In a recent study posted to the medRxiv* preprint server, researchers evaluated the neutralization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2, BA.4, and BA.5 sub-variants by therapeutic monoclonal antibodies (mAbs).
SARS-CoV-2 spike-directed mAbs have been used in therapeutic and prophylactic settings. Therapeutic administration is 85% efficacious in preventing hospitalization or deaths due to coronavirus disease 2019 (COVID-19). However, Omicron (sub)variants substantially evade mAbs, leading to the discontinuation of sotrovimab and Ronapreve cocktail (imdevimab and casirivimab) after the emergence of BA.1.
Antibodies could trigger effector functions through fragment crystallizable (Fc) fragments. These Fc-effector functions destroy infected cells by activating antibody-dependent cellular cytotoxicity (ADCC) via natural killer (NK) cells or eliminate viral particles through antibody-dependent phagocytosis (ADP) mediated by macrophages.
The study and findings
The present study assessed the neutralization and ADCC activity of six therapeutic mAbs against SARS-CoV-2 Omicron BA.4 and BA.5 isolates. First, they tested the sensitivity of BA.4 and BA.5 authentic isolates to neutralization by six mAbs used in patients (tixagevimab, bebtelovimab, and cilgavimab) or discontinued (casirivimab, sotrovimab, and imdevimab) due to Omicron escape. SARS-CoV-2 Delta and Omicron BA.2 were used as controls.
The half-maximal inhibitory concentration (IC50) values of sotrovimab, casirivimab, imdevimab, and tixagevimab were higher for BA.4 and BA.5 variants than Delta. Although active, imdevimab and sotrovimab lost neutralizing potency. Moreover, sotrovimab was 15- and 17-fold less potent against SARS-CoV-2 BA.4 and BA.5. Imdevimab was more potent against BA.4 and BA.5 than sotrovimab.
Notably, cilgavimab and bebtelovimab were highly potent against BA.4 and BA.5 and showed minimal or no changes in potency relative to the Delta variant. The neutralization of BA.4 and BA.5, relative to that of BA.2, by sotrovimab and imdevimab, was slightly improved.
Further, when Ronapreve and Evusheld (cocktail of tixagevimab and cilgavimab) were tested, the authors noted that the two cocktails had lower potency against BA.4 and BA.5 than Delta variant, albeit the decrease was less pronounced for Evusheld.
Next, the mAbs were tested for their ability to bind to the spike of BA.4/5 and induce ADCC. Antibody binding was assessed by flow cytometry in BA.4/5 spike-expressing Raji cells. Delta, BA.2 spike, and cells transduced with empty vectors served as controls. All tested mAbs bound to Delta spike with a half-maximal effective concentration (EC50) less than 100 ng/ml.
BA.2 and BA.4/5 spikes had similar binding profiles, exhibiting a higher antibody evasion than Delta. Casirivimab and tixagevimab failed to recognize BA.4/5 spike even at a high concentration. The authors used a surrogate assay measuring the activation of the cluster of differentiation 16 (CD16) pathway to assess the ADCC-activation of mAbs. CD16 activation was detected in Raji cells expressing Delta, BA.2, or BA.4/5 spike, but not in Raji-empty cells.
Sotrovimab showed the highest efficiency in inducing ADCC irrespective of the SARS-CoV-2 variant. Evusheld cocktail or its constituents (tixagevimab and cilgavimab) did not activate ADCC. Casirivimab and imdevimab separately, or as the Ronapreve cocktail, showed intermediate ADCC activation.
Furthermore, the team evaluated serum antibody levels and neutralization of SARS-CoV-2 Delta, Omicron BA.2, or BA.5 by 40 immunocompromised subjects who received 300 or 600 mg of Evusheld as pre-exposure prophylaxis (PrEP). Of those who received 300mg Evusheld, 17 previously received Ronapreve as PrEP, with a median time of 35 days before the first Evusheld injection.
Similarly, two patients on the 600 mg Evusheld course had received Ronapreve 160 median days before the first Evusheld injection. Patients were categorized into five groups: naïve, Ronapreve, Ronapreve + Evusheld, Evusheld (300 mg), and Evusheldx2 (600 mg). Serum from naïve subjects failed to neutralize either variant, except for one sample that neutralized SARS-CoV-2 Delta.
Neutralization titers for Evusheldx2 individuals were higher against the tested variants. Overall, serum neutralization activity of Ronapreve and Evusheld recipients was reduced against BA.2 and BA.5 variants. Longitudinal samples were available for up to 186 days for eight individuals receiving Evusheld; five were naïve, and three received Ronapreve as PrEP.
Antibodies peaked 28 days after Evusheld administration and slowly decreased to 500 binding antibody units (BAU)/ml after 176 days. Similarly, serum neutralization activity was higher at administration and declined steadily by six months. Five Evusheld recipients had detectable neutralization against all tested variants after six months.
In summary, the study found that SARS-CoV-2 Omicron BA.4 and BA.5 evade neutralization by most therapeutic mAbs. Bebtelovimab was the most potent mAb, followed by cilgavimab. Sotrovimab was the most potent mAb to activate ADCC, despite the lower neutralization of Omicron. The ADCC activity might explain the clinical activity of sotrovimab against SARS-CoV-2 BA.2.
Assessment of sera revealed that Evusheld recipients had detectable neutralizing activity against BA.2 and BA.5, whereas Ronapreve recipients barely neutralized Omicron. Overall, the predominant SARS-CoV-2 Omicron BA.5 variant was sensitive to Evusheld, albeit the decay of neutralization activity was accelerated.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.