Abstract
Background.
Tixagevimab–cilgavimab (Tix-Cil) was authorized for prophylaxis against COVID-19 in immunocompromised patients from December 2021 through January 2023. Real-world effectiveness for solid organ transplant (SOT) recipients has been unclear.
Methods.
We enrolled 911 SOT recipients into a longitudinal COVID-19 serology study, of whom 381 (42%) received ≥1 dose of Tix-Cil. We collected and analyzed data on incident SARS-CoV-2 infections and antibody kinetics for all patients from January 2022 to March 2023, including periods dominated by Omicron BA and BQ subvariants.
Results.
Over 253±131 days of follow-up, there were 324 new-onset SARS-CoV-2 infections: 117 (31%) in Tix-Cil treated and 207 (39%) in Tix-Cil untreated patients (P=0.012). In analyses adjusting for demographic, clinical, and COVID-19 exposure factors, any Tix-Cil treatment was associated with lower infection risk (OR 0.52, 95% CI 0.27–0.96, P=0.039) throughout the surveillance period including when more resistant BQ.1 and BQ.1.1 subvariants had emerged (12/1/2022 onwards). Among treated patients, receiving a Tix-Cil dose was associated with substantial and sustained increase in anti-spike IgG antibody and angiotensin-converting enzyme 2 binding inhibition levels (Abbott Architect assay) that together also demonstrated association with lower infection risk (P=0.042). During the full surveillance period, the frequency of infections requiring hospitalization was low overall (N=26, 2.9% of the total cohort) and not significantly different between Tix-Cil recipients (N=12, 3.2% of treated patients) and non-Tix-Cil recipients (N=14, 2.6% of untreated patients) with unadjusted P=0.31 for between-group difference.
Conclusion.
In a large cohort of SOT recipients, we found that Tix-Cil reduced infection risk even amidst emergent Omicron subvariants. Additionally, the extent of measurable humoral response to Tix-Cil may indicate relative effectiveness. Pre-exposure monoclonal antibody therapy may represent a strategy that will continue to offer clinical benefit for immunocompromised persons who are known to derive limited protection from vaccinations.
Keywords: Monoclonal antibody treatments, pre-exposure therapy, SARS-CoV-2, COVID-19
Graphical Abstract
In a surveillance study of solid organ transplant recipients, tixagevimab-cilgavimab reduced infection risk even amidst emergent Omicron subvariants. Measures of circulating humoral response to treatment also appeared to predict clinical effectiveness. Monoclonal antibody therapies may continue to offer protection from SARS-CoV-2 for immunocompromised patients who gain limited benefit from vaccinations.
Introduction
Omicron lineage variants of SARS-CoV-2 emerged in the fall of 2022 as the primary source for COVID-19 events world-wide. As of September 2022, the most dominant variant worldwide was the BA.5 sublineage.1 Subsequently, the sublineage that dominated most regions of the United States was BQ1.1 by December 2022, and then XBB sublineage by February 2023.2 The rapidly evolving virus brought substantial challenges for development of durable and effective vaccines, especially for immunocompromised patients who often remain isolated and social distanced from family and loved ones. This was especially true for solid organ transplant (SOT) recipients who demonstrated poor B-cell and T-cell immune responses to the commonly available mRNA vaccines,3–6 and higher mortality from infections.7,8 One study also showed that poor IgG antibody responses to vaccines was associated with higher risk for breakthrough COVID infections.9 Thus, development of passive immunotherapy with monoclonal antibodies emerged as an important option to reduce infectivity and modify disease severity in those who became infected, especially with the Omicron variants.
The development of neutralizing monoclonal antibodies that target the receptor binding domain (RBD) of the SARS-CoV-2 spike protein have evolved for use in immunocompromised individuals.1,10 Two therapeutic approaches were developed using a combination of two monoclonal antibodies. The first, imdevimab plus casirivimab (Regeneron), was discontinued due to lack of efficacy against Omicron variants. The second, tixagevimab-cilgavimab (AstraZeneca), consists of two Fc engineered IgG monoclonals aimed at RBD domains for prophylaxis against SARS-CoV-2 infections in immunocompromised individuals. Although data are available on the efficacy of tixagevimab-cilgavimab (Tix-Cil) in immunocompromised humans,11–13 an assessment of real-world efficacy in solid organ transplant (SOT) recipients has been limited.14 In January 2023, the U.S. FDA removed authorization for use of Tix-Cil, given concerns from in vitro data regarding lack of efficacy against the most recently emergent Omicron subvariants; however, it has been unclear whether reduced in-vitro susceptibility translated to reduced clinical effectiveness – particularly for patient populations with chronic substantially immunocompromised states. For this reason, we conducted a study of SOT recipients on chronic immunosuppressive therapy who received Tix-Cil during the FDA authorized use period to gain a clearer understanding of the nature and extent of measurable clinical benefit gained amid exposure to varying SARS-CoV-2 Omicron subvariants.
