key: cord-1049996-whbalkf7 authors: Gueguen, Juliette; Colosio, Charlotte; Del Bello, Arnaud; Scemla, Anne; N’Guyen, Yohan; Rouzaud, Claire; Carvalho-Schneider, Claudia; Vargas, Gabriela Gautier; Tremolières, Pierre; Eddine, A. Jalal; Masset, Christophe; Thaunat, Olivier; Chabannes, Melchior; Malvezzi, Paulo; Pommerolle, Pierre; Couzi, Lionel; Kamar, Nassim; Caillard, Sophie; Gatault, Philippe title: Early administration of Anti-SARS-CoV-2 Monoclonal Antibodies prevents severe Covid-19 in Kidney Transplant Patients date: 2022-03-26 journal: Kidney Int Rep DOI: 10.1016/j.ekir.2022.03.020 sha: 49735a407dcce59fd61cc745196daf44acd4c23e doc_id: 1049996 cord_uid: whbalkf7 Kidney transplant recipients (KTRs) are prone to develop severe coronavirus disease 2019 (Covid-19) and are less well protected by vaccine than immunocompetent subjects. Thus, the use of neutralizing monoclonal anti-SARS-CoV-2 antibody (MoAb) to confer a passive immunity appears attractive in KTRs. Methods. We performed a French nation-wide study to compare Covid-19-related hospitalization, 30-days-admission to intensive care unit (ICU) and 30-days-death between KTRs who received an early infusion of MoAb (MoAb group) and KTRs who did not (control group). Controls were identified from the COVID-SFT registry (NCT04360707) using a propensity score matching with the following covariates: age, sex, delay between transplantation and infection, induction and maintenance immunosuppressive therapy, initial symptoms and comorbidities. Results. Eighty KTRs received MoAb between February and June 2021. They were matched to 155 controls. Covid-19-related hospitalization, 30-days-admission to intensive care unit (ICU) and 30-days-death were less frequently observed in MoAb group (35.0% vs 49.7%, p=0.032; 2.5% vs 15.5%, p=0.002, 1.25% vs 11.6%, p=0.005, respectively). No patients required mechanical ventilation in MoAb group. The number of patients to treat to prevent one death was 9.7. Conclusion. The early use of MoAb in KTRs with a mild form of Covid-19 largely improved outcomes in KTRs. The high frequency of severe comorbidities in kidney transplant recipients (KTRs) makes them very likely to develop severe coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (1) (2) (3) . In addition, their immunization rates following vaccination is lower than in immunocompetent subjects after one, two and even three injections of vaccines, with often a low level of anti-SARS-CoV-2 spike protein antibodies (4, 5) . Thus, a large proportion of KTRs remains currently exposed to the risk of severe Covid-19 despite vaccination (6) . In this context, the use of neutralizing monoclonal anti-SARS-CoV-2 antibody (MoAb) to confer a passive immunity appears attractive in these patients. Two large clinical trials have been conducted in high-risk outpatients with recent mild to moderate Covid-19. Based on a similar virologic primary outcome, both studies demonstrated that monoclonal therapeutic antibodies targeting Receptor-Binding Domain accelerated the viral load decline (7) (8) (9) . In addition, these two trials suggested that combinations of bamlanivimab-etesivimab and casirivimab-imdevimab would reduce the proportion of patients requiring further hospitalizations or visits for worsening Covid-19. Finally, FDA then EMA delivered an emergency use authorization for those therapeutic antibodies in patients at risk of severe Covid-19, including KTRs. So far, data about the use of these MoAbs in KTRs remain limited. Two small case series reported a good tolerance profile and a low rate of Covid-19-related hospitalization following an early infusion of bamlanivimab (10, 11) . Similar results were obtained in 25 solid organ transplant (SOT) recipients treated with casirivimab-imdevimab (12) . Finally, Del Bello et al. To investigate the efficacy of anti-SARS-Cov-2 MoAb to prevent severe Covid-19 in KTRs, we conducted a nation-wide case control study comparing outcomes between all KTRs in France who had received MoAb between March and June 2021 in France and matched KTRs issued from the French SOT COVID registry (1) using the propensity-score matching method. We compared their risk of Covid-19-related hospitalization, intensive care unit (ICU) admission and death. In France, the use of MoAb binding the SARS-CoV-2 spike protein was approved on February 2, 2021 for SARS-CoV-2 infected immunosuppressed patients. Eligibility criteria for MoAb infusion were: 1) positive reverse transcriptase-polymerase chain reaction test performed on nasopharyngeal swab specimens, 2) recent symptoms (≤ 5 days) and 3) no need of oxygen. We included all KTRs who received MoAb between February and June 15, 2021 in France. Control group was issued from the French SOT COVID registry (NCT04360707, ethical approval by the Institutional Review Board of the Strasbourg University) that enrolled 1567 KTRs from 31 centers suffering from COVID-19 until December 31, 2020. The patients with missing data for one of the variables needed for matching (n=377) and those with a negative rt-PCR test (N=96) were excluded from the study (Figure 1 ). Data were collected retrospectively using hospital databases and clinical records for all patients. Each medical record was individually and manually reviewed by a medical doctor in each center. Data collection included patient (age, sex, smoking status, comorbidities: diabetes mellitus, body mass index (BMI), hypertension, cardiopathy, chronic lung disease, kidney function) and transplant (induction and maintenance immunosuppressive therapy, donor type, J o u r n a l P r e -p r o o f rank) characteristics, as well as Covid-19 