Efficacy of Tixagevimab/Cilgavimab Prophylaxis and Vaccination on Omicron Variants (BA.1, BA.2, BA.5, and BQ.1.1) in Kidney Transplant Recipients

Solid organ transplantation recipients are at very high risk of developing severe coronavirus disease 2019 (COVID-19).¹ Despite the implementation of a third dose of mRNA vaccine, the efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination on humoral and cellular immunities is reduced in this population.² In this context, we and other teams reported that the use of Evusheld (tixagevimab/cilgavimab) as monoclonal antibodies providing passive immunization in kidney transplant recipients with weak or no response to vaccine, during the Omicron surge, was effective in the prevention of severe and nonsevere COVID-19.³ Nevertheless, Benotmane et al. reported, in a retrospective study without a control group, the occurrence of breakthrough COVID-19 cases despite prophylaxis with tixagevimab/cilgavimab in kidney transplant recipients.⁴ However, although clinical data remain very scarce and concern BA.1 and BA.2 Omicron variants, little is known about the efficacy of such a strategy in BA.5 and BQ.1.1 variants in a clinical setting. In vitro studies have suggested that monoclonal antibodies may have limited efficacy against these recent variants, especially BQ.1.1 and XBB.⁵

In France, prophylactic use of monoclonal antibodies (Evusheld tixagevimab/cilgavimab from 12/2021) was recommended in solid organ transplantation patients with a complete vaccine scheme and no or weak humoral response (<264 BAU/ml⁶) 1 month after the last injection. Here, we report the occurrence and severity of COVID-19 in 697 fully vaccinated kidney transplant recipients between December 23, 2021, and December 31, 2022, during Omicron outbreak from a single center of kidney transplantation.

During the study period, BA.1 variant was predominant until the end of February 2022 (period 1); then, BA.2 became predominant until June 12, 2022, (period 2); then, BA.5 became predominant until September 24 (period 3) and then BQ.1.1 (period 4) became predominant (www.santepubliquefrance.fr). All patients were instructed to systematically report potential symptoms of COVID-19 and/or the positivity of a nasopharyngeal swab for SARS-CoV-2. None of the patients in this cohort were reported infected with other COVID-19 variants before Omicron. All patients received at least three doses of anti–SARS-CoV-2 mRNA vaccine. Outcomes were studied according the immunization status:

• - Group 1: vaccine-induced immunization, 283 patients. Anti–SARS-CoV-2 antibody level was measured at least 1 month after the third dose of vaccine, and the median titer was 1344 BAU/ml, interquartile range, 648–2430.

• - Group 2: insufficient vaccine-induced immunization but passive immunization with tixagevimab/cilgavimab, 322 patients. All kidney transplant recipients of group 2 received two intramuscular injections of 150 mg tixagevimab+150 mg cilgavimab between December 23, 2021, and February 2022, then two intramuscular injections of 150 mg tixagevimab+150 mg cilgavimab between April 2022 and May 2022, and then two intramuscular injections of 300 mg tixagevimab+300 mg cilgavimab between September and December 2022.

• - Group 3: insufficient vaccine-induced immunization, 92 patients. In this group, kidney transplant recipients did not receive prophylaxis with tixagevimab/cilgavimab (patient refusal, patient on anticoagulant therapy, patient unreachable at the time of monoclonal antibodies proposal).

Among kidney transplant recipients of group 2 and 3 with insufficient immunization, 324 of 414 (78%) patients did not develop humoral response.

Baseline characteristics of the patients are reported in Figure 1A. During follow-up, 329 patients (47%) presented an Omicron infection, of whom 285 were symptomatic (86.6%). Forty-seven patients (7%) required hospitalization, including 15 (2%) in intensive care unit (ICU). Nine patients (1%) died of COVID-19. Among the 47 patients hospitalized for Omicron SARS-CoV-2 infection, the characterization of the viral strain was possible for 39 patients (83%). The following strains were reported in the nasopharyngeal swab: BA.1 in 21 patients (54%), BA.2 in four patients (10%), BA.5 in two patients (5%), and BQ.1.1 in 12 patients (31%). The occurrence of infection, symptomatic infection, hospitalization, ICU hospitalization, and of COVID-19 death are significantly increased in patients of group 3 compared with groups 1 and 2 and in group 2 compared with group 1 (Figure 1B). Nevertheless, group 2 had comparable outcomes compared with group 1 during the first three periods (BA.1, BA.2, and BA.5), but hospitalization (4% versus 0%, P = 0.004), ICU requirement (3% versus 0%, P = 0.02), and death (1.5% versus 0%, P = 0.08) were more frequent during the BQ1.1 period (period 4) in group 2 compared with group 1. No serious adverse event was reported in our cohort with the use of tixagevimab/cilgavimab.

Figure 1.

Baseline characteristics of the patients and cumulative incidence of Omicron infection. (A) Baseline characteristics of the patients. (B) Cumulative incidence of Omicron infection. The log-rank test was used to make a comparison across the three groups and was considered as significant when P < 0.05. P^a is the P value for the log-rank test comparing group 1 and group 2; P^b is the P value for the log-rank test comparing group 2 and group 3; P^c is the P value for the log-rank test comparing group 1 and group 3. AZA, azathioprine; F, female; G1, group 1; G2, group 2; G3, group 3; ICU, intensive care unit; M, male; MMF, mycophenolate mofetil. Figure 1 can be viewed in color online at www.cjasn.org.

Despite potential bias linked to the retrospective design, our study demonstrates once again the potential utility of passive immunization prophylaxis with monoclonal antibodies in the protection of kidney transplant recipients without vaccine-induced immunity in a large cohort of kidney transplant recipients over a long period of Omicron SARS-CoV-2 infection. It also confirms, for the first time in a clinical setting, the reduced efficacy of tixagevimab/cilgavimab against BQ1.1 variant recently reported in vitro, even with the use of higher dose of monoclonal antibodies. The continued evolution of omicron variants reinforces the need for new therapeutic monoclonal antibodies for COVID-19, active on new variants such as BQ.1.1 and XBB variants. In the meantime, awaiting new monoclonal antibodies, antiviral drugs as nirmetralvir/ritonavir⁷ could be an alternative, although modified dosing is needed given the major interaction with calcineurin inhibitors.

Disclosures

S. Candon reports research funding from CSL Behring. S. Grange reports consultancy for Alexion and AstraZeneca and an advisory or leadership role for Alexion. All remaining authors have nothing to disclose.

Funding

None.

Author Contributions

Conceptualization: Dominique Bertrand, Dominique Guerrot.

Data curation: Dominique Bertrand.

Formal analysis: Dominique Bertrand.

Investigation: Dominique Bertrand, Sophie Candon, Dominique Guerrot, Charlotte Laurent, Ludivine Lebourg, Veronique Lemée.

Methodology: Dominique Bertrand.

Validation: Dominique Bertrand.

Visualization: Dominique Bertrand.

Writing – original draft: Dominique Bertrand.

Writing – review & editing: Dominique Bertrand, Sophie Candon, Tristan de Nattes, Steven Grange, Dominique Guerrot, Mélanie Hanoy, Charlotte Laurent, Frank Le Roy, Ludivine Lebourg, Veronique Lemée, Mathilde Lemoine, Dorian Nezam, Diana Pruteanu.