Breakthrough COVID-19 after SARS-CoV-2 Vaccination in Solid Organ Transplant Recipients: An Analysis of Symptomatic Cases and Monoclonal Antibody Therapy

Abstract

Background:

Solid organ transplant (SOT) recipients are at increased risk for complications from SARS-CoV-2 infection. Little is known regarding clinical course and outcomes of breakthrough COVID-19 in the fully vaccinated SOT population. We sought to describe our cohort of SOT recipients who developed symptomatic breakthrough COVID-19 after full vaccination.

Methods:

We conducted a retrospective review of SOT recipients diagnosed with COVID-19 at least 14 days after completing SARS-CoV-2 vaccination. Patients were analyzed according to those presenting with mild-to-moderate and severe COVID-19, respectively. We described presenting characteristics, COVID-19 therapy, and analyzed outcomes including emergency department (ED) visits, hospitalization, and intensive care unit (ICU) admission.

Results:

Thirty-five patients met inclusion criteria. These had a mean age of 60.8 years and kidney transplant was the most common SOT type. Five patients presented with severe COVID-19 at diagnosis, all requiring hospitalization without ICU admission. From the 30 patients who presented with mild-to-moderate infection, 28 received casirivimab-imdevimab. Four of these 28 (14.3%) had an ED visit, with one requiring hospital admission (3.4%). No patients required ICU admission.

Conclusion:

Breakthrough COVID-19 may occur in SOT recipients after full vaccination, though they appear to have acceptable outcomes. Anti-spike monoclonal antibody therapy for eligible SOT patients may have mitigated clinical progression and improved the outcomes. Further study with large cohorts is warranted.

Social Media:

In this single-center study, SOT recipients with breakthrough COVID-19 had low rates of progression to severe infection, which may have been improved by use of anti-spike monoclonal antibody therapy.

1. Introduction

Solid organ transplant (SOT) recipients are at high risk for complications and poor outcomes from coronavirus disease 2019 (COVID-19).¹ Clinical trials of several vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have shown reduction in incidence of COVID-19 and have been granted emergency use authorization (EUA) for most adults, including the SOT population.^2–4 However, SOT recipients have been shown to produce lesser antibody responses to SARS-CoV-2 vaccination and may be at higher risk for breakthrough COVID-19.^5,6 While the vaccines are protective against severe disease, reports of breakthrough COVID-19 in high-risk populations, and specifically SOT recipients, have demonstrated high rates of severe clinical disease and mortality.^7,8 However, data remains sparse on the clinical course and outcomes of breakthrough COVID-19 in SOT recipients.

Concurrently, there has been an emergence in the use of passive immunotherapy with anti-spike monoclonal antibodies to mitigate the risk of COVID-19 progression to severe disease. Initial studies found this antibody therapy to reduce hospitalization and medically attended visits among patients with high-risk comorbidities.^9,10 While these early studies did not initially evaluate transplant recipients, later observational studies found similar results in SOT recipients^11,12 and other high-risk populations.^13–16 In the setting of prior COVID-19 vaccination, however, it is less clear how effective these monoclonal antibody therapies may be.

We sought to evaluate our cohort of SOT recipients who underwent SARS-CoV-2 vaccination and subsequently were diagnosed with breakthrough COVID-19, focusing on the clinical course to assess the progression to severe COVID-19 among those who received anti-spike monoclonal antibody therapy.

2. Methods

2.1. Study design and participants

We conducted a single-center retrospective review of SOT recipients who have completed a full COVID-19 vaccination series and were subsequently diagnosed with breakthrough COVID-19. Patients were ascertained by querying our internal COVID-19 database for those diagnosed from the start of the vaccination program through September 16, 2021. Inclusion criteria were adults who underwent solid organ transplantation and were at least 14 days from completing a full SARS-CoV-2 vaccination series at the time of COVID-19 diagnosis. Exclusion criteria were age less than 18 years, lack of or incomplete SARS-CoV-2 vaccination, COVID-19 diagnosis less than 14 days after completing a vaccination series, lack of COVID-19 confirmation by SARS-CoV-2 polymerase chain reaction (PCR) or antigen testing, or lack of research authorization per Minnesota law. For those who have had multiple breakthrough COVID-19 episodes, the first was used for this analysis.