Material and Methods
Study Cohort
We enrolled patients at Cedars-Sinai Medical Center, an academic medical center in Southern California, into a longitudinal study of COVID-19 risks and outcomes. Participants completed surveys on medical history, COVID-19 exposures (including infections and vaccines received), and symptoms at baseline and at serial timepoints over the course of the study, according to previously detailed protocols.15,16 All participants were invited to complete monthly health update surveys and were also invited to contact study staff by phone or email at any time regarding health status updates including information regarding interval SARS-CoV-2 infections or doses of COVID-19 vaccine received. All participants were also invited to contribute up to monthly blood draws for COVID-19 serological assays described previously and below.15,16 To verify self-reported absence or presence of comorbidities for study participants, medical charts were reviewed by trained study staff via the electronic health record (EHR).16
Participants for the current analysis were enrolled from the source cohort of Cedars-Sinai Health System employees and patients who were recruited into the above described longitudinal surveillance study of SARS-CoV-2 exposures and risks.16 The sampling strategy for the current analysis is shown in Supplemental Figure 1. In brief, of the 10,341 participants enrolled in the source cohort, 946 adults were identified as SOT recipients, of whom 911 were not missing any data on key covariates and thus comprised the final sample for analyses. Of this study sample, 381 (42%) had received at least 1 dose of Tix-Cil during the study period and had at least 1 blood draw with specimen collection that underwent SARS-CoV-2 antibody assays, between dates 9/24/21 and 3/11/23. All study participants provided written informed consent for all protocols, which were approved by the Cedars-Sinai institutional review board.
Serological Assessment
Serological testing for antibodies to the RBD of the S1 subunit of the viral spike protein [IgG (S-RBD)], and antibodies targeting the viral nucleocapsid protein [IgG(N)], was performed at Abbott Labs (Abbott Park, IL) using the SARS-CoV-2 IgG II assay and SARS-CoV-2 IgG assay, respectively.17 Additionally, as a high-throughput method of directly assessing viral inhibition (or neutralization), we also employed a research ACE2 binding inhibition assay to measure the ability of detected IgG(S-RBD) antibodies to inhibit viral spike protein from binding to ACE2 receptors.18 This ACE2 binding inhibition assay, which we applied to the post-vaccination samples, is known to correlate well with SARS-CoV-2 PRNT methodology and exhibits a high correlation with the IgG(S-RBD) assay threshold employed (r2=0.95). This delayed 1-step immunoassay was originally developed using ancestral spike antigen and provides quantitative assessment of neutralizing antibodies that block the interaction between viral spike RBD and the ACE2 cell surface receptor; specifically, SARS-CoV-2 spike RBD antigen-coated paramagnetic microparticles are incubated with sample, followed by the addition of ACE2 receptor antigen acridinium-labeled conjugate and further incubation, prior to initiation of a chemiluminescent reaction used to measure the quantity of ACE2 binding.19
Infection Assessment
All primary data regarding SARS-CoV-2 infections and their timing were extracted from the EHR using algorithm-based scripts and from the REDCap electronic survey database.20 For infections that were not captured by our EHR system because they occurred outside our health system, manual verification was conducted by trained study staff according to a standardized protocol. Self-reported infection events were verified based on verified outside records of PCR or other testing. Prior and intercurrent infections were also assessed based on serological data where evidence of a prior infection was determined based on having an IgG-N index level ≥1.4 from the Abbott Architect assay and any subsequent new infection was identified based on change in subsequent IgG-N index level from <1.2 to ≥1.4.17 Information regarding symptoms and medical care, including hospitalizations, around infection events were captured through review of the medical record, self-reported surveys, phone and email logs, and health update questionnaires administered at each study visit. To ascertain the frequency of distinct variants and subvariants of SARS-CoV-2 reported as in transmission in the local community, we compiled Los Angeles County surveillance data collected and reported from December 2021 through March 2023;21 we considered a given single or set of variant(s) or subvariant(s) as dominant for a given time period if reported at >50% prevalence for that time period.
Statistical Analyses
In the total cohort of enrolled SOT recipients (N=911), we used t-tests and chi-square tests to compare demographic and clinical characteristics between those who received any Tix-Cil and those who never received any Tix-Cil dosing during the study period. In this total cohort, we used multivariable-adjusted logistic regression analyses to examine the associations of any Tix-Cil use with risk for adjudicated infection during the surveillance period. The main model adjusted for demographic and clinical characteristics in addition to type and timing of COVID-19 exposures including total number of prior SARS-CoV-2 infections, total number of prior SARS-CoV-2 vaccine doses, and total follow up time in the study.
