Tixagevimab-cilgavimab as an early treatment for COVID-19 in kidney transplant recipients (preprint)

Objective This single-center retrospective study evaluated the use of tixagevimab-cilgavimab as an early treatment for COVID-19 in kidney transplant recipients (KTRs) during the omicron wave. Methods KTRs were deemed at high risk for moderate-to-severe COVID-19 in presence of at least one comorbidity (age >60 years, diabetes, obesity, or cardiovascular disease) associated with a weak humoral response (<264 BAU/mL). All other KTRs were considered at low risk. The two groups were stratified according to the administration of tixagevimab-cilgavimab and compared in terms of COVID-19-related hospitalization, oxygen need, ICU admission, and mortality. Results Of the 61 KTRs at high risk, 26 received tixagevimab-cilgavimab. COVID-19-related hospitalizations (3.8% versus 34%, p=0.006) and oxygen need (3.8% versus 23%, p=0.04) were significantly less frequent in patients who received tixagevimab-cilgavimab. In addition, non-significant trends towards a lower number of ICU admissions (3.8% versus 14.3% p=0.17) and deaths (0 versus 3, p=0.13) were observed after administration of tixagevimab-cilgavimab. Ten of the 73 low-risk KTRs received tixagevimab-cilgavimab, and no significant clinical benefit was observed in this subgroup. Conclusion Early administration of tixagevimab-cilgavimab may be clinically useful in high-risk KTRs with COVID-19; however, no major benefit was observed for low-risk patients.

Development and Validation of Multivariable Prediction Models of Serological Response to SARS-CoV-2 Vaccination in Kidney Transplant Recipients (preprint)

Background Repeated vaccination against SARS-CoV-2 increases serological response in kidney transplant recipients (KTR) with high interindividual variability. No decision support tool exists to predict SARS-CoV-2 vaccination response in KTR. Methods We developed, internally and externally validated five different multivariable prediction models of serological response after the third and fourth vaccine dose against SARS-CoV-2 in KTR. Using 27 candidate predictor variables, we applied statistical and machine learning approaches including logistic regression (LR), LASSO-regularized LR, random forest, and gradient boosted regression trees. For development and internal validation, data from 585 vaccinations were used. External validation was performed in four independent, international validation datasets comprising 191, 184, 254, and 323 vaccinations, respectively. Findings LASSO-regularized LR performed on the whole development dataset yielded a 23- and 11- variable model, respectively. External validation showed AUC-ROC of 0.855, 0.749, 0.828, and 0.787 for the sparser 11-variable model, yielding an overall performance 0.819. Interpretation An 11-variable LASSO-regularized LR model predicts vaccination response in KTR with good overall accuracy. Implemented as an online tool, it can guide decisions when choosing between different immunization strategies to improve protection against COVID-19 in KTR.

Pre-exposure prophylaxis with Evusheld™ elicits limited neutralizing activity against the omicron variant in kidney transplant patients (preprint)

The combination of cilgavimab-tixagevimab (Evusheld, Astra Zeneca) became the mainstay for protecting transplant recipients with poor response to vaccination against the omicron variant. Serum neutralizing capacity against SARS-CoV-2 is positively associated with protection against severe forms of Covid-19. Both anti-RBD IgG titers and neutralizing antibody titers against the omicron BA.1 variant were measured in serum samples collected from 63 adult kidney transplant recipients who received prophylactic injections of Evusheld. Patients who received prophylactic Ronapreve (casirivimab-imdevimab, n = 39) and those who were infected with SARS-CoV-2 during the fifth wave of the pandemic (n = 14) served as negative and positive controls, respectively. After a median interval from injection of 29 days (interquartile range 29-33 days), only 9.5% of patients who received Evusheld were able to neutralize the omicron variant compared to 71% of patients who were infected with SARS-CoV-2 and 2.6% of those who received Ronapreve. Interestingly, convalescent patients displayed higher levels of neutralizing antibodies than those who received Evusheld (median: 2.3 log IC50, IQR: 1.5-2.7 versus 0.00 log IC50, IQR: 0- 0.05; p<0.001). A high interindividual variability in anti-RBD IgG titers was observed after Evusheld (range: 262-7032 BAU/mL). This variability was largely explained by the patients' body mass index, which showed an inverse correlation with anti-RBD IgG titers. These findings suggest that Evusheld given at a dose of 300 mg is not sufficient to elicit an anti-RDB titer that confers in vivo neutralizing activity and support recent FDA recommendations, derived from in vitro models, regarding the need to increase the dose of Evusheld.