Abstracted data included demographics, transplant characteristics, SARS-CoV-2 vaccination status, COVID-19 diagnosis, COVID-19 severity at diagnosis, complications, and therapy, and outcomes including emergency department (ED) evaluation, hospitalization, intensive care unit (ICU) admission, and mortality. Patients were followed up to 30 days after COVID-19 diagnosis. Study data were collected and managed using REDCap (Research Electronic Data Capture) tools hosted at Mayo Clinic.^17,18 This study was approved by our local institutional review board and granted an exception (IRB# 20–012919).

2.2. Study definitions

Full vaccination was defined as either receipt of a minimum two doses of an mRNA vaccine (Moderna, Pfizer-BioNTech) or one dose of an adenovirus vector vaccine (Johnson & Johnson). As recommendations evolved during the study period, others may have received a third mRNA vaccine dose. Mild-to-moderate COVID-19 was defined as mild symptoms without hypoxia (oxygen saturation ≥ 94%), with or without evidence of lower respiratory infection.¹⁹ Date of COVID-19 diagnosis was defined as the day a positive SARS-CoV-2 PCR or antigen assay was performed. Charlson comorbidity index (CCI) was calculated as previously defined.²⁰ Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m² or those requiring hemodialysis. eGFR was calculated according to the 2021 Chronic Kidney Disease Epidemiology Collaboration.²¹ For patients who have undergone multiple transplantation procedures, the date of the first transplantation was used.

2.3. Monoclonal antibody allocation process

The Mayo Clinic monoclonal antibody treatment program (MATRx) was established on November 7, 2020, with the creation of COVID-19 dedicated outpatient infusion units and multidisciplinary teams.²² The MATRx team developed the Monoclonal Antibody Selection Score (MASS) that automatically and rapidly identified all eligible patients from the electronic health record system. Under the EUA, all transplant recipients were eligible for monoclonal antibodies if they have positive SARS-CoV-2 PCR or antigen test, have mild-to-moderate COVID-19, and are within 10 days of symptom onset. Patients who were admitted for an indication other than COVID-19 were considered for monoclonal antibody therapy if otherwise eligible.

The MATRx providers reviewed all patients identified from this registry of patients with positive SARS-CoV-2 PCR tests and self- and provider-referred patients. All eligible patients were proactively approached for education about monoclonal antibodies, and discussion about their potential benefits and adverse reactions. Patients who agreed with treatment were immediately scheduled for infusion. Monoclonal antibodies were infused over 30–60 minutes followed by another hour of monitoring for adverse effects. Patients were subsequently followed by remote monitoring program and/or were provided a phone number to call back to report any untoward reactions.²³

2.4. Statistical analysis

Continuous variables were summarized as either median with interquartile range (IQR) or mean with standard deviation. Fisher’s exact test was utilized for categorical variables and Mann-Whitney U test for continuous variables. Statistical significance was defined as p-value of less than 0.05 from two-sided tests. All analyses were performed using BlueSky Statistics version 7.10 software (BlueSky Statistics LLC, Chicago, Illinois).

3. Results

3.1. Patient characteristics

Our registry query yielded 35 eligible SOT patients who underwent analysis (Table 1). This cohort was predominantly male with a mean age of 60.8 years (range: 32–77). The most common SOT type was kidney (62.9%), followed by liver (14.3%). Hypertension and CKD were present in most patients, with 2 patients (5.7%) receiving hemodialysis at the time of COVID-19 diagnosis. The majority were receiving tacrolimus, mycophenolate, and prednisone as maintenance immunosuppression. No patients had an episode of rejection in the 6 months prior to diagnosis. These cases were primarily diagnosed in August and the analyzed portion of September 2021 – a period dominated by the SARS-CoV-2 B.1.617.2 delta variant (Figure 1).