characteristics and outcomes (delay between transplantation and Covid-19, symptoms, hospitalization, ICU admission, death). Primary analyses included Covid-19-related hospitalization-, ICU admission-and death-rates for the first 30 days after the diagnosis. Covid-19 related hospitalization was defined as hospitalization needed because of the severity of the symptoms. For this reason we did not consider hospitalization for MoAb infusion (as initially recommended by French Authorities) and nosocomial Covid-19 if patients did not show any exacerbation during hospitalization. We secondary analyzed rate of severe COVID-19 defined as admission (or transfer) to ICU, need for mechanical ventilation, or death. We finally provided 3-months patient survival defined as the time between the date of positive rt-PCR test and the date of death or last follow-up. KTRs in the MoAb group were matched to KTRs issued from COVID SFT Registry by a propensity score, using a 1:2 ratio, nearest neighbor method and a caliper of 0.3 with the following covariates: age, sex, time between transplant and positive SARS-CoV-2 rt-PCR test, induction therapy, maintenance immunosuppression; BMI, diabetes mellitus, history of cardiovascular disease, hypertension, chronic lung disease and creatinine, fever and dyspnea at time of MoAb infusion (or Covid-19 diagnosis). The balance of covariate distribution between the two groups was assessed using standardized mean differences (Supplementary data). Propensity score matching method requires fully completed data. To keep all KTRs included in the study, we imputed the few missing data in the MoAb group as followed: 3 data were missing for induction and were imputed by "Basiliximab" to allow matching with Basiliximab treated J o u r n a l P r e -p r o o f controls in order to favour the control group, 1 data was missing for BMI and was imputed using the median of BMI for the same age and gender . Patients with missing data in the control group were excluded before matching. Continuous variables were described using medians and interquartile ranges (IQRs) and compared using the Mann-Whitney ranksum test. Categorical variables were described using proportions and compared using Fisher-exact test. Survivals were represented using Kaplan-Meier curves and compared using a 2-sided log-rank test. Statistical analyses were performed using Stata and R Studio (Version 1.2.1335). All statistical tests were 2-sided, and P values <0.05 were considered as significant. Overall, 80 KTRs from 13 transplant centers received MoAb. They were initially treated with bamlanivimab (n = 8), then with bamlanivimab-etesivimab (n = 39) or casirivimab-imdevimab (n = 33) ( Figure 2 ). The mean delay between the first symptoms and the administration of MoAb was 3.8 ± 2.4 days with 6 patients treated beyond the 5 th day. The matching process identified 155 control patients among 1094 patients included from the COVID SFT Registry. Their basal characteristics were compared with those of patients treated with MoAb (Table 1) . As expected, no significant differences were observed regarding age, immunosuppressive regimen, delay of transplantation and comorbidities. Of note, the proportion of asymptomatic KTRs was lower in the MoAb group than in the control group The mortality in the control group was higher with 21 deaths (13.6%) notified during the followup (Figure 3 ). Of 21 deaths, 18 (85.7%) occurred in the first month. The 30-days mortality rate was lower in MoAb group (p=0.008), as shown in the Table 2 . Based on an absolute risk reduction of 10.35%, we estimated that 9.7 patients should be treated to avoid one death. In this carefully designed multicenter case-control study, we investigated the effectiveness of early infusion of neutralizing monoclonal antibody in the treatment of mild or moderate Covid-19 in KTRs. We demonstrate that an early infusion of MoAb reduces the risk of severe Covid-19 with a 10-fold lower risk of admission to intensive care units and death, and therefore strongly comforts preliminary results reported in SOT recipients without major side effects (11) (12) (13) . This remarkable effectiveness of MoAb is the result of the strong potency of anti-spike MoAb to limit the spread of virus at the first stage of the infection. As most of neutralizing antibodies in SARS-CoV-2 infected patients that contribute to the protection of patients, currently available MoAb recognize the receptor-binding domain located on the S1 subunit of viral spike, which is the main antigenic domain with the N-terminal domain (14) . Because these domains are less conserved than other parts of the spike protein, SARS-CoV-2 variants can escape to MoAb neutralization (15, 16) . It occurred for bamlanivimab unable to neutralize the now dominant SARS-CoV-2 variant B.1.617 and therefore revoked as monotherapy. In our study, patients in the MoAb group were mostly exposed to B.1.1.7 variant considered as more pathogenic than ancestor Wuhan strain still dominant when control patients were infected, because the period of enrollment differed between the two groups (17, 18) . While MoAb could J o u r n a l P r e -p r o o f be more broadly used as preventive therapy in non-responder to vaccination or in prolonged 20) , it is important to keep in mind that effectiveness of these treatment must regularly be updated (21) and therapeutic strategies potentially refined taking account the geographic distribution of different SARS-CoV-2 strains. The last illustration is the recent propagation of Omicron variant that escapes to casirivimab and imdevimab. The use of antibodies that targets highly conserved epitopes, such