Prophylactic role of tixagevimab/cilgavimab for COVID-19 in newly transplanted kidney recipients: Single-center experience and review of literature

Abstract

BACKGROUND

Kidney transplant recipients (KTRs) are most vulnerable to infection in the first year after transplantation. Tixagevimab and cilgavimab are neutralizing monoclonal antibodies directed against different epitopes of the receptor-binding domain of the severe acute respiratory syndrome coronavirus 2 spike protein. The purpose of this study is to report experience with tixagevimab/cilgavimab administered to KTRs who were within 1 year of transplantation.

AIM

To describe outcomes of KTRs who received tixagevimab/cilgavimab early posttransplant to prevent coronavirus disease 2019 (COVID-19).

METHODS

This is a single-center retrospective cohort study of adult KTRs who underwent kidney transplantation from January 1, 2022 to September 30, 2022 and received tixagevimab/cilgavimab 300 mg/300 mg for prevention of COVID-19. Outcomes of interest were adverse events associated with tixagevimab/cilgavimab, COVID-19 breakthrough infection and COVID-19-associated hospitalization and complications. We also conducted a systematic review of the literature for the use of tixagevimab/cilgavimab as pre-exposure prophylaxis for COVID-19 in solid organ transplant recipients (SOTRs) from inception to December 31, 2023.

RESULTS

There were 104 patients included with median age of 50 years (range 21-72 years). Omicron strain of the COVID-19 virus was the predominantly circulating variant at the time of current study. Patients testing positive for COVID-19 were given tixagevimab/cilgavimab for prophylaxis of complications during the median of 3 days (range 0-201 days) after kidney transplant, of whom 97 (93.3%) received the antibodies prior to discharge. No discernable adverse effects attributable to the medication were observed during the time they received prophylaxis. The efficacy of the drug assessed through the absence of breakthrough infections were observed in 91 patients. 13 (12.5%) patients developed COVID-19 breakthrough infections during an overall median follow-up period of 125 days (range 10-257 days) after tixagevimab/cilgavimab. These infections were observed at median 105 days (range 6-211 days) after receiving the prophylactic medication. 5 (4.8%) of overall patients required hospitalization and there were no reported deaths in the cohort. Findings of the systematic review were consistent with our findings wherein tixagevimab/cilgavimab was well tolerated by SOTRs.

CONCLUSION

Tixagevimab/cilgavimab has a favorable safety profile when administered in newly transplanted kidney recipients. Although breakthrough infections were not uncommon, there was a low rate of hospitalization and no deaths. This study highlights the need to examine the efficacy of novel monoclonal antibodies administered for COVID-19 prophylaxis in newly transplanted recipients.

Key Words: Pre-exposure prophylaxis; kidney transplant; COVID-19; SARS-CoV-2; tixagevimab/cilgavimab; Early posttransplant period

Core Tip: This study reports on the use of tixagevimab/cilgavimab in newly transplanted kidney recipients. There were no adverse events related to the drug, and a 12.5% breakthrough infection rate, 4.5% hospitalization rate, and no deaths. The results suggest reassuring outcomes in newly transplanted kidney recipients who received tixagevimab/cilgavimab 300 mg/300 mg as prevention for coronavirus disease 2019 during the omicron wave. A systematic literature review of studies reporting outcomes of solid organ transplant recipients who received tixagevimab/cilgavimab found that the drug was well tolerated and a higher dose (300 mg/300 mg) was more protective against breakthrough infections and hospitalization than the lower dose (150 mg/150 mg).