Table 1:

Cohort Characteristics of 35 Solid Organ Transplant Recipients with Breakthrough COVID-19

	Total (n=35)	Mild-to-moderate COVID-19 (n=30)	Severe COVID-19 (n=5)	p-value1
Age, years, mean (SD)	60.8 (11.4)	61.3 (11.3)	58.0 (13.2)	0.60
Male gender	20	15 (50)	5 (100)	0.06
Race				1
- Asian	1 (2.9)	1 (3.3)	0
- Black	1 (2.9)	1 (3.3)	0
- White	33 (94.3)	28 (93.3)	5 (100)
Transplant type				0.62
- Kidney	22 (62.9)	18 (60)	4 (80)
- Kidney-pancreas	1 (2.9)	1 (3.3)	0
- Pancreas	2 (5.7)	2 (6.7)	0
- Liver	5 (14.3)	5 (16.7)	0
- Heart	2 (5.7)	1 (3.3)	1 (20)
- Heart-kidney	2 (5.7)	2 (6.7)	0
- Lung	1 (2.9)	1 (3.3)	0
Time from transplant to COVID-19 diagnosis, months, median (IQR)	143.5 (64.0–275.3)	141.1 (64.4–260.7)	143.5 (133.1–283.0)	0.45
BMI, kg/m2, mean (SD)	32.5 (5.5)	32.9 (5.2)	30.5 (7.4)	0.64
Hypertension	25 (71.4)	21 (70)	4 (80)	1
Congestive heart failure	5 (14.3)	3 (10)	2 (40)	0.14
COPD	4 (11.4)	3 (10)	1 (20)	0.48
Diabetes mellitus	14 (40)	13 (43.3)	1 (20)	0.63
Malignancy	3 (8.6)	3 (10)	0	1
Cirrhosis	1 (2.9)	1 (3.3)	0	1
Chronic kidney disease	23 (65.7)	19 (63.3)	4 (80)	0.64
Hemodialysis	2 (5.7)	2 (6.7)	0	1
eGFR, mL/min/1.73 m2, mean (SD)2	51.4 (19.3)	53.2 (18.9)	41.9 (20.9)	0.23
CCI, mean (SD)	4.3 (2.2)	4.3 (2.3)	4.4 (1.8)	0.81
Leukocyte count at diagnosis, x109/L, median (IQR)3	4.8 (3.9–5.8)	9.5 (5.5–12.3)	6.0 (5.0–8.0)	0.43
Lymphocyte count at diagnosis, x109/L, median (IQR)4	1.0 (0.6–1.5)	1.1 (0.7–1.6)	0.5 (0.4–0.8)	0.09
Baseline immunosuppression
- Tacrolimus	31 (88.6)	26 (86.7)	5 (100)	1
- Cyclosporine	1 (2.9)	1 (3.3)	0	1
- Sirolimus	2 (5.7)	2 (6.7)	0	1
- Mycophenolate	27 (77.1)	23 (76.7)	4 (80)	1
- Azathioprine	2 (5.7)	2 (6.7)	0	1
- Belatacept	1 (2.9)	1 (3.3)	0	1
- Prednisone	32 (91.4)	28 (93.3)	4 (80)	0.38
Prednisone daily dose, mg, median (range)5	5 (5–5)	5 (4–10)	5 (5)	0.59
Vaccine received				0.69
- Johnson & Johnson	1 (2.9)	1 (3.3)	0
- Moderna	12 (34.3)	11 (36.7)	1 (20)
- Pfizer-BioNTech	22 (62.9)	18 (60)	4 (80)
Time from symptom onset to COVID-19 diagnosis, days, median (IQR)	2 (1–6)	2 (1–6)	3 (2–4)	0.96
Time from full vaccination to COVID-19 diagnosis, days, median (IQR)	133 (109.5–164.0)	139.5 (116.3–169.3)	98.0 (69–114)	0.04
Time from last vaccine dose to COVID-19 diagnosis, days, median (IQR)	127.0 (76.5–146.5)	128.0 (84.3–156.8)	98.0 (69–114)	0.24
Received third vaccine dose	4 (11.4)	6 (20.7)	0	0.56

All data are n (%) unless otherwise specified. Bold indicated a p-value less than 0.05.

¹Comparing mild-to-moderate COVID-19 to severe COVID-19.