In the subset of SOT recipients who received Tix-Cil and had serial serology measures available for analyses (N=350), we examined the pattern and predictors of the longitudinal IgG-S response over time leading up to and after Tix-Cil dosing. Specifically, we generated a mixed-effects linear model with each individual’s repeated IgG-S measures treated as random effects to estimate the mean of log10(IgG-S) associated with time indexed from the date of last vaccine dose. We used natural cubic splines for modeling graphical display of the output. We also used multivariable-adjusted logistic regression models to examine the association of Tix-Cil associated humoral response and timing of dose administrations with risk of post-Tix-Cil SARS-CoV-2 infection during the study period. All analyses were conducted using R v4.1.2, with a two-tailed P<0.05 considered significant.
Results
Demographic and clinical characteristics of the patient cohort are shown in Table 1. Of the total cohort (n=911), a total of 381 (42%) of SOT recipients received any Tix-Cil during the study period. Compared to SOT patients who did not receive any Tix-Cil treatment, those who were Tix-Cil recipients were more likely to be older, non-Hispanic white, and recipients of heart or lung organ transplants (Table 1). Tix-Cil recipients were also more likely to have received a greater number of SARS-CoV-2 vaccine doses. The total study follow-up period for SOT patients who received Tix-Cil was 272±126 days and for SOT patients who did not receive Tix-Cil was 239±133 days (Supplemental Figure 2).
Table 1.
Demographic and clinical characteristics of the study sample.
| Characteristics | Overall (N=911) | Tix-Cil Recipients (N=381) | Non-Tix-Cil Recipients (N=530) | P value |
|---|---|---|---|---|
| Age, Mean (SD) | 57.03 (14.28) | 60.53 (13.47) | 54.51 (14.33) | <0.001 |
| Male sex, N (%) | 529 (58.1) | 220 (57.7) | 309 (58.3) | 0.920 |
| Non-Hispanic White, N (%) | 425 (46.7) | 224 (58.8) | 201 (37.9) | <0.001 |
| Organ Transplant type, N (%) | ||||
| Kidney | 449 (49.3) | 142 (37.3) | 307 (57.9) | <0.001 |
| Heart | 158 (17.3) | 84 (22.0) | 74 (14.0) | |
| Lung | 91 (10.0) | 75 (19.7) | 16 (3.0) | |
| Liver | 66 (7.2) | 28 (7.3) | 38 (7.2) | |
| More than one | 129 (14.2) | 50 (13.1) | 79 (14.9) | |
| Other | 18 (2.0) | 2 (0.5) | 16 (3.0) | |
| No. total SARS-CoV-2 infection times, mean (SD) | 1.19 (0.41) | 1.15 (0.39) | 1.21 (0.42) | 0.094 |
| Total number of Tix-Cil administrations, mean (SD) | 1.60 (0.77) | 1.60 (0.77) | – | – |
| Total number of Tix-Cil administrations, N (%) | ||||
| 1 | 213 (23.4) | 213 (55.9) | – | – |
| 2 | 118 (13.0) | 118 (31.0) | ||
| 3 | 41 (4.5) | 41 (10.8) | ||
| 4 | 9 (1.0) | 9 (2.4) | ||
| Total Tix-Cil dosage in mg received, mean (SD) | 957 (465) | 957 (465) | – | – |
| Total number of blood draws, mean (SD) | 3.18 (2.87) | 3.57 (3.15) | 2.89 (2.61) | <0.001 |
| Total number of SARS-CoV-2 vaccines received, mean (SD) | 3.82 (1.23) | 4.18 (0.98) | 3.57 (1.32) | <0.001 |
| Total number of SARS-CoV-2 vaccines, N (%) | ||||
| 0 | 28 (3.1) | 2 (0.5) | 26 (4.9) | <0.001 |
| 1 | 7 (0.8) | 0 (0.0) | 7 (1.3) | |
| 2 | 64 (7.0) | 8 (2.1) | 56 (10.6) | |
| 3 | 227 (24.9) | 86 (22.6) | 141 (26.6) | |
| 4 | 291 (31.9) | 131 (34.4) | 160 (30.2) | |
| ≥5 | 294 (32.3) | 154 (40.4) | 140 (26.4) | |
| Initial SARS-CoV-2 vaccine series completed, N (%) | 879 (96.5) | 379 (99.5) | 500 (94.3) | <0.001 |
Association of Treatment with Infection Risk
Over the course of the full surveillance period (1/7/22 through 3/20/23), there were 324 adjudicated SARS-CoV-2 infections including 117 (31%) occurring in Tix-Cil treated patients and 207 (39%) in non-Tix-Cil treated patients (unadjusted P=0.012). For patients who developed an infection, the length of follow-up time after infection was 7.4±4.2 months overall and similar for patients who did receive Tix-Cil (7.7±3.9 months) compared to those who did not receive Tix-Cil (7.2±4.3 months) (Supplemental Figure 2). In the initial surveillance period (1/7/22 through 11/30/22), during which B.1 through BA.5 subvariants were dominant (excluding periods during which BQ.1 and BQ.1.1 emerged) (Figure 1), there were 244 adjudicated SARS-CoV-2 infections including 81 (21%) in Tix-Cil treated patients and 163 (31%) in non-Tix-Cil treated patients (unadjusted P=0.002). During the full surveillance period, the frequency of infections requiring hospitalization was low overall (N=26, 2.9% of the total cohort) and not significantly different between Tix-Cil recipients (N=12, 3.2% of treated patients) and non-Tix-Cil recipients (N=14, 2.6% of untreated patients) with unadjusted P=0.31 for between-group difference. Overall, the frequency and timing of infections mirrored that of the larger source cohort of predominantly immunocompetent adults and corresponded with local community patterns of infection surges occurring in the setting of changing predominance the Omicron subvariants (Figure 1).
