEB MAb use lacked efficacy in patients with SARS-CoV-2 Omicron subvariants (mainly BA.2, BA.2.12.1, and BA.5) in the Banner Healthcare System in the Southwestern United States.

SARS-CoV-2 neutralizing antibody bebtelovimab – a systematic scoping review and meta-analysis

“…Instead of just combining different neutralizing monoclonal antibodies, targeting mutated S protein with multivalent nanobody conjugates that can precisely display neutralizing antibodies against SARS-CoV-2 variants has been suggested to have the potential for enhancing the antiviral efficacy ( 67 ). However, a recent retrospective cohort study revealed evidence of lack of treatment efficacy among patients infected with SARS-CoV-2 Omicron BA.2, BA.2.12.1, and BA.5 subvariants ( 68 ). Hence, well-designed real-world evidence observational studies are important to confirm the efficacy and usage of bebtelovimab.…”

Allosteric Signal within the Receptor-Binding Domain of the SARS-CoV-2 Spike Protein Mediated by a Class 3 Monoclonal Antibody Revealed through Molecular Dynamics Simulations and Protein Residue Networks

“…Thus, the use of class 3 antibodies, e.g., bebtelovimab, is with some advantages over the class 1 and class 2 antibodies because (i) the epitope on the RBD surface for class 3 antibodies contains relatively conserved amino acids compared with other regions in the RBM and (ii) the epitope is exposed for mAbs’s binding either at the “closed” or “opened” RBD states . A deep mutational scanning study suggested that mutations at the bebtelovimab binding residues 444–446 and 499–500 resulted in the complete antibody escape found in XBB and BQ.1 variants, which led to the revocation of emergency use authorization for bebtelovimab in the United States and posed further challenges on the development of new vaccines and neutralizing antibodies due to multiple spike protein mutations. − However, as the BA.2, BA.4, and BA.5 omicron subvariants still contained the conserved residues 444–446 and 499–500 outside the heavily mutated regions of RBD, bebtelovimab still displayed its neutralizing efficacy against those subvariants, including the recently emerged BA.2.75.2. ,, …”

Outcomes of Monoclonal Antibody Use in Patients with COVID-19 (Preprint)

“…Later, in the fall of 2021, sotrovimab use also seemed to decrease odds of hospitalization and mortality [13,14]. Later studies of bebtelovimab use, however, found mixed results [15,16].…”