INTRODUCTION

Kidney transplant recipients (KTRs) have worse outcomes and higher mortality when they contract severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)[1]. This is partly attributed by the comorbidities in transplant recipients patients making them more susceptible to the poor prognosis due to coronavirus disease 2019 (COVID-19) infection. The robust immunosuppression provided to these patients during the induction period makes adds to the enhanced risk[2,3]. In November 2021, the omicron (B.1.1.529) variant was identified as the predominant strain of SARS-CoV-2 worldwide. While the delta variant resulted in higher mortality rates in KTRs, the omicron variant resulted in less severe disease but was more infectious[4]. The lack of mountable anti-spike antibody responses in solid organ transplant recipients (SOTRs) even after 2 doses of the COVID-19 mRNA vaccine suggest that KTRs continue to remain at a higher risk for COVID-19 and breakthrough infections[5]. Similarly, with the omicron variant, data indicates diminished responses after 3 doses of the COVID-19 mRNA vaccine[6,7]. Accordingly, an additional layer of protection for KTRs from SARS-CoV-2 is needed. Monoclonal antibodies were developed to provide enhanced immunity in immunocompromised individuals and their use against SARS-CoV-2 was proposed in those individuals that are at a higher risk due to their low response to the COVID-19 mRNA vaccines[8].

Tixagevimab-cilgavimab (Evusheld^®) is a monoclonal antibody combination consisting of two neutralizing antibodies which neutralizes the viral growth by binding to the SARS-CoV-2 spike-protein receptor[9]. These antibodies have an extended half-life and were found to have prophylactic and therapeutic effects in preventing COVID-19[9]. Levin and colleagues studied the role of tixagevimab-cilgavimab in 5197 adults who were identified having an inadequate response to vaccination against COVID-19, an increased risk of exposure to SARS-CoV-2, or both[9]. They observed symptomatic infection in 0.2% of tixagevimab-cilgavimab group as compared to 1.0% patients who received placebo group (relative risk, 0.767 (0.46; 0.90). It provided insights to the protective role of tixagevimab-cilgavimab as a single dose and it was observed to be well tolerated.

The protective effect, however, seems to be dose-dependent. A study by Benotmane and colleagues showed that 150 mg of each antibody does not adequately protect KTRs against the Omicron variant of SARS-CoV-2[10]. Conversely, Al Jurdi et al[11] showed that 300 mg of tixagevimab and 300 mg of cilgavimab is associated with a low risk of breakthrough infections as compared to the low dose (150 mg of each antibody) group. Therefore, the minimum dose of tixagevimab-cilgavimab required to offer protection was established to be 300 mg/300 mg.

Prior studies reporting on outcomes of KTRs who received tixagevimab/cilgavimab have included patients at various timepoints from transplantation. The primary objective of the current study was to observe any adverse outcomes to assess safety profile in the suspectable KTRs population. The efficacy of the medication was assessed through the prevention of breakthrough infections. In addition, we provide a summary of the literature of tixagevimab-cilgavimab and its use in SOTRs. Findings of this study provides insights beyond the prevention of COVID-19 infection to prevent complications in KTRs by highlighting similarity in prophylactic mechanisms.

MATERIALS AND METHODS

Study setting and participants

We conducted a retrospective single-center cohort study of adult patients at Vanderbilt University Medical Center who received a kidney transplant from January 1, 2022, to September 13, 2022. Patients were identified by generating a list of KTRs in the specified time period and performing a manual chart review. The included patients required them to have received tixagevimab/cilgavimab 300 mg/300 mg for prevention of COVID-19. The Vanderbilt University Institutional Review Board (IRB No. 210132) approved the study. The consent was obtained from patients before enrolment into the study and Helsinki declaration was followed.

Recruitment process

Before inclusion, all adult patients who received a kidney transplant were offered tixagevimab/cilgavimab 300 mg/300 mg for prevention of COVID-19 prior to discharge from the index hospitalization for transplant. Patients who gave consent received tixagevimab/cilgavimab during inpatient hospitalization and were included. Those who did not give consent during inpatient stay, received an offer again for the medication during subsequent follow-up clinic visits. Patients receiving medication during clinic visit were included as well.

Exposure and comparator

The kidney transplant patients who received medication during the recruitment period comprised the exposure group and the comparator was comprised of kidney transplant patients during the same recruitment period who did not receive the prophylaxis and served as reference.

Data collection

Clinical characteristics were collected from the electronic medical record and tabulated in a Research Electronic Data Capture tool[12,13]. These included demographic and baseline characteristics (age, sex, race, panel reactive antibody, co-morbidities, kidney function), transplant characteristics (date and type of transplant, Australian Breast Device Registry mismatch, kidney donor profile index, delayed graft function, induction and maintenance immunosuppression), and date of tixagevimab/cilgavimab administration.