Figure 1.
Tix-Cil Dosing and Infections During the Study Period. The frequency and timing of Tix-Cil dosing and SARS-CoV-2 infections occurring in the study cohort is shown in Panel A. The background frequency and timing of infections in the larger source study population is shown in Panel B. Changing predominance of Omicron subvariants in the local community is shown in Panel C.
In multivariable logistic regression analyses, having received any Tix-Cil dosing was associated with lower risk for SARS-CoV-2 infection during the initial surveillance period (OR 0.44, 95% CI 0.21–0.88, P=0.021) after adjusting for age, sex, race/ethnicity, type of transplanted organ type, major comorbidities, total number of prior SARS-CoV-2 infections or vaccinations, total Tix-Cil dosage, and total follow-time in the study (Table 2). Results were similar when analyses were repeated to assess the association of Tix-Cil treatment with risk of any infection occurring during the full surveillance period that included a time period when BQ.1 and BQ.1.1 had emerged (OR 0.52, 95% CI 0.27–0.96, P=0.039).
Table 2.
Multivariable-adjusted associations of any Tix-Cil treatment with risk of SARS-CoV-2 infection with emergent Omicron subvariants in SOT recipients.
| Initial Infection Surveillance Time Period: 1/1/22 to 11/30/22 Dominant Subvariants: Omicron B.1, BA.1, BA.2, BA.4, BA.5 |
Full Infection Surveillance Time Period: 1/1/22 to 3/11/23 Dominant Subvariants: Omicron B.1, BA.1, BA.2, BA.4, BA.5, BQ.1, BQ.1.1 |
|||
|---|---|---|---|---|
| OR (95% CI) | P value | OR (95% CI) | P value | |
| Age, decade in years | 0.92 (0.80, 1.04) | 0.182 | 0.93 (0.83, 1.05) | 0.263 |
| Male sex | 0.87 (0.62, 1.21) | 0.395 | 0.96 (0.71, 1.30) | 0.786 |
| Non-Hispanic/White ethnicity/race | 1.14 (0.80, 1.64) | 0.458 | 1.09 (0.78, 1.51) | 0.628 |
| Any versus no Tix-Cil treatment | 0.44 (0.21, 0.88) | 0.021 | 0.52 (0.27, 0.96) | 0.039 |
| Total no. prior SARS-CoV-2 infections | 0.66 (0.43, 1.00) | 0.056 | 0.84 (0.57, 1.21) | 0.345 |
| Total no. prior SARS-CoV-2 vaccines | 0.85 (0.69, 1.03) | 0.098 | 1.02 (0.84, 1.23) | 0.857 |
| Total Tix-Cil dosage in grams | 1.69 (0.95, 3.01) | 0.072 | 1.47 (0.86, 2.48) | 0.154 |
| Total follow-up time, month | 1.00 (0.96, 1.04) | 0.840 | 0.99 (0.96, 1.03) | 0.723 |
| Organ transplant type | ||||
| Liver | Reference | Reference | ||
| Heart | 0.83 (0.38, 1.87) | 0.647 | 0.97 (0.47, 2.04) | 0.945 |
| Kidney | 1.14 (0.60, 2.28) | 0.694 | 1.17 (0.64, 2.21) | 0.616 |
| Lung | 0.57 (0.23, 1.42) | 0.230 | 0.87 (0.40, 1.93) | 0.734 |
| More than one | 1.07 (0.51, 2.34) | 0.853 | 1.15 (0.57, 2.37) | 0.691 |
| Other | 0.80 (0.20, 2.77) | 0.738 | 0.81 (0.23, 2.61) | 0.733 |
| Autoimmune disease | 0.90 (0.60, 1.33) | 0.597 | 0.94 (0.65, 1.35) | 0.741 |
| Current or past cancer | 1.04 (0.67, 1.61) | 0.855 | 0.94 (0.63, 1.40) | 0.770 |
| Cardiac disease | 0.88 (0.59, 1.30) | 0.530 | 0.85 (0.59, 1.22) | 0.378 |
Among patients with no missing model covariate data, during the initial surveillance period (1/1/22 to 11/30/22, featuring subvariant dominance by Omicron B.1, BA.1, BA.2, BA.4, BA.5), there were a total of 64 infections adjudicated among 295 Tix-Cil recipients (22% crude infection rate) and 157 infections adjudicated among 509 non-Tix-Cil recipients (31% crude infection rate) with unadjusted P=0.005 for between-group difference. During the full surveillance period (1/1/22 to 3/11/23, featuring subvariant dominance by Omicron B.1, BA.1, BA.2, BA.4, BA.5, BQ.1, BQ.1.1), there were a total of 91 infections adjudicated among 295 Tix-Cil recipients (31% crude infection rate) and 200 infections adjudicated among 509 non-Tix-Cil recipients (39% crude infection rate) with unadjusted P=0.016 for between-group difference. For the most recent limited surveillance period (12/1/22 to 3/11/23, featuring subvariant dominance by Omicron BQ.1, BQ.1.1, and initial emergence of XBB), there were 27 infections adjudicated among Tix-Cil recipients (12% crude infection rate for N=231 remaining at risk) and 43 infections adjudicated among non-Tix-Cil recipients (12% crude infection rate for N=352 remaining at-risk) with unadjusted P=0.85 for between-group difference.
