We conducted a retrospective single-center study of lung transplant recipients receiving tixagevimab-cilgavimab PrEP during the Omicron period. We included all consecutive LTx recipients who received tixagevimab-cilgavimab PrEP in our institution between 10th June 2022 and 13th December 2022. As per national recommendations [17], the indication for tixagevimab-cilgavimab PrEP in immunocompromised patients was: SARS-CoV-2 anti-Spike antibody titers <260 Binding Antibody Units (BAU)/mL (AdviseDx SARS-CoV-2 IgG II assay, Abbott, IL, United States) assessed >14 days after the second COVID-19 booster vaccine (i.e., fully vaccinated patients with insufficient seroconversion, considered at risk for severe COVID-19). Tixagevimab-cilgavimab was provided by the National Health Authorities to eligible immunocompromised patients, in whom this antibody titer cut-off was mandatory and thus country-specific. PrEP was administered as a single dose (tixagevimab 150 mg/cilgavimab 150 mg, two separate consecutive intramuscular injections). The dominant circulating SARS-CoV-2 variant in Belgium during the study period was Omicron BA.5. In our center, PrEP was routinely offered to all patients with the above indication by their treating transplant physician at their outpatient follow-up visits, provided they had no symptoms suggestive of COVID-19, and subsequently administered upon informed consent. Patients were subsequently monitored for 1 h after PrEP for possible serious adverse events, which required reporting to the National Health Authorities in case these occurred.

Data on demographics, reports of positive SARS-CoV-2 PCR, and clinical outcomes of interest were extracted from the patients’ electronic medical records. Demographics included age, sex, body mass index (BMI), time and type of transplant, type of immunosuppressive regimen and comorbidities, including diabetes mellitus, chronic kidney disease and heart disease. Pre-existing chronic kidney disease was defined as severe chronic renal insufficiency stage 4, with eGFR <30 mL/min/1.73 m². Pre-existing heart disease was defined as ischemic heart disease (IHD), non-ischemic heart failure with or without reduced ejection fraction (HF), or arrythmia (AR).

SARS-CoV-2 positivity was defined by a positive PCR test; rapid antigen tests were not included, due to possible reporting bias. All patients with new clinical symptoms suggestive for COVID-19 were instructed to undergo COVID-19 PCR testing, either by their general practitioner or at the transplant center, which allowed to clinically assess the patient’s symptoms at each new COVID-19 diagnosis, and refer/admit to hospitalization, if deemed necessary. The PCR results were prospectively documented in the patient’s medical records and a centralized database.

Prevalence of symptomatic COVID-19 breakthrough infections, hospitalization, ICU admission and all-cause mortality were assessed up to 6 months after tixagevimab-cilgavimab administration. Patients with a recently confirmed COVID-19 infection prior to (<3 weeks) (n = 6) or post (<5 days) PrEP (n = 0) were excluded for analysis. We allocated the term mild disease to patients who solely required ambulatory care, moderate disease to those who were hospitalized and severe disease to those in need of intensive care unit management.

Patient characteristics and variables of interest/endpoints were summarized using descriptive statistics, and results are expressed as total value, proportions, mean (standard deviation) or median (interquartile range), wherever appropriate. Proportions were compared using Chi-square testing. Groups were compared using paired t-tests, unpaired Mann-Whitney tests, or Wilcoxon matched-pairs signed rank tests for repeated measures. Correlation analyses were performed using Spearman rank testing. A p-value <0.05 was considered significant. All statistical analyses were performed using GraphPad Prism 10.0 (Dotmatics, Boston, MA, United States).

At listing for LTx, all patients provide signed informed consent to use their clinical data for scientific research purposes by affiliated researchers of University Hospitals Leuven. Tixagevimab-cilgavimab PrEP was standard of care and administered after oral consent of the LTx recipient following therapeutic proposal by their treating physician. The institutional Ethics Review Board waived approval for the current retrospective, observational study (MP024291, S68119).

A total of 285 LTx recipients (40.3% of our total LTx population of 708 patients) were eligible for tixagevimab-cilgavimab PrEP. The flow chart of included and excluded patients is given in Figure 1. The 264 included patients received PrEP between 10th June 2022 and 13th December 2022, at which moment Omicron BQ.1 (a subvariant of BA.5) replaced BA.5 (BF) as the main circulating Omicron variant in Belgium (Figures 2, 3), and consequently administration of tixagevimab-cilgavimab PrEP was no longer recommended by the National Health Authorities because of reduced neutralizing efficacy against this BQ.1 subvariant [19, 20]. Median time between LTx and PrEP was 79.8 (43.0–138.5) months, and time between last SARS-CoV-2 booster vaccine and PrEP 173 (145–202.5) days. No serious adverse events (i.e., serious hypersensitivity reactions, including anaphylaxis) were seen immediately following PrEP administration, in addition, none of the included patients experienced a cardiovascular serious adverse event (i.e., myocardial infarction or stroke) during the 6-month post-PrEP study period.

Patient demographics are summarized in Table 1. Most patients were female (51.5%), and median age was 64 (55–68) years. 254 patients (96.2%) underwent lung transplantation only, 5 patients combined heart-lung transplantation, 3 others combined liver-lung transplantation, 1 patient a kidney-lung transplantation and another a liver-kidney-lung transplantation. Most patients (n = 235, 89.0%) were on a tacrolimus-based immunosuppressive regimen. None of the included patients was treated with a m-TOR inhibitor, had nor had received lymphocyte-depleting treatment (e.g., total lymphoid irradiation, antithymocyte globulin, or rituximab) for progressive chronic lung allograft dysfunction (CLAD) within 4–6 weeks prior to PrEP administration (as patients were required to be clinically stable to safely allow PrEP administration). Median BMI in our study population was in the normal range (23.4 (20.7–26.8), chronic lung allograft dysfunction (CLAD) was present in 27.7% (N = 73) of patients, 30.7% suffered from diabetes mellitus (n = 81), 17.8% from chronic renal insufficiency (n = 47) and 26.5% from pre-existing heart disease (n = 70).