Outcomes

Outcomes of interest were adverse events associated with tixagevimab/cilgavimab, COVID-19 breakthrough infection, and COVID-19-associated hospitalization and complications. Breakthrough infection was defined by a positive COVID-19 antigen or polymerase chain reaction test after receiving tixagevimab/cilgavimab. Hospitalizations were attributed to COVID-19 if patients received COVID-19 directed therapies including steroids, immunosuppression adjustment, remdesivir, or tocilizumab. Administration of fluids or treatment of symptoms were not considered COVID-19 directed therapies. For hospitalizations that were ambiguous, two authors (El Chediak A and Concepcion BP) independently adjudicated and came to a consensus as to whether the hospitalization was for COVID-19 directed treatment.

Literature review

We conducted a systematic review of the literature for the use of tixagevimab/cilgavimab as pre-exposure prophylaxis for COVID-19 in SOTRs from inception to December 31, 2023. The PubMed search engines utilized for literature search include: "Cilgavimab and tixagevimab drug combination" [MeSH terms] OR "cilgavimab/tixagevimab"[tw] OR "tixagevimab/cilgavimab"[tw] OR "Evusheld"[tw] for finding relevant literature for Evusheld. We further combined our search with “AND” Boolean operator for reviewing studies pertaining to transplant. The search engine utilized for this included: “Transplantation” [MeSH terms] OR “Transplant” [tw]. After excluding duplicates, reviewing for relevance, and including those that met our eligibility criteria, 14 studies were selected which are summarized in Table 1. A flowchart illustrating our search criteria is illustrated in Figure 1.

Figure 1  PRISMA flowchart for literature review.

Table 1 Summary of studies on the use of tixagevimab-cilgavimab in solid organ transplant recipients.

Ref.	Country	Study design	Intervention	Number of patients	Types of SOTRs	Duration of SOTRs	Age (year)	Female (%)	Outcomes	Conclusions
Al Jurdi et al[11]	United States	Retrospective multicenter	150-150 mg: 90; 300-300 mg: 131	444	Kidney, lung, liver, multi-organ	3.8 years	65 (55-72)	39	Breakthrough: 5%; hospitalization: 1; death: 0	Lower breakthrough infection in higher dose group; well tolerated in kidney and lung recipients
Sanayei et al[17]	United States	Prospective single center	Dose not specified	323	Liver, kidney, pancreas	7 years	61.5 (10.5)	35.5	Breakthrough: 10.5%; hospitalization: 2; death: NA	Pre-exposure prophylaxis reduced infection; no significant mortality difference
Bravo González-Blas et al[18]	Spain	Prospective cohort	150-150 mg	55	Kidney only	9 years	67.8 (10)	51	Breakthrough: 12.7%; hospitalization: 1; death: 1	Safe and efficacious in immunocompromised kidney recipients