²n = 33, excluding those receiving hemodialysis (mild-to-moderate COVID-19 n = 28, severe COVID-19 n = 5)

³n = 21 (mild-to-moderate COVID-19 n = 16, severe COVID-19 n = 5)

⁴n = 20 (mild-to-moderate COVID-19 n = 16, severe COVID-19 n = 4)

⁵n = 32 (mild-to-moderate COVID-19 n = 28, severe COVID-19 n = 4)

Abbreviations: BMI, body mass index; CCI, Charlson comorbidity index; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease-2019; eGFR, estimated glomerular filtration rate; IQR, interquartile range; SD, standard deviation

Figure 1:

Number of breakthrough COVID-19 cases depicted by month of diagnosis, through September 16, 2021.

Twenty-two patients received Pfizer-BioNTech mRNA vaccine, including 4 who had received a third dose. Median time from third dose administration to COVID-19 diagnosis was 21 days (IQR: 18–24.5). All patients were diagnosed by various types of SARS-CoV-2 PCR assays. Seven patients’ samples underwent viral gene mutation analyses, and 4 were consistent with the delta variant, 2 were wild-type, and 1 was the alpha variant. All patients had full 30-day follow-up at the time of this analysis.

3.2. Severe COVID-19

Five (14.3%) of the 35 patients presented with severe COVID-19 at diagnosis. All 5 were hospitalized, although none required ICU admission. One patient required supplemental oxygen with high-flow nasal cannula, set as high as 40% FiO₂. The other four had transient hypoxia and did not require continued supplemental oxygenation. Two patients had both anti-spike and anti-nucleocapsid antibodies assessed, all being negative. None of these 5 patients had received a third vaccine dose. As all five presented with severe disease, ranging 0–7 days from symptom onset, they were not candidates for anti-spike monoclonal antibody therapy. All patients did receive non-monoclonal antibody therapies, including 4 who received remdesivir, 3 who received augmented corticosteroid dose, 2 who received convalescent plasma, and 1 who received tocilizumab. Two patients had reduction in their mycophenolate dose. None of these patients died. The only variable associated with presenting with severe disease was a shorter time from vaccination to diagnosis (p = 0.04).

3.3. Monoclonal antibody therapy for mild-to-moderate COVID-19

From the 30 patients with mild-to-moderate COVID-19 at the time of diagnosis and eligible for monoclonal antibody therapy, almost all (n=28) consented and received the therapy. The two patients who declined monoclonal antibody therapy included 1 patient who self-isolated at home and 1 who was admitted for pyelonephritis. Neither patient progressed to severe disease. One of those who declined monoclonal antibody therapy underwent a reduction in immunosuppression, which included reducing their mycophenolate dose and holding belatacept beyond their usual dosing interval.

All 28 patients who consented to passive immunotherapy received the casirivimab-imdevimab combination. Patients were infused a median 3 days after symptom onset (IQR: 3–8) and 2 days after diagnosis (IQR: 1–2). These patients were median 147 days from completing vaccination (IQR: 127.8–172.5). Only 1 adverse effect potentially attributable to the monoclonal antibody therapy was noted, which was chills immediately following infusion. No anaphylactic reactions were noted. Only two of 28 patients had anti-spike antibodies assessed prior to breakthrough COVID-19 diagnosis, 1 of which was positive (titer: > 250 units/mL). The patient with a negative anti-spike antibody was also negative for anti-nucleocapsid antibody.

Four patients (14.3%) sought an ED evaluation within 30 days at a median 18.5 days following monoclonal antibody infusion (range: 2–26). One (3.6%) patient was deemed to have progressed to severe COVID-19 and was hospitalized for 2 days. The patient was treated with remdesivir but did not require supplemental oxygen or ICU care. Computed tomography of the chest showed patchy, bilateral ground-glass opacities without pulmonary embolism. Five patients (17.9%) underwent reduction in mycophenolate dosing, including the individual who progressed to severe infection. No patients who presented with mild-to-moderate COVID-19 died.

4. Discussion

Breakthrough COVID-19 after vaccination is a significant issue for SOT recipients. Our study highlights that SOT patients remain at risk for severe disease, which required hospitalization, although the severity of clinical presentation appeared less than previously described in the pre-vaccination era.¹ Notably, none of these patients required ICU admission or died and only one patient required oxygen supplementation.