Models for each surveillance period were constructed such that the outcome variable was SARS-CoV-2 infection and primary predictor variable was Tix-Cil treatment (any versus none) with adjustment for all covariates shown including age, sex, race/ethnicity, total number of prior SARS-CoV-2 infections, total number of prior SARS-CoV-2 vaccines received, total Tix-Cil dosage in grams received, total follow-up time, organ transplant type, autoimmune disease, current or prior cancer, and cardiac disease (coronary heart disease or heart failure).
Post-Treatment Serological Response
For all SOT recipients who received Tix-Cil, we found that when comparing pre-treatment to post-treatment antibody levels, both IgG-S and ACE2 binding levels increased significantly after receiving Tix-Cil (Supplemental Figure 3). Furthermore, we found that these augmented antibody levels persisted over 30 weeks (Figure 2). In longitudinal analyses, the substantial and sustained increase in both IgG-S (P<0.001) and ACE2 binding (P<0.001) antibody levels following Tix-Cil administration was significant even after adjusting for demographic and clinical characteristics and timing of COVID-19 exposures (Table 3). In effect, elevation of IgG-S antibody and ACE2 binding levels following Tix-Cil administration persisted over time such that the model estimates for these measures, represented by their estimated value in relation to time (in weeks) from Tix-Cil administration, remained positive as well as significant in the fully-adjusted longitudinal regression model. Results were unchanged in analyses additionally adjusting for total dose of Tix-Cil received or time since first dose of Tix-Cil received. We did note that some SOT recipients compared to others had a less substantial antibody level response, with relative differences that were particularly notable for kidney transplant recipients (Table 3).
Figure 2.
Association of longitudinal SARS-CoV-2 IgG-S antibody response in relation to having received any prior Tix-Cil dosing. Splines are derived from the multivariable adjusted models in Table 3, showing results for patients who had any blood draw for antibody measure.
Table 3.
Multivariable-adjusted associations of longitudinal SARS-CoV-2 antibody response in relation to having received any prior Tix-Cil dosing in SOT recipients.
| Model A Outcome: Log10 IgG-S level |
Model B Outcome: ACE2 binding |
|||
|---|---|---|---|---|
| Beta (SE) | P value | Beta (SE) | P value | |
| Timing in weeks after last Tix-Cil dosing | 1.01 (0.10) | <0.001 | 35.73 (2.56) | <0.001 |
| Number of prior Tix-Cil doses | 0.13 (0.05) | 0.005 | 0.92 (1.11) | 0.41 |
| Number of prior SARS-CoV-2 infections | 0.25 (0.05) | <0.001 | 1.04 (1.23) | 0.40 |
| Number of prior SARS-CoV-2 vaccine doses | 0.17 (0.05) | <0.001 | 1.65 (1.07) | 0.12 |
| Time from most recent SARS-CoV-2 vaccine | 0.01 (0.02) | 0.58 | 0.07 (0.55) | 0.90 |
| Age, decade in years | −0.03 (0.03) | 0.37 | 0.30 (0.66) | 0.66 |
| Male sex | 0.10 (0.07) | 0.20 | 1.90 (1.68) | 0.26 |
| Non-Hispanic/White ethnicity/race | −0.17 (0.08) | 0.036 | −2.34 (1.79) | 0.19 |
| Organ Transplant type | ||||
| Liver | Referent | Referent | ||
| Kidney | −0.53 (0.15) | <0.001 | −5.03 (3.42) | 0.14 |
| Heart | −0.37 (0.15) | 0.018 | −3.56 (3.50) | 0.31 |
| Lung | −0.41 (0.16) | 0.010 | −3.39 (3.54) | 0.34 |
| More than one type | −0.30 (0.17) | 0.08 | −1.26 (3.79) | 0.74 |
| Other | −0.71 (0.51) | 0.17 | −2.92 (12.35) | 0.81 |
Models are adjusted for all the covariates shown, with all analyses performed in patients with at least 1 blood draw with serology assayed before as well as after any Tix-Cil dosing.