Ordaya et al[19]	United States	Retrospective multicenter	300-300 mg (92.6%), 150-150 mg (7.4%)	163	Heart, heart/lung, heart + abdomen	2.5 years	61 (48-69)	34.4	Breakthrough: 14.7%; hospitalization: 1; death: 0	Well tolerated; tacrolimus users more prone to infection
Angelico et al[20]	Italy	Single-center observational	All received Tix-cil	306	Kidney: 197; liver: 109	5.2 years	Kidney: 57.5	Kidney: 41.1	Breakthrough: 22.9%; hospitalization: 8; death: 0	Safe and effective in kidney recipients; comparable to protective antibody titres
Morado et al[21]	United States	Retrospective single-center	300-300 mg (93.3%), 150-150 mg (6.7%)	90	Kidney, lung, liver, heart	94 days	50.2 (14.5)	48.9	Breakthrough: 6.7%; hospitalization: 0; death: 0	Lower infection rate in Tix-cil group; well tolerated during Omicron
Alejo et al[22]	United States	Prospective observational study	150-150 mg (48%), 300-300 mg (52%)	392	Kidney, liver, lung, heart and multi-organ	150-150 mg: 4.7 years, 300-300 mg: 6.75 years	64	58.2	Breakthrough: 9.2%; hospitalization: 0.5%	Well-tolerated and improvement in patient reported outcomes
Sindu et al[14]	United States	Retrospective single center	300-300 mg (37.1%)	546	Lung	2.1 years	67.5 (59.6-73.9)	39	Breakthrough: 16.3%; hospitalization: 6.04%; death: 2.2%	Moderate effectiveness in lung transplant recipients
Jordan et al[23]	United States	Prospective single center	Tix-cil (41.8%)	911	Kidney, heart, lung, lover, multi-organ	Not reported	60.53 (13.5)	41.9	Breakthrough: 35.6%; hospitalization: 2.9%; death: 0	Reduction in breakthrough infections
Benotmane et al[10]	France, Europe	Retrospective single center	124 (100%)	124	Kidney	5.5 years	55	34.7	Breakthrough: 91.1%; hospitalization: 12.9%; death: 2.42%	Early administration of prophylaxis in high-risk kidney transplant patients associated with favorable outcomes
Kaminski et al[8]	France, Europe	Retrospective single center	77.42%	430	Kidney	8.2 years	59.2	37.9	Breakthrough: 19.3%; hospitalization: 3.5%; death: 0.7%	Significant reduction in infections and hospitalizations with a dose dependent benefit
Abraham et al[24]	United States	Retrospective single center	100%	481	Kidney, liver, heart, lung, multi-organ	19 months	58.8	35.1	Hospitalization: 5.4%; death: 1.6%	Reduced hospitalizations and severity of infections
Al Jurdi et al[25]	United States	Retrospective multicenter	50%	1266	Kidney, lung, heart, liver, multi-organ	4.6 years	63.5	38.3	Breakthrough: 11.2%; hospitalization: 1.2%; death: 0	Tix-cil not associated with significant reduction of outcomes in BA.5 period
Sindu et al[26]	United States	Retrospective single center	12.3%	195	Lung	3.3 years	66.6	41.5	Hospitalization: 57.9%; death: 24.1%	Less virulent omicron strain associated with poorer outcomes in elderly; No significant reduction of adverse outcomes with Tix-cil

