Low neutralizing activity of AZD7442 against current SARS-CoV-2 Omicron variants in patients with B cell malignancies.

Individuals who are immunocompromised, including patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia (NHL/CLL), often mount ineffective antibody responses after SARS-CoV-2 vaccination(1-3) and remain at a high risk of severe COVID-19.(4) Several monoclonal antibodies against the SARS-CoV-2 spike protein have been developed for prophylaxis or treatment against infection.(5) AZD7442 is a combination of 2 such antibodies (tixagevimab and cilgavimab) with a half-life of -90 days.(6) It received emergency use authorization (EUA) for use as preexposure prophylaxis in patients who are immunocompromised based on the PROVENT trial, which showed a reduced risk of symptomatic infection among patients deemed at risk of inadequate vaccine response or increased viral exposure.(7) However, only 7.2% of the participants had cancer, and 3.2% received immunosuppressive therapy. Importantly, PROVENT was conducted before the emergence of the B.1.1.529 (Omicron) variant. Using purified antibodies and/or pseudoviruses, some studies showed that many antibody formulations developed against the original SARS-CoV-2, including AZD7442, lost significant in vitro activity against Omicron variants.(8) Additionally, sera from patients who received AZD7442 blocked the binding between the wild-type spike receptor binding domain (RBD) and plates coated with its receptor ACE2 but had minimal efficacy at blocking the binding between Omicron BA.1 RBD and ACE2.(9) Reduced efficacy against Omicron variants was observed in patients treated with half-dose AZD7442,10 and -10% of AZD7442-treated kidney transplant recipients developed COVID-19 afterwards, with 35.9% of them requiring hospitalization.11 Although these reports raise concerns that AZD7442 has limited efficacy against Omicron variants, the neutralizing activity of full dose AZD7442 against live, contemporary Omicron variants after administration to patients who are immunocompromised remains unknown. We measured the antibody binding and neutralizing activities of plasma from AZD7442-treated patients with NHL/CLL for several live SARS-CoV-2 variants, including Omicron BA.2.75, BA.5, BQ.1.1, and XBB, which are currently in circulation. Adult patients with NHL/CLL at the Winship Cancer Institute of Emory University who received AZD7442 in accordance with the EUA fact sheet were enrolled in this prospective observational study approved by the institutional review board of Emory University. As such, patients received either a dose of 150 mg of each antibody followed by a repeat dose within 3 months or a single dose of 300 mg of each antibody. Blood was drawn after providing written informed consent, and antibody binding and live virus neutralization activities were measured as described previously1,12 and in the supplemental Material.