Median SARS-CoV-2 anti-Spike antibody titer prior to PrEP was 13.2 (3.0–91.3) BAU/mL in the 264 included patents (i.e., <260 BAU/mL to be eligible for PrEP). In comparison, median SARS-CoV-2 anti-Spike antibody titer was 2243.0 (716.3–4785.0) BAU/mL in the 319 patients not eligible for PrEP (p < 0.0001).

A total of 29 (11.0%) patients had confirmed COVID-19 within 3 months after PrEP, of whom 8 (27.6%) were hospitalized, one of whom was admitted to ICU (3.4%). There was one COVID-19 related death (3.4%), being the ICU-hospitalized patient. Median time between PrEP and breakthrough infection was 43 (28–50) days.

Relevant clinical variables and immunosuppressant regimen in the patients with or without breakthrough infection within 3 months after PrEP are summarized in Table 2; and did not differ between both groups. All, but one, COVID-19 patients were single organ (lung only) transplant recipients. There was one COVID-19 patient who had received a combined heart-lung transplantation, this patient only suffered from mild disease (i.e., not hospitalized).

Another 17 patients had confirmed COVID-19 within 3–6 months after PrEP, resulting in a total of number of 46 patients (17.4% of all PrEP patients) with COVID-19 breakthrough infection within 6 months after PrEP (Figure 4). Demographics of all lung transplant recipients with COVID-19 within 6 months after tixagevimab-cilgavimab PrEP, according to time to COVID-19 breakthrough infection since PrEP (i.e., <3 months and 3–6 months), are summarized in Table 3. There were no significant differences between patients infected <3 months vs. 3–6 months after PrEP.

Main outcomes in the 46 COVID-19 patients, according to time of breakthrough infection after PrEP, are summarized in Table 4. Median time to breakthrough infection was 54 (36–124) days.

Of these patients, 17 (37%) were hospitalized and 3 (6.5%) were admitted to ICU. Mortality in the COVID-19 group (4.3%) was comparable to the total study group (5.3%) (p = 0.37). In total 11 out of 46 COVID-19 patients had pre-existing CLAD (8 BOS, 1 Mixed, 2 RAS). Of these, 1 patient demonstrated CLAD (BOS) progression with a FEV₁ decline of >10% during the 6 months study period, 1 patient (RAS) died due to COVID-19, and in the 9 other patients FEV₁ remained stable pre-COVID-19 vs. 6 months post-COVID-19 [FEV₁ 1.66 (1.18–2.15) L vs. 1.72 (1.05–1.96) L, p = 0.74].

Relevant clinical variables according to disease severity (mild vs. moderate to severe) in these 46 COVID-19 patients are summarized in Table 5. Patients presenting with mild disease were on average sooner infected after PrEP compared to patients requiring hospitalization: 47 (34–99) vs. 114 (61–121) days (p = 0.006). Patients with pre-existing heart disease tended to be more hospitalized (47.1% vs. 27.6%, p = 0.09), but no increased hospitalization risk was seen for concurrent CLAD, diabetes mellitus or chronic renal insufficiency, nor for type of immunosuppressive regimen.

Furthermore, only one COVID-19 patient had received lymphoid-depleting treatment with total lymphoid irradiation for allograft rejection within the 6 months prior to PrEP, none had received antithymocyte globulin treatment. Only four COVID-19 patients received remdesivir, all were hospitalized, and one died in the ICU (Table 3). None of the infected patients received nirmatrelvir/ritonavir for COVID-19 treatment in our programme.

Notably, SARS-CoV-2 anti-Spike antibody titer pre-PrEP was lower in COVID-19 patients (n = 46) compared to non-infected patients (n = 218): 3.1 (3.0–49.8) vs. 18.5 (3.0–98.3) BAU/mL (p = 0.039). Likewise, in a subgroup of patients (n = 36, 13.6%) in whom SARS-CoV-2 anti-Spike antibody titer was measured post-PrEP, a significantly lower antibody titer was seen in COVID-19 patients (n = 10) compared to non-infected patients (n = 26): 1261.6 (857.7–1835.1) vs. 2201.7 (1380.4–3405.7) BAU/mL (p = 0.0185) (Table 6).

In the COVID-19 patients, anti-Spike antibody titer pre-PrEP was similar in patients infected <3 months compared to those infected after 3–6 months: 3.0 (3.0–27.2) vs. 4.6 (3.0–91.7) (p = 0.16). Also, anti-Spike antibody titer pre-PrEP was similar in patients with mild COVID-19 compared to those with moderate to severe COVID-19: 3.0 (3.0–140.3) vs. 3.1 (3.0–37.7) BAU/mL (p = 0.65) (Table 4).

Relevant COVID-19 related outcome variables in the 17 hospitalized COVID-19 patients are summarized in Table 7. Overall, hospitalization duration was short (mean 12.2 ± 10.7 days), and respiratory support requiring non-invasive ventilation (n = 1), intubation with mechanical ventilation (n = 1), or extracorporeal support (n = 1) was rarely needed. COVID-19 associated pulmonary aspergillosis was diagnosed in two patients.