Cilgavimab and tixagevimab as pre-exposure prophylaxis in vaccine non-responder kidney transplant recipients during a period of prevalent SARS-CoV-2 BA.2 and BA.4/5 variants-a prospective cohort study (RESCUE-TX)

Abstract

Background: The response to severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) vaccination is severely impaired in patients on maintenance immunosuppression after kidney transplantation.

Methods: We conducted a prospective cohort study of 194 kidney transplant recipients (KTR) who exhibited no response to SARS-CoV-2 vaccinations (i.e., SARS-CoV-2 spike protein antibodies ≤264 U/mL) and had no prior documented infection. Patients received 300 mg of cilgavimab/tixagevimab as SARS-CoV-2 pre-exposure prophylaxis (PrEP) between March 4, 2022, and May 3, 2022 and were contrasted to a matched cohort of 186 KTRs also without immunization again defined as SARS-CoV-2 spike protein antibodies ≤264 U/mL and no documented prior infection. The primary outcome was the serum kinetics of cilgavimab/tixagevimab, the secondary endpoints were time to SARS-CoV-2 breakthrough infection, severity of disease and variant specific live viral in vitro neutralization tests of patient sera.

Findings: Longitudinal serum level monitoring showed a half-life of 91 days for both antibodies (95% CI 86-95 days for cilgavimab and 85-96 days for tixagevimab) in KTRs. In vitro neutralization tests showed effectiveness against the BA.2 omicron subvariant but not BA.5. The cumulative incidence of SARS-CoV-2 infections until May 15, 2022, (BA.2 dominance) was 15/194 vs 36/186 in the PrEP and control group respectively (OR = 0.35, 95% CI 0.18-0.66) but was not different thereafter (BA.4/5 dominance). The number of severe infections during the BA.2 period was lower in the prophylaxis than in the control group (OR = 0.37, 95% CI 0.17-0.79).

Interpretation: This study showed that SARS-CoV-2 PrEP with cilgavimab/tixagevimab demonstrated clinical effectiveness against variants that are neutralised (BA.2) but not against BA.4/5.

Funding: This study was funded by the Medical University of Vienna and an unrestricted grant from AstraZeneca (ESR-21-21585).

Keywords: COVID-19; Cilgavimab/tixagevimab; Kidney transplant; Vaccine non-responder.

Fig. 1

Study recruitment flow chart: The screening of 316 patients was required to enroll the 194 PrEP patients. The control group was assembled from all kidney transplant recipients attending our outpatient clinic in the months prior and during the recruitment phase who had a current SARS-CoV-2 antibody level measurement (n = 914). Of those, 196 patients fulfilled the inclusion criteria of the study (SARS-CoV-2 spike antibody levels ≤264 U/mL and no documented prior infection) and were not part of the PrEP group. These patients were paired 1:1 with patients in the PrEP group in order to synchronize the begin of observation time between the two groups. For ten of the 196 potential control patients no appropriate partner could be identified and thus these had to be excluded. The remaining 186 control patients who could be successfully paired with a PrEP patient formed the control group.

Fig. 2

Serum concentration of cilgavimab (left panel) and tixagevimab (right panel) over 48 weeks. The grey line indicates a smoothed estimate for concentration levels from linear mixed models, starting at the peak concentration level two weeks after PrEP.

Fig. 3

Variant specific live-virus neutralization tests (NT) of patient sera for BA.2 (left panel) and BA.5 omicron (right panel) subvariants at two, four, eight, 12 and 24 weeks after PrEP. The dashed (grey) line indicates the in vitro efficacy threshold of NT titers ≥10.

Fig. 4

Cumulative infections in patients with cilgavimab/tixagevimab prophylaxis against the background infection rate (black line) in the general population of Austria during the two omicron variant periods BA.2 (until mid May) and BA.4/5 (mid August).

Fig. 5

Event-free survival from breakthrough infection for the study cohort and control group during the era of BA.2 prevalence (until May 15) (left panel) and during the BA.4/5 period (May 16-August 15) (right panel). The p-value for a difference between groups was derived using a log-rank test. A stratified log-rank test accounting for the pairing-procedure yielded a p-value of 0.0003 for the first era. Note: The noticeable drop in patients at risk after 7.5 weeks in the left figure is due to the right censoring at the end of the era of BA.2 prevalence. As patients were recruited over roughly two months their available follow up until this date varied hence causing the number of patients at risk in the Kaplan–Meier analysis to decrease.

Fig. 6

Severity of infections during BA.2. During the BA.2 period until May 15, 15 patients in the PrEP group and 36 in the control group were SARS-CoV-2 PCR positive. Overall, statistically less patients in the PrEP group experienced a severe infection or required hospital admission (OR = 0.37, 95% CI 0.17–0.79, p = 0.0082). No difference was observed thereafter during the BA.4/5 wave.