Omicron's binding to sotrovimab, casirivimab, imdevimab, CR3022, and sera from previously infected or vaccinated individuals

Abstract

SARS-CoV-2 Omicron is the first pandemic variant of concern exhibiting an abrupt accumulation of mutations particularly in the receptor-binding domain that is a critical target of vaccination induced and therapeutic antibodies. Omicron's mutations did only marginally affect the binding of ACE2, and the two antibodies Sotrovimab and CR3022 but strongly impaired the binding of Casirivimab and Imdevimab. Moreover, as compared with Wuhan, there is reduced serum reactivity and a pronounced loss of competitive surrogate virus neutralization (sVN) against Omicron in naïve vaccinees and in COVID-19 convalescents after infection and subsequent vaccination. Finally, although the booster vaccination response conferred higher titers and better sVN, the effect was nonetheless significantly lower compared with responses against Wuhan. Overall, our data suggest that the antigenicity of Omicrons receptor binding motive has largely changed but antibodies such as Sotrovimab targeting other conserved sites maintain binding and therefore hold potential in prophylaxis and treatment of Omicron-induced COVID-19.

Keywords: Biological sciences; Health sciences; Immunology; Medicine.

Graphical abstract

Figure 1

ELISA binding profiles of 10 different RBDs of SARS-CoV-2 VOCs and VUIs and SARS-CoV-1 against a panel of monoclonal antibodies, soluble ACE2, and a representative convalescent plasma (A) Topological map displaying Omicron’s amino acid exchanges within a spike protein’s protomer and its RBD, respectively. RBM: receptor binding motif; triangles: Furin [black] and TMPRSS2 [gray] cleavage site; NTD: N-terminal domain; SD1: subdomain 1: SD2, subdomain 2; FP: fusion peptide; HR1: heptad repeat 1; HR2: heptad repeat 2; TM: transmembrane region. Binding profiles from ELISA experiments using (B) soluble ACE2, (C) CR3022, which was isolated based on its binding against SARS-CoV-1, (D) Casirivimab (REGN10933), (E) Imdevimab (REGN10987), (F) Sotrovimab (S309), and (G) a representative plasma from a COVID-19 convalescent donor from the first wave of SARS-CoV-2 infections. Titrations of the monoclonal antibodies were started at a concentration of 80 nM and eight 4-fold serial dilutions were measured. Convalescent serum was diluted 2-fold starting from a 1:50 dilution. Mean and standard deviation of duplicate measurements are given for all titrations. (H) Half maximal effective concentrations (EC₅₀) were calculated from the binding curves (a low EC₅₀ corresponds to a high affinity of the ligand).

Figure 2

Time course of serum binding titers against Wuhan and Omicron RBD Time course of binding titers (expressed as EC₅₀ values) in COVID-19 convalescent (left side of the vertical dashed line, circles) and SARS-CoV-2 naïve subjects (right side of the vertical dashed line, triangles) against Wuhan (blue) and Omicron (red) RBD. Both groups include an equal number of subjects (n = 24), which were monitored over time. Median and interquartile ranges are given for every group. Significance was calculated using one-way analysis of variance (ANOVA) with Geisser-Greenhouse correction, and the respective p-values are given.

Figure 3

Time course of serum neutralizing reactivity against Wuhan and Omicron in a sVNT Time course of neutralizing antibodies against Wuhan and Omicron as measured by a surrogate virus neutralization test. The assay measures the residual binding of ACE2 to the respective RBD variant after incubation with an analyzed serum at 1:50 dilution. Thus, values at 100% reflect absence of antibodies that neutralize by competition with the receptor, and values at 0% represent a very strong neutralization with no remaining binding signal from the soluble receptor. The two analyzed groups are COVID-19 convalescent (left side of the vertical dashed line, circles, n = 24) and SARS-CoV-2 naïve subjects (right side of the vertical dashed line, triangles, n = 24). The antigens were Wuhan (blue) and Omicron (red) RBD. Median and interquartile ranges are given for every group. Significance was calculated using one-way ANOVA with Geisser-Greenhouse correction and the respective p-values are given.