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 February 22, 2022, of the in vitro activity of authorized mAbs against the Omicron variants. Thirty-three studies were eligible including 33 containing Omicron BA.1 susceptibility data and five that also contained Omicron BA.2 susceptibility data. The first two authorized mAb combinations, bamlanivimab/etesevimab and casirivimab/imdevimab, were inactive against the Omicron BA.1 and BA.2 variants. In 24 studies, sotrovimab (third authorized mAb) displayed a median 4.1-fold (IQR: 2.4-7.6) reduced activity against Omicron BA.1 and, in four studies, a median 26-fold (IQR:16-35) reduced activity against Omicron BA.2. In 18 studies, cilgavimab and tixagevimab independently displayed median reductions in activity of >300-fold against Omicron BA.1, while in ten studies, the cilgavimab/tixagevimab combination (fourth authorized mAb preparation) displayed a median 63-fold (IQR: 26-145) reduced activity against Omicron BA.1. In two studies, cilgavimab was approximately 100-fold more susceptible to BA.2 than to BA.1. In two studies, bebtelovimab, the most recently authorized mAb, was fully active against both the Omicron variants. Disparate results between assays were common as evidenced by a median 42-fold range (IQR: 25-625) in IC50 between assays for the eight authorized individual mAbs and three authorized mAb combinations. Highly disparate results between published assays indicates a need for improved mAb susceptibility test standardization or inter-assay calibration.

Determinants of passive antibody efficacy in SARS-CoV-2 infection

“…Firstly, it aggregates studies using different therapeutics and with different enrolment and outcome criteria. Secondly, it tries to equate administered doses of convalescent plasma and monoclonal antibodies based on a single study comparing in vitro neutralisation of pseudovirus 21 (although this study reports IC-50s that are relatively consistent with the meta-analysis reported by Tao et al 7 , Fig. S4 ).…”

“…Unfortunately, even this calculation is not straightforward, as different studies often report different changes in IC-50 for the same antibody-variant combination. Tao et al 7 have comprehensively summarised the literature on neutralising potency of mAbs against the Omicron subvariants BA.1 and BA.2, and we have used this data to estimate the mean change in IC-50 and uncertainty in this estimate for different mAb-variant combinations. In addition to this, we added neutralisation data on BA.4 and BA.5 from four studies ( Fig.…”

“…The analysis above compares antibodies by reference to their neutralisation titre against ancestral (Wuhan-like) virus. However, a number of Omicron sub-variants including Omicron BA.1, BA.2, BA.4 and BA.5 have been shown to have greatly reduced in vitro neutralisation by therapeutic monoclonal antibodies 7 . Thus, a major clinical question is which monoclonal antibody regimens are likely still effective against existing or emerging variants.…”

“…A systematic review of the literature on in vitro neutralisation of monoclonal antibodies against BA.1 and BA.2 was published previously 7 , in which the combined data on IC50s from all studies was made available. In addition, we conducted our own review of the literature to find all in vitro neutralisation data of monoclonal antibodies against BA.4/5 available up to 14 July 2022 (n=4 studies identified [8][9][10][11] , search strategy described in supplementary methods).…”

Clinical antiviral efficacy of remdesivir and casirivimab/imdevimab against the SARS-CoV-2 Delta and Omicron variants

“…In laboratory studies casirivimab has no significant in vitro activity against Omicron variants 21-23 . For imdevimab mutations (N440K and G446S) in the ACE2 receptor binding site cause reduced in vitro neutralizing activity 21-23,29-31 . N440K occurs in all Omicron subvariants and 2-3log decrease in in vitro neutralization whereas G446S, which causes a substantially larger reduction in in vitro activity, occurs only in BA.1, BA.2.75 and BA.3 lineages.…”