Tix-cil: Tixagevimab-cilgavimab; SOTRs: Solid organ transplant recipients.

Statistical analysis

Categorical variables were presented as frequencies (percentages) and continuous variables were presented as medians (range). Wilcoxon Mann Whitney U test and χ² test were utilized as appropriate to compare groups. A statistical significance was achieved when the P value was < 0.05. Analysis was performed using STATA SE version 15.0 (StataCorp, College Station, TX).

RESULTS

Patient and transplant characteristics

There were 104 patients included with characteristics summarized in Table 2. The median age was 50 years (range 21-72 years). Forty-nine percent of patients were Black while 47% were White. Thirty-nine percent of patients received 2 doses of the COVID-19 mRNA vaccine while 2.9% were unvaccinated. Eighty-three percent of patients received a deceased donor kidney with 17% having delayed graft function. Majority of patients were induced with alemtuzumab (98%) and were maintained on a three-drug immunosuppressive regimen consisting of tacrolimus, mycophenolate and prednisone (96%).

Table 2 Characteristics of study population.

Characteristics	All patients (n = 104)	No COVID-19 infection (n = 91)	COVID-19 breakthrough infection (n = 13)	P value
Median age (IQR), year	50 (41-59)	50 (41-59)	50 (44-59)	0.48
Gender, n (%)				0.33
Female	45 (43.3)	41 (45.1)	4 (30.8)
Male	59 (56.7)	50 (54.9)	9 (69.2)
Race, n (%)				0.65
Black	51 (49.0)	44 (48.4)	7 (53.8)
White	49 (47.1)	44 (48.4)	5 (38.5)
Hispanic	3 (2.9)	2 (2.2)	1 (7.7)
Asian/Pacific Islander	1 (1.0)	1 (1.1)	0
Comorbidities, n (%)
Hypertension	100 (96.1)	87 (85.6)	13 (100)	0.44
Diabetes	49 (47.1)	39 (42.9)	10 (76.9)	0.21
COPD	4 (3.8)	3 (3.3)	1 (7.7)	0.44
Asthma	4 (3.8)	4 (4.4)	0	0.44
Current smoker	5 (4.8)	5 (5.5)	0	0.39
Coronary artery disease	10 (9.6)	10 (11.0)	0	0.21
Prior kidney transplant, n (%)	11 (10.6)	11 (12.1)	0	0.18
COVID-19 vaccine dose, n (%)				0.6
0	3 (2.9)	3 (3.3)	0
1	6 (5.8)	5 (5.5)	1 (7.7)
2	41 (39.4)	38 (41.8)	3 (23.1)
3	38 (36.5)	31 (34.1)	7 (53.8)
4	16 (15.4)	14 (15.4)	2 (15.4)
Donor type, n (%)				0.45
Deceased	83 (79.8)	71 (78.0)	12 (92.3)
Living	21 (20.2)	20 (22.0)	1 (7.7)
KDPI (%), n (%)				0.27
0-20	24 (29.3)	22 (31.4)	2 (16.7)
21-34	14 (17.1)	13 (18.6)	1 (8.3)
35-85	44 (53.7)	35 (50.0)	9 (75.0)
cPRA (%), n (%)				0.02
0	36 (34.6)	32 (35.2)	4 (30.8)
1-20	19 (18.3)	18 (19.8)	1 (7.7)
21-79	26 (25.0)	18 (19.8)	8 (61.5)
80-97	13 (12.5)	13 (14.3)	0
98-100	10 (9.6)	10 (11.0)	0
ABDR Ag mismatch, n (%)				0.15
0	7 (6.7)	4 (4.4)	3 (23.1)
1	3 (2.9)	3 (3.3)	0
2	6 (5.8)	6 (6.6)	0
3	17 (16.3)	16 (17.6)	1 (7.7)
4	28 (26.9)	25 (27.5)	3 (23.1)
5	27 (26.0)	22 (24.2)	5 (38.5)
6	16 (15.4)	15 (16.5)	1 (7.7)
Delayed graft function, n (%)	17 (16.3)	15 (16.5)	2 (15.4)	0.92
Induction immunosuppression, n (%)	102 (98.1)	89 (97.8)	13 (100)	0.59
Alemtuzumab	2 (1.9)	2 (2.2)	0
Basiliximab
Maintenance immunosuppression, n (%)				1
Tacrolimus	104 (100.0)	91 (100.0)	13 (100.0)
Mycophenolate	104 (100.0)	91 (100.0)	13 (100.0)
Prednisone	96 (92.3)	84 (92.3)	12 (92.31)

COVID-19: Coronavirus disease 2019; COPD: Chronic obstructive pulmonary disease; KDPI: Kidney donor profile index; cPRA: Calculated panel reactive antibody; Ag: Antigen; ABDR: Australian Breast Device Registry.

Prophylactic medication was administered at a median of 3 days (IQR: 0-201 days) after transplant, of whom 97 (93.3%) received the antibodies prior to discharge from the index transplant hospitalization. The remaining 7 patients received tixagevimab/cilgavimab at 13 days, 23 days, 24 days, 25 days, 28 days, 147 days, 201 days posttransplant.

Outcomes

The enrolled patients did not report any significant adverse events attributing to safety of the medication during the follow up period of 125 days (IQR: 10-257 days). The efficacy was assessed through the prevention of breakthrough infections. During the follow-up period, 13 (12.5%) patients developed breakthrough infection at 105 days (range 6-211 days) after prophylaxis. Two of these patients developed a breakthrough infection after 180 days (diagnosed at 182 days and 211 days posttransplant).

There were 5 (4.8%) patients who required hospitalization due to COVID-19. Two of those 5 patients developed acute kidney injury, and none required intubation or admission to the intensive care unit. Three of the patients received remdesivir and steroids. There were no deaths.

Comparator group

There were 36 patients who were offered tixagevimab/cilgavimab but declined. COVID-19 breakthrough infection in this group was lower at 8.3% (3 of 36 patients) compared to 12.5% in patients who received tixagevimab/cilgavimab. Due to the small number of comparators, there was insufficient power to determine if this difference was statistically significant.

