Pre-exposure prophylaxis with 300 mg Evusheld elicits limited neutralizing activity against the Omicron variant

To the editor:

Immunocompromised patients show an impaired vaccine-induced immune response, resulting in an increased risk of severe coronavirus disease 2019 (COVID-19).¹ In an effort to address this issue, health authorities in the US and various European countries have subsequently authorized the use of anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies for pre-exposure prophylaxis. Although the combination of casirivimab–imdevimab (Ronapreve, Roche Regeneron) has been shown to confer satisfactory protection against the Delta variant, it has limited neutralizing activity against Omicron.² In March 2022, the combination of cilgavimab–tixagevimab (Evusheld, AstraZeneca) was approved in the UK for protecting transplant recipients with poor response to vaccination against the Omicron variant.³ In France also, Evusheld was granted approval as of December, 2021. Although the Phase III Double-blind, Placebo-controlled Study of AZD7442 for Pre-exposure Prophylaxis of COVID-19 in Adult (PROVENT) study showed good efficacy for 300 mg Evusheld in the context of Delta-variant circulation, the question of whether this dosage is sufficient to prevent Omicron infection remains unanswered. Previous data indicated that the serum-neutralizing capacity against SARS-CoV-2 is positively associated with protection against severe forms of COVID-19.⁴ Here, we analyzed the neutralizing capacity of Evusheld against Omicron in a cohort of kidney transplant recipients who received the drug for pre-exposure prophylaxis.

Both anti–receptor binding domain (RBD) IgG titers and neutralizing antibody titers against the Omicron BA.1 variant were measured in serum samples collected from 63 adult kidney transplant recipients who received gluteal i.m. prophylactic injections of Evusheld (150 mg tixagevimab and 150 mg cilgavimab) in the Lyon and Strasbourg University Hospitals. Recipients with a history of COVID-19 or positive anti-nucleocapsid IgG were excluded. Patients who received prophylactic Ronapreve (600 mg casirivimab and 600 mg imdevimab, n = 39) and those who were infected with SARS-CoV-2 during the fifth wave of the pandemic (n = 14) were used as the negative and positive control groups, respectively. The study protocol was approved by the local ethics committees (identifier: DC-2013–1990 and DC-2021-4460), and written informed consent was obtained from all participants.

After a median interval from injection of 29 days (interquartile range: 29–33 days), patients who received Evusheld had a low level of neutralizing activity (Figure 1 a), and only 9.5% of them (6 of 63) were able to neutralize the Omicron variant, compared with 71% of patients (10 of 14) who were infected with SARS-CoV-2, and 2.6% (1 of 39) of those who received Ronapreve. Interestingly, convalescent patients displayed higher levels of neutralizing antibodies than those who received Evusheld (median: 2.3 log IC50, interquartile range: 1.5−2.7 vs. 0.00 log IC50, interquartile range: 0−0.05; P < 0.001). Although anti-RBD IgG titers were generally low after Evusheld injection (median: 2583 binding antibody units (BAU)/ml, interquartile range: 1906−3611 BAU/ml), a high interindividual variability was observed (range: 262−7032 BAU/ml; Figure 1b). This variability was explained largely by the patients’ body mass index, which showed an inverse correlation with anti-RBD IgG titers (Figure 1c). Further analysis revealed that participants with anti-RBD titers <2500 BAU/ml after Evusheld injection had no neutralizing activity (Figure 2 ). Furthermore, 7 patients of this cohort developed symptomatic COVID-19, including 2 who required hospitalization. All had negative neutralizing activity at the time of infection diagnosis.

Figure 1.

(a) Serum-neutralizing IgG titers (log IC50) measured with a previously described in-house viral pseudoparticle-based assay⁴in 3 groups of kidney transplant recipients. Orange circles denote titers measured at 28 days post-injection in patients (n = 63) who received Evusheld (300 mg; AstraZeneca), whereas yellow triangles indicate titers quantified at 31 days post-injection in patients (n = 39) who received Ronapreve (1200 mg; Roche Regeneron). Red squares denote titers measured at 27 days post-infection in patients (n = 14) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Dotted line represents the neutralizing positivity threshold (1.6 log IC50). Groups were compared with the Kruskal-Wallis test. The contingency graphs at the bottom of the figure indicate the percentages of patients with neutralizing activity in each group (with positive in red and negative in yellow; the percentage is reported in the middle). (b) Anti–receptor binding domain (RBD) IgG titers (binding antibody units [BAU]/ml, Abbott Architect) 28 days after Evusheld injection (300 mg) in 27 patients who did not receive Ronapreve™ before Evusheld. (c) Correlation between body mass index (kg/m²) and anti-RBD IgG titers (BAU/ml, Abbott Architect) 28 days after Evusheld injection (300 mg) in 27 patients who did not receive Ronapreve before Evusheld; r² = 0.595. BMI, body mass index.

Figure 2.

Correlation between anti–receptor binding domain (RBD) IgG (Abbott Architect) and neutralizing antibody titers³in 3 groups of kidney transplant recipients. Orange circles denote titers measured at 28 days post-injection in patients (n = 63) who received Evusheld (300 mg; AstraZeneca), and yellow triangles indicate titers quantified at 31 days post-injection in patients (n = 39) who received Ronapreve (300 mg; Roche Regeneron). Red squares denote titers measured at 27 days post-infection in patients (n = 14) who were infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). BAU, binding antibody units.

Taken together, these data indicate that less than 10% of patients who received Evusheld were able to neutralize the Omicron BA.1 variant at 29 days post-injection. Therefore, the dose of 300 mg Evusheld is likely insufficient to achieve the required neutralization activity in vivo. These findings corroborate those of a recent study conducted in transplant recipients who received 3 vaccine doses⁵; specifically, the authors reported that anti-RBD levels associated with serum neutralizing activity against Omicron in this population were approximately 8500 BAU/ml.⁵ Finally, our study also supports recent FDA recommendations,⁶ derived from in vitro models, regarding the need to increase the dose of Evusheld. To our knowledge, data on the effectiveness of tixagevimab−cilgavimab in the prevention of Omicron BA.2 infection have not yet been published. Research aimed at assessing the correlation between anti-RBD titers after Evusheld administration and the in vivo neutralizing capacity against the BA.2 Omicron variant is currently ongoing.

Disclosure

SC and OT have received consultant fees from AstraZeneca. All the other authors declared no competing interests.