Model A: N=1353 blood draws in N=350 patients.
Model B: N=1353 blood draws in N=348 patients.
Post-Treatment Serological Response and Clinical Outcomes
To examine the association between humoral response to Tix-Cil and infection risk, we considered ACE2 binding level as a marker of relative neutralizing potential in relation to the IgG-S level which was seen to typically rise dramatically in response to Tix-Cil administration (Supplemental Figure 3). Accordingly, the peak ACE2 binding level was strongly but not perfectly correlated with peak IgG-S level in our cohort (Spearman rho=0.79), while also demonstrating a left-skewed distribution (Supplemental Figure 4). Given the non-normality as well as interdependence of this measure in relation to total IgG-S, we calculated the ratio of peak ACE2 binding to peak IgG-S antibody level and considered this variable as a measure of relative humoral response. Although peak ACE2 binding level was not significantly associated with subsequent infection risk (P=0.26), the ratio of ACE2 binding to peak IgG-S antibody level was significantly associated (P=0.001) (Table 4), suggesting that that a larger absolute deficiency in ACE2 binding capacity accounting for the degree of total IgG-S response was a marker of infection susceptibility. Notably, the ratio of peak ACE2 binding to peak standardized log-IgG-S antibody level following Tix-Cil dosing was associated with a significantly lower risk for post-Tix-Cil infection occurring during the both the initial infection surveillance period dominated by BA subvariants (OR 0.61, 95% CI 0.44–0.81) and the full surveillance period. In effect, the higher the putative neutralizing capacity was in relation to the total IgG-S elevation, the lower the risk of actual infection; conversely, the larger the deficiency in ACE2 binding capacity while accounting for total IgG-S response, the greater the infection susceptibility. This finding was somewhat attenuated but remained significant in analyses of post-Tix-Cil infection occurring during the periods dominated by either BA or BQ subvariants with OR 0.78 (0.60, 0.98, P=0.042). We also observed that later rather than earlier timing of first Tix-Cil administration, corresponding to receiving a dose closer in timing to periods of COVID-19 surge (Figure 1), was also significantly associated with lower risk of infection during the BA period (P<0.001) as well as during the overall combined BA and BQ period (P=0.046). This finding suggests that although the serological response to Tix-Cil administration along with its clinical effectiveness in protecting against infection were found to persist through the study period, there is likely a waning of these effects over time. The total number of Tix-Cil doses received was not significantly associated with infection risk in any model (P>0.14).
Table 4.
Association of serological responses to Tix-Cil and risk of SARS-CoV-2 infection with emergent Omicron subvariants.
| Initial Infection Surveillance Time Period: 1/1/22 to 11/30/22 Dominant Subvariants: Omicron B.1, BA.1, BA.2, BA.4, BA.5 |
Full Infection Surveillance Time Period: 1/1/22 to 3/11/23 Dominant Subvariants: Omicron B.1, BA.1, BA.2, BA.4, BA.5, BQ.1, BQ.1.1 |
|||
|---|---|---|---|---|
| OR (95% CI) | P value | OR (95% CI) | P value | |
| Post-Tix-Cil peak ACE2-to-Log(IgG-S) level* | 0.61 (0.44, 0.81) | 0.001 | 0.78 (0.60, 0.98) | 0.042 |
| Timing of first Tix-Cil dose† | 0.81 (0.72, 0.91) | <0.001 | 0.91 (0.82, 1.00) | 0.046 |
Among patients with no missing model covariate data, there were a total of 60 infections adjudicated among 259 Tix-Cil recipients (23% crude infection rate) during the initial surveillance period (1/1/22 to 11/30/22, featuring subvariant dominance by Omicron B.1, BA.1, BA.2, BA.4, BA.5); there were a total of 86 infections adjudicated among 259 Tix-Cil recipients (33% crude infection rate) during the full surveillance period (1/1/22 to 3/11/23, featuring subvariant dominance by Omicron B.1, BA.1, BA.2, BA.4, BA.5, BQ.1, BQ.1.1).
Each model is adjusted for the following covariates: age, sex, solid organ transplant type, autoimmune disease, cancer status, and cardiac disease status.
Post-Tix-Cil ACE2-to-Log(IgG-S) level analyses are performed in patients with at least 1 blood draw with serology assayed after any Tix-Cil dosing.
Calculated for each patient as the number of months elapsed between date of the study period start (January 1, 2022) and date of first Tix-Cil dose received.