Our SOT cohort was notable for the high uptake of casirivimab-imdevimab therapy, with 28 of 30 eligible patients receiving this intervention. This may have accounted for the favorable outcomes seen by patients who presented with mild-to-moderate infection. A separate report of monoclonal antibody use in SOT recipients prior to widespread vaccination showed similar outcomes, including no mortality and little ICU utilization.¹¹ Contrasting this, a more recent report of breakthrough COVID-19 in SOT recipients showed a 36% rate of severe COVID-19 in a cohort where only 50% received anti-spike monoclonal antibodies.²⁴ Another report of vaccinated kidney transplant recipients with COVID-19 also showed higher rates of severe disease and mortality, although monoclonal antibody use was not mentioned.⁸ It is plausible that passive anti-spike monoclonal antibody therapy remains an effective intervention to mitigate disease progression even among vaccinated SOT recipients, although our cohort did not have an appropriate control group who did not receive this therapy to confirm this. In our recent report of breakthrough COVID-19 among fully vaccinated patients with high-risk comorbidities, there was significant reduction in hospitalization rates among patients who received monoclonal antibody therapy compared to those who did not receive treatment.²⁵

The association between shorter time between vaccination to COVID-19 diagnosis and severe COVID-19 at presentation was unexpected. However, it should be noted that this is a univariable association and likely affected by confounding. Furthermore, the “healthy user effect” may be influencing this association, where certain health maintenance measures can be associated with improved outcomes as they represent adherence to health maintenance overall and an overall improved state of health in general.²⁶ It is conceivable that patients who were early adopters to vaccination have either improved access to healthcare or more adequately controlled comorbid conditions, affecting this risk for more severe infection. Additionally, only those who presented with mild-to-moderate COVID-19 had received a third dose of SARS-CoV-2 vaccine, which may have affected this relationship as well. This is supported by there being no statistically significant relationship between time from last vaccine dose to COVID-19 diagnosis and presenting with severe disease.

Our study has several limitations of note. This was a retrospective review and is susceptible to sources of bias intrinsic to this study design. It is possible we missed cases of breakthrough COVID-19 that were diagnosed at other centers, as well as asymptomatic or mildly symptomatic cases that did not undergo testing. We also have a relatively small number of cases and outcomes, limiting any statistical testing to univariable analyses that must be interpreted cautiously. We did not have an unvaccinated control group, limiting our ability to detect differences in outcomes based on vaccination status. The high uptake of vaccination among transplant recipients will make such a study difficult to perform. Furthermore, we did not have an appropriate control group of those that did not receive monoclonal antibodies because of the high uptake of this passive immunotherapy among our cohort. While 7 SOT patients did not receive this therapy, there are systematic differences between these patients and those that did receive monoclonal antibody therapy. Finally, only few patients underwent serologic testing since this is not a standard clinical practice in our program, thereby limiting our ability to analyze our cohort based on SARS-CoV-2 serostatus. Future studies should consider incorporating immunologic tests, such as serology to assess anti-spike and anti-nucleocapsid antibodies, to further ascertain if there is an association with risk and outcomes of breakthrough COVID-19. Likewise, correlation between viral load and outcomes of breakthrough COVID-19 deserves further study.

In conclusion, breakthrough COVID-19 remains a significant problem among vaccinated SOT recipients. Our data imply that breakthrough SARS-CoV-2 infection after vaccination appears to have relatively good clinical outcomes, which may partially be due to the use of anti-spike monoclonal antibody therapy. Proactive outreach, education, and administration of this antibody therapy should be encouraged for those at high-risk for poor outcomes, such as SOT recipients. Larger, ideally prospective, cohorts are required to fully assess the effect of monoclonal antibodies in vaccinated SOT recipients and to further analyze risk factors for poor outcomes in SOT recipients who have undergone SARS-CoV-2 vaccination.

Abbreviations

COVID-19

Coronavirus disease 2019

CKD

Chronic kidney disease

ED

Emergency department

eGFR

Estimated glomerular filtration rate

EUA

Emergency use authorization

ICU

Intensive care unit

MATRx

Mayo Clinic monoclonal antibody treatment program

PCR

Polymerase chain reaction

SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2

SOT

Solid organ transplant