Susceptibility of SARS-CoV-2 Omicron Variants to Therapeutic Monoclonal Antibodies: Systematic Review and Meta-analysis

Abstract

SARS-CoV-2 Omicron variants contain many mutations in its spike receptor-binding domain, the target of all authorized monoclonal antibodies (MAbs). Determining the extent to which Omicron variants reduced MAb susceptibility is critical to preventing and treating COVID-19. We systematically reviewed PubMed and three preprint servers, last updated 11 April 2022, for the in vitro activity of authorized MAbs against the Omicron variants. Fifty-one studies were eligible, including 50 containing Omicron BA.1 susceptibility data and 17 containing Omicron BA.2 susceptibility data. The first two authorized MAb combinations, bamlanivimab/etesevimab and casirivimab/imdevimab, were largely inactive against the Omicron BA.1 and BA.2 variants. In 34 studies, sotrovimab displayed a median 4.0-fold (interquartile range [IQR]: 2.6 to 6.9) reduction in activity against Omicron BA.1, and in 12 studies, it displayed a median 17-fold (IQR: 13 to 30) reduction in activity against Omicron BA.2. In 15 studies, the combination cilgavimab/tixagevimab displayed a median 86-fold (IQR: 27 to 151) reduction in activity against Omicron BA.1, and in six studies, it displayed a median 5.4-fold (IQR: 3.7 to 6.9) reduction in activity against Omicron BA.2. In eight studies against Omicron BA.1 and six studies against Omicron BA.2, bebtelovimab displayed no reduction in activity. Disparate results between assays were common. For authorized MAbs, 51/268 (19.0%) results for wild-type control variants and 78/348 (22.4%) results for Omicron BA.1 and BA.2 variants were more than 4-fold below or 4-fold above the median result for that MAb. Highly disparate results between published assays indicate a need for improved MAb susceptibility test standardization or interassay calibration. IMPORTANCE Monoclonal antibodies (MAbs) targeting the SARS-CoV-2 spike protein are among the most effective measures for preventing and treating COVID-19. However, SARS-CoV-2 Omicron variants contain many mutations in their spike receptor-binding domains, the target of all authorized MAbs. Therefore, determining the extent to which Omicron variants reduced MAb susceptibility is critical to preventing and treating COVID-19. We identified 51 studies that reported the in vitro susceptibility of the two main Omicron variants BA.1 and BA.2 to therapeutic MAbs in advanced clinical development, including eight authorized individual MAbs and three authorized MAb combinations. We estimated the degree to which different MAbs displayed reduced activity against Omicron variants. The marked loss of activity of many MAbs against Omicron variants underscores the importance of developing MAbs that target conserved regions of spike. Highly disparate results between assays indicate the need for improved MAb susceptibility test standardization.

Keywords: COVID-19; Omicron variant; SARS-CoV-2; antiviral therapy; monoclonal antibody; multidrug resistance; neutralization; spike protein.

FIG 1

Flow chart of study selection process. Of 985 deduplicated studies identified through a search of PubMed and three preprint servers using the search string “SARS-CoV-2 AND Omicron AND (Neutralization OR Antibody OR Treatment),” 111 were read in their entirety following an initial review of titles and abstracts. Forty-six studies met our inclusion criteria in that they contained neutralizing susceptibility data for one or more FDA-authorized monoclonal antibodies (MAbs). Five additional data sets, including three FDA fact sheets and two data sets available on the NIH NCATs website, were also included. The number of studies containing susceptibility data for the Omicron BA.1 and BA.2 variants and the number of studies for each of the clinical-stage MAbs are shown. BAM, bamlanivimab; ETE, etesevimab; CAS, casirivimab; IMD, imdevimab; SOT, sotrovimab; CIL, cilgavimab; TIX, tixagevimab; REG, regdanvimab; ADI, adintrevimab; BEB, bebtelovimab; AMU, amubarvimab; ROM, romlusevimab. The presence of two MAbs separated by “/” indicates the combination was tested and/or that each individual MAb in the combination was also tested.

FIG 2

For each MAb, the top of the RBD and two side views are depicted using coordinates from PDB 6M0J. Positions mutated in Omicron BA.1, BA.1.1, and BA.2 are shown in red. The MAb epitope is shown in dark blue. Those positions at which Omicron mutations overlap the MAb epitope are shown in purple. The MAb epitopes for bamlanivimab (BAM), etesevimab (ETE), casirivimab (CAS), imdevimab (IMD), cilgavimab (CIL), tixagevimab (TIX), sotrovimab (SOT), and bebtelovimab (BEB) were determined from their PDB structures.

FIG 3

Neutralizing susceptibility to the Omicron BA.1 variant for 18 individual MAbs or MAb combinations. Each plot shows the IC₅₀s of the wild-type control variant (on the left) connected by a line to the IC₅₀s of the Omicron BA.1 variant (on the right) performed in the same study. The cyan boxes encompass the interquartile range. IC₅₀s at or above 10,000 ng/mL or recorded as being above “>1,000 ng/mL” are plotted as 10,000 ng/mL. Several values below 1 ng/mL are plotted at 1 ng/mL. The distribution of fold reductions in susceptibility is shown beneath each plot. Studies that used a Delta variant control are not included in the plots.

FIG 4

Neutralizing susceptibility to the Omicron BA.2 variant for 18 individual MAbs or MAb combinations. Each plot shows the IC₅₀s of the wild-type control variant (on the left) connected by a line to the IC₅₀s of the Omicron BA.1 variant (on the right) performed in the same study. The cyan boxes encompass the interquartile range. IC₅₀s at or above 10,000 ng/mL or recorded as being above “>1,000 ng/mL” are plotted as 10,000 ng/mL. The distribution of fold reductions in susceptibility is shown beneath each plot. Two studies that used a Delta variant control are not included in the plots.

FIG 5

The distribution of fold changes in IC₅₀s relative to the normalized median IC₅₀ for all authorized MAbs against wild-type variants (A) and the distribution of fold reductions in susceptibility (Omicron variant IC₅₀/wild-type control IC₅₀) relative to the normalized median fold reduction for all authorized MAbs (B). Results that were more than 4-fold (2⁻²) below or 4-fold (2²) above the median result for an MAb were classified as outliers.

FIG 6

Neutralizing susceptibility for MAbs for which two or more infectious virus (authentic virus [AV]) assays (red points) and two or more pseudotyped virus (PV) assays (blue points) were performed. Such results were available for each of the authorized MAbs (both individually and in combination) except for bebtelovimab, for which just PV assays were available. Results were also available for regdanvimab (REG). Horizontal lines indicate median values. Fold changes are indicated at the top of each plot. Those with asterisks have a P value of <0.05 by the Wilcoxon rank sum test. BAM, bamlanivimab; ETE, etesevimab; CAS, casirivimab; IMD, imdevimab; SOT, sotrovimab; CIL, cilgavimab; TIX, tixagevimab.