Discussion
The SARS-CoV-2 pandemic and extension of infection engendered by rapidly mutating variants constitutes one of the most daunting health care challenges of the past century. It is now well established that the morbidity and mortality of SARS-CoV-2 infections is increased especially in immunocompromised individuals due to a demonstrable lack of humoral and cellular immune responses to vaccines.3–8,22 Monoclonal antibody treatments emerged as agents of passive immunity designed to protect individuals with compromised humoral and cellular immunity that renders them especially susceptible SARS-CoV2 and evolving variants. In particular, Tix-Cil was provided emergency use authorization by the U.S. FDA in December 2021.23 In January 2023, Tix-Cil was no longer authorized given the concern for lack of effective neutralization of the newly emergent Omicron subvariants at that time. Our findings indicate clinical benefit from Tix-Cil in SOT recipients during the early-to-mid phase of authorized use, when more susceptible subvariants were predominant; further, we also found evidence of some persisting benefits in the midst of the presumed more evasive subvariants.24 Notwithstanding the limits of antigen-specific therapies as newer variants continue to emerge over time, our results underscore the clinical success of the pre-exposure monoclonal antibody therapeutic experience for treated patients throughout the authorization period – and highlights what may well be an ongoing need for similar therapeutics for immunocompromised patients in the future.
Our findings from the early-to-mid phase of Tix-Cil authorization are consistent with other published experience. In a prior study assessing clinical effectiveness of Tix-Cil in the Omicron era,25 investigators used a meta-analysis methodology to examine the outcomes among 24,773 immunocompromised participants across 17 international studies, 10,775 who were deemed to have received significant clinical benefit from Tix-Cil given as prophylaxis. The authors reported that the treatment was 86% (95% CI 6.2% to 99.7%; P=0.04) effective for preventing COVID-19 specific death, 88% (47.1% to 98.7%; P<0.001) effective in preventing intensive care admission, 69% (50.8% to 81.6%; P<0.001) effective in preventing hospital admission, and 40% (29.8% to 49.7%; P<0.001) effective in preventing SARS-CoV-2 infection. Other analyses in various studies have also shown similar outcomes.12–14 However, there have been scant reports focused on SOT recipients14 whom we and others have shown to have the severely deficient immune responses to SARS-CoV-2 vaccination.16 A prior report from France evaluated the effectiveness of Tix-Cil in a group of 860 kidney transplant recipients who were fully vaccinated yet demonstrated weak or deficient humoral immune responses. The study was performed when the BA.1 & BA.2 Omicron variants were predominant. The authors concluded that patients who received Tix-Cil for prophylaxis had outcomes similar to those who had protective antibodies after vaccination, and had significantly fewer infections (severe and non-severe) compared to the kidney transplant recipients who had poor vaccine-induced immunity to SARS-CoV-2 and Omicron variants, in whom higher death rates were also observed. Extending from prior work, our study offers findings that demonstrate clinical usefulness of Tix-Cil prophylaxis in poor vaccine responders during a time period preceding and leading up through eras of the pandemic when more resistant Omicron subvariants were emerging.14 In particular, we found that prophylaxis with Tix-Cil in SOT recipients was associated with a reduction by almost half in the odds of Omicron infection (OR 0.52, 95% 0.27–0.96, P=0.039) after adjusting for multiple potential confounders and throughout a surveillance period that extended beyond 30 weeks and that even included emergence and predominance of BQ.1 and BQ.1.1. subvariants. Although we found Tix-Cil associated with reduced risk for breakthrough infection, we did not find a significant association of Tix-Cil with reduced risk for infection-related hospitalization. This apparent discrepancy could have been related to widespread use of monoclonal antibody and nirmatrelvir/ritonavir antiviral treatments contributing to relatively low rates of hospitalization overall.
In context, the question of durability from passive immunity therapeutic, amidst dynamic shifts in subvariant predominance, has certainly garnered well-deserved attention. Bruel et al. had previously reported on neutralization of SARS-CoV-2 Omicron BA.2, BA.4 and BA.5 variants in patients receiving monoclonal antibodies for prophylaxis, observing that BA.4 and BA.5 sublineages escape most of the monoclonals, although cilgavimab and bebtelovimab remained fully active.1 In analyzing patients receiving Tix-Cil, the authors found that neutralization could be detected for Delta, BA.2 and BA.5 up to 6 months after administration of the Tix-Cil dose, thus likely capable of rendering protection from infection.1 While these data are encouraging, the half-life of the Tix-Cil monoclonals has been a concern, given the half-life of most IgG molecules in the human body is ~24 days. This is dependent on the Fc receptor neonatal (FcRn) recycling, which preserves precious proteins such as IgG and albumin molecules.26 Recent technological advances may enhance and enable longer half-lives for IgG monoclonal antibodies by increasing their binding to FcRn and, thus, allowing for longer persistence in the circulation as well as potentially more lasting effectiveness.