DISCUSSION

In this study, we found that tixagevimab/cilgavimab 300 mg/300 mg given to newly transplanted kidney recipients has a favorable safety profile. In addition, we found that although breakthrough infections were not uncommon, there was a low rate of hospitalization and no deaths. This data provides reassurance that patients who receive tixagevimab/cilgavimab in the early posttransplant period do rather well even with breakthrough COVID-19 infections. To the best of our knowledge, this report is unique in that this cohort was composed of patients who received tixagevimab/cilgavimab early posttransplant. While several studies have reported outcomes of tixagevimab/cilgavimab in SOTRs which we summarized in our literature review, our report bridges the gap in knowledge of outcomes of KTRs in the early posttransplant period, a patient population that to the best of our knowledge has not been examined exclusively in prior studies.

Our literature search yielded 14 studies which are summarized in Table 1. Our findings were consistent with prior studies wherein tixagevimab/cilgavimab was well tolerated by patients who received solid organ transplants. In addition, the safety profile was particularly better in kidney and lung transplants than other SOTRs. A higher dose (300 mg/300 mg) was more protective against breakthrough COVID-19 infections and hospitalization compared to the lower dose regimen (150 mg/150 mg). Kaminski et al[8] concluded that 150 mg/150 mg dose was insufficient to produce a humoral response compared to higher dose regimen and emphasized preference for a higher dose of 300 mg/300 mg. Benotmane et al[10] studied the usage of tixagevimab/cilgavimab in high and low risk individuals based on comorbidities and immune response to prior vaccinations, and concluded the importance of an early administration in high risk groups significantly reducing hospitalizations and death. The Omicron variant of COVID-19 is less virulent but poses a high risk for the elderly and transplant recipients. Studies conducted by Sindu et al[14] and Al Jurdi et al[7] showed insufficient efficacy against the Omicron variant while tixagevimab/cilgavimab was well tolerated and efficacious for other strains. Cochran et al[15] studied the efficacy of tixagevimab/cilgavimab and bebtelovimab and concluded that infections, hospitalizations and deaths were fewer in patients who received tixagevimab/cilgavimab.

Taken together, these prior studies suggest that tixagevimab/cilgavimab dosed at 300/300 mg seems to provide adequate protection to KTRs. In our study, breakthrough infections were not uncommon and occurred at a higher rate compared to prior studies, although most generally remained mild. This finding, however, should not be construed as lack of efficacy in preventing breakthrough infections. Notably, these breakthrough infections occurred at a median of 125 days after tixagevimab/cilgavimab administration, with two patients developing the breakthrough infection greater than 180 days after tixagevimab/cilgavimab administration. We hypothesize that the efficacy of tixagevimab/cilgavimab may wane over time even within the 180-day period in which it is thought to be effective, noting that pharmacokinetic data indicates that tixagevimab/cilgavimab has an extended half-life of approximately 90 days[9]. In addition, breakthrough infections in our cohort also occurred at a higher rate compared to a small comparator group of KTRs who did not receive tixagevimab/cilgavimab. Whether tixagevimab/cilgavimab is less effective in newly transplanted KTRs warrants further study.

This study’s strength is that it focused on a relatively large number of patients who received early administration of tixagevimab/cilgavimab (median of 3 days after kidney transplant). This allows examination of outcomes in a patient population that is at greater risk for infection due to a higher level of immunosuppression early posttransplant. Our findings should be taken in the context of its limitations. This study was a single-center, retrospective observational study design, and limited by the absence of an adequate control group that could provide sufficient statistical power to make meaningful comparisons. The determination of the outcome of COVID-associated hospitalization could be prone to bias although when the outcome was ambiguous, two authors (El Chediak A and Concepcion BP) independently adjudicated and came to a consensus on the outcome.

CONCLUSION

In summary, our brief report suggests reassuring outcomes in newly transplanted kidney recipients who received tixagevimab/cilgavimab 300 mg/300 mg as prevention for COVID-19 during the omicron wave. Although tixagevimab/cilgavimab is currently no longer approved for use due to viral resistance patterns[16], this study highlights the need to examine the efficacy of novel monoclonal antibodies that are under development in newly transplanted KTRs including appropriate dosing and timing.