as sotrovimab, could represent an attractive alternative (22) (23) (24) . It is important to consider the efficacy of MoAb in the light of risk profile of the population. The two first sponsored clinical trials were conducted in immunocompetent patients supposed to be at high risk of worsening Covid-19. The clinical benefit observed in patients treated with bamlanivimab-etesivimab and casirivimab-imdevimab remained uncertain because of the unexpected low number of hospitalization (7, 9) . Several observational studies brought more convincing results with a lower risk of hospitalization in patients treated with MoAb (25, 26). However, one of the studies that compared 594 patients to 5536 unmatched contemporaneous patients and 7404 historical patients, failed to show a clear effect on mortality (26) . This was likely due to the short follow-up (14 days) and again the fairly low risk of death in control patients (1%). In our study, 11.6% of matched KTRs passed away during the first month, close to the proportion found in a well-designed case-control study that found a strong reduction of mortality using MoAb (0% vs 9.4%) (25). It is of note that real-life studies who included a large number of immunocompromised patients unfortunately did not discriminate SOT from other causes of immunosuppression (hematopoietic stem cell transplant recipient, HIV, or currently receiving chemotherapy) and did not specifically investigate the efficacy of MoAb in immunocompromised patients (26, 27) . Finally, we can conclude that immunosuppression confers a high-risk of worsening Covid-19 but does not alter the efficacy of MoAb. Today, the first-line weapon against Covid-19 is obviously vaccines, especially mRNA-based vaccines (28) (29) (30) . Nowadays, it is clear that immune response to Covid-19 vaccination is affected by immunosuppressive drugs. Indeed, while mRNA-based vaccine elicits antibody response in more than 95 % in general population, the proportion of SOT recipients who developed anti-spike protein after one dose is meager, estimated between 5 and 17% (4, 31, The number of patients treated with bamlanivimab as monotherapy (n=8), bamlanivimab-etesevimab (n=39) or casirivimab-imdevimab (n=33) are represented by month. Figure 3 . 90-days patient survival in the patients treated with an early injection of anti-SARS-Cov-2 therapeutic antibody was greater than and matched control-recipients. Patients treated with therapeutic antibodies and control patients are presented by continuous and dotted line, respectively. The survival was higher in the patients treated with monoclonal antibodies (log rank, p=0.004). An initial report from the French SOT COVID Registry suggests high mortality due to COVID-19 in recipients of kidney transplants Is COVID-19 infection more severe in kidney transplant recipients? severity in kidney transplant recipients is similar to nontransplant patients with similar comorbidities Immunogenicity of a Single Dose of SARS-CoV-2 Messenger RNA Vaccine in Solid Organ Transplant Recipients Three Doses of an mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients Occurrence of severe COVID-19 in vaccinated transplant patients Neutralizing Antibody Cocktail, in Outpatients with Covid-19 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19 Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial Bamlanivimab for treatment of COVID-19 in solid organ transplant recipients: Early single-center experience Initial experience of bamlanivimab monotherapy use in solid organ transplant recipients Casirivimab-Imdevimab for Treatment of COVID-19 in Solid Organ Transplant Recipients: an Early Experience The antigenic anatomy of SARS-CoV-2 receptor binding domain SARS-CoV-2 variant B.1.617 is resistant to bamlanivimab and evades antibodies induced by infection and vaccination Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study Successful Clearance of 300 Day SARS-CoV-2 Infection in a Subject with B-Cell Depletion Associated Prolonged (B-DEAP) COVID by REGEN-COV Anti-Spike Monoclonal Antibody Cocktail Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19 SnapShot: SARS-CoV-2 antibodies Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab Broad betacoronavirus neutralization by a stem helix-specific human antibody Crossneutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody Bamlanivimab use in mild-to-moderate COVID-19 disease: A matched cohort design Effectiveness and Tolerability of Monoclonal Antibody Therapy for Ambulatory Patients With Early COVID-19 Real-World Clinical Outcomes of Bamlanivimab and Casirivimab-Imdevimab among High-Risk Patients with Mild to Moderate Coronavirus Disease Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting Weak anti-SARS-CoV-2 antibody response after the first injection of an mRNA COVID-19 vaccine in kidney transplant recipients Efficiency of a boost with a third dose of anti-SARS-CoV-2 messenger RNA-based vaccines in solid organ transplant recipients Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients Covid-19: coronavirus disease 2019 EMA: European Medicines Agency FDA: Food and Drug Administration HIV: human immunodeficiency virus ICU: intensive care unit IQR : interquartile range KTR: kidney transplant recipient mTOR: mammalian target of rapamycin MoAb: monoclonal antibody rt-PCR: real-time polymerase chain reaction SARS-CoV-2: severe acute respiratory syndrome coronavirus -Loveplot for balance of covariances between KTRs in MoAb group and control group before and after adjustment (PDF) -STROBE statement (PDF) Supplementary information is available at KI Report's website.J o u r n a l P r e -p r o o f