In the absence of definitive information regarding durability of effectiveness following a given dose of Tix-Cil, we analyzed the humoral response to Tix-Cil in treated SOT patients to both discern the longitudinal patterns of response and assess the extent to which a post-treatment humoral measure could serve as an indicator of clinical effectiveness. We found persistence of high titer neutralizing antibodies to spike protein lasting for more than 30 weeks after administration. Furthermore, we found that a higher degree of augmented humoral response corresponded with relatively lower susceptibility to infection over the duration of the surveillance period. Specifically, we found that a higher ratio of peak ACE2 binding inhibition to peak IgG-S antibody levels provoked by Tix-Cil administration (representing relative neutralizing capacity for a given level of persistence of elevated circulating anti-spike antibody concentration) was significantly associated with 22% lower risk of infection over the course of the entire ~14 month study duration; this effect was particularly pronounced with a 39% lower infection risk seen during the ~11 month period dominated by BA subvariants. We also found that timing of the Tix-Cil dosing was significantly associated with lower post-Tix-Cil infection rate; for every 1 month closer to the timing of a community surge that a first Tix-Cil dose was received, the risk post-Tix-Cil infection was 9% lower overall and 19% lower during the period dominated by BA subvariants. It is important to note that there were no deaths in our cohort of vaccinated patients possibly indicating some level of protection, likely at the T-cell level, despite known historically poor antibody responses to vaccine in this patient group. Of course, we cannot discount the importance of masking and social distancing that likely contributes to good outcomes in a group of patients that are generally ardently devoted to protecting themselves from exposure to SARS-CoV-2 and variants.
It is notable that we observed variation in the IgG-S antibody levels by type of transplanted organ, with particularly lower levels seen among kidney transplant recipients. Between-organ variation in antibody responses to SARS-CoV-2 related exposures have been observed previously, by our group and others,27–29 and the sources of variation are likely multifactorial. In particular, chronically reduced renal function is likely to have impaired both B cell and T cell function even preceding transplant and the active initiation of T cell depleting agents.27–29 Importantly, however, despite presence of between-organ variation in the humoral response to Tix-Cil, there no observed between-organ variation in the observed clinical effectiveness of protection from infection during the surveillance period.
Several limitations of our study merit consideration. In our assessment of humoral response to Tix-Cil administration, we were unable to directly assay AZD levels and so used anti-spike IgG levels as an indirect measure. Given the inability to measure all potential confounders, including behavioral factors that could have contributed to lower infection rates in the Tix-Cil group, we cannot exclude the possibility of residual confounding. For patients who experienced infections, we did not have access to complete data on any COVID-19 therapies received and these could have served to mitigate associated outcomes; additional studies are needed to understand these potential associations. We ascertained presumed subvariant type of Omicron infection based on local community prevalence and not direct genotyping given inability to collect infection surveillance samples in real-time. Thus, the relative effectiveness of Tix-Cil protection from specific Omicron subvariants, particularly during the period transition from BA to BQ predominance, can only be estimated. Furthermore, the relatively low number of infection events during the BQ period precludes effectiveness analyses restricted to this time period. Additional analyses in even larger cohorts with more events would be useful for validating our analyses as well as assessing the generalizability of our results from a single-center study.
Although the FDA withdrew the emergency use authorization (EUA) for Tix-Cil based on laboratory data indicating that Tix-Cil is likely to have no neutralizing activity against the newest SARS-CoV-2 variants, our study observations offer insights regarding lessons learned from the pre-exposure prophylaxis experience and highlight the potential effectiveness of similar future monoclonal preparations against emerging variants of the future. Importantly, it is likely recipients of SOT, as well as other immunocompromised patients, will continue to demonstrate impaired immunity to the bivalent vaccines; thus, there will remain an ongoing need for passive immunotherapies that can protect patients who will continue to harbor excess risk for the adverse sequelae of COVID-19 due to their impaired immune responses to vaccines.
Supplementary Material
Acknowledgments
We are grateful to all our patients and to the frontline healthcare workers in our health system who continue to be dedicated to delivering the highest quality care. We would like to especially thank the staff of the Comprehensive Transplant Center, the Advanced Heart Disease Center, and the Institute for Research on Healthy Aging.
Funding
This work was supported in part by the Erika J. Glazer Family Foundation, Sapient Bioanalytics, LLC, and NIH Grant: K23HL153888.
Role of the Sponsors
The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Abbreviations
- ADCC
antibody-dependent cellular cytotoxicity
- HER
electronic health record
- EUA
emergency use authorization
- FcRn
Fc receptor neonatal
- FDA
Food and Drug Administration
- RBD
receptor binding domain
- SOT
solid organ transplant
Footnotes
Potential Conflicts of Interest
JCP works for Abbott Diagnostics, a company that performed the serological assays on the biospecimens that were collected for this study. KS has served as a consultant for Abbott Diagnostics. SYJ has served as a consultant for Sapient Bioanalytics, a company that supported the collection and processing of samples for this study. The remaining authors have no relevant potential conflicts.
Data Availability
Deidentified participant data will be made available with publication, to investigators whose proposed use of the data is research and following approval of a proposal and completion of a signed data access agreement. All data requests can be submitted to biodatacore@cshs.org.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Deidentified participant data will be made available with publication, to investigators whose proposed use of the data is research and following approval of a proposal and completion of a signed data access agreement. All data requests can be submitted to biodatacore@cshs.org.