Breakthrough Covid-19 cases despite tixagevimab and cilgavimab (Evusheld™) prophylaxis in kidney transplant recipients (preprint)

While the combination of casirivimab-imdevimab (Ronapreve Roche Regeneron) has been shown to confer satisfactory protection against the delta variant kidney transplant recipients (KTRs) with COVID-19, it has limited neutralizing activity against the current variants of concern (Omicron BA.1, BA.1.1 and BA.2). In contrast, cilgavimab-tixagevimab combination (Evusheld, Astra Zeneca) retains a partial neutralizing activity against omicron in vitro. We examined whether preexposure prophylaxis with Evusheld can effectively protect kidney transplant recipients (KTRs) against the Omicron variant. Of the 416 KTRs who received intramuscular prophylactic injections of Evusheld (150 mg tixagevimab and 150 mg cilgavimab), 39 (9.4%) developed COVID-19. With the exception of one patient, all KTRs were symptomatic. Hospitalization and admission to an intensive care unit were required for 14 (35.9%) and three patients, respectively. Two KTRs died of COVID-19-related acute respiratory distress syndrome. SARS-CoV-2 sequencing was carried out in 15 cases (BA.1, n = 5; BA.1.1, n = 9; BA.2, n=1). Viral neutralizing activity of the serum against BA.1 variant was negative in the 12 tested patients, suggesting that this prophylaxis strategy provides insufficient protection against this variant of concern. Preexposure prophylaxis with Evusheld does not adequately protect KTRs against Omicron. Further clarification of the optimal dosing can assist in our understanding of how best to harness its protective potential.

Changing of therapeutic trends between the 1st and 2nd wave did not reduce COVID-19 related mortality of renal transplant recipients: a national registry study. (preprint)

SARS-CoV-2 pandemic evolved in two consecutive waves over 2020 (for France: 1st wave from March 1 to July 31; and 2nd wave from August 1 to December 31). Improvements in the management of COVID-19 led to a reduction of mortality rates in hospitalized patients during the second wave. Whether this progress also benefited to kidney transplant recipients (KTR), a population particularly vulnerable to severe COVID-19, remained unclear. In France, 957 KTR were hospitalized for COVID-19 in 2020 and their data were prospectively collected in the French SOT COVID registry. The presentation, management, and outcomes of the 359 KTR diagnosed during the 1st wave were compared to those of the 598 of the 2nd wave. Baseline comorbidities were largely similar between KTR of the 2 waves. Maintenance immunosuppression was reduced in most patients but withdrawal of antimetabolite (73.7% vs 58.4%, p<0.001) or CNI (32.1% vs 16.6%, p<0.001) was less frequent during the 2nd wave. Hydroxychloroquine and azithromycin that were commonly used during the 1st wave (21.7% and 30.9%, respectively) were almost abandoned during the 2nd. In contrast, the use of high dose corticosteroids doubled (19.5% vs. 41.6%, p<0.001). Despite these changing trends in COVID-19 management, 60-day mortality was not statistically different between the 2 waves (25.3% vs. 23.9%; Log Rank, p=0.48). We conclude that changing of therapeutic trends during 2020 did not reduce COVID-19 related mortality in KTR. Our data indirectly support the importance of vaccination and monoclonal neutralizing anti-SARS-CoV-2 antibodies to protect KTR from severe COVID-19.

A fourth dose of the mRNA-1273 SARS-CoV-2 vaccine improves serum neutralization against the delta variant in kidney transplant recipients (preprint)

In immunocompetent subjects, the effectiveness of SARS-CoV-2 vaccines against the delta variant appears three-to five-fold lower than that observed against the alpha variant. Additionally, three doses of SARS-CoV-2 mRNA-based vaccines might be unable to elicit a sufficient immune response against any variant in immunocompromised kidney transplant recipients. This study describes the kinetics of the neutralizing antibody (NAbs) response against the delta strain before and after a fourth dose of a mRNA vaccine in 67 kidney transplant recipients who had experienced a weak antibody response after three doses. While only 16% of patients harbored NAbs against the delta strain prior to the fourth injection - this percentage raised to 66% afterwards. We also found that, after the fourth dose, the NAbs titer increased significantly (p=0.0001) from <7.5 (IQR : <7.5 -15.1) to 47.1 (IQR <7.5-284.2). Collectively, our data indicate that a fourth dose of the mRNA-1273 vaccine in kidney transplant recipients with a weak antibody response after three previous doses improves serum neutralization against the delta variant.

Antibody response to a fourth mRNA Covid-19 vaccine boost in weak responder kidney transplant recipients (preprint)

The US FDA has recently authorized immunocompromised people to receive a third dose of mRNA Covid-19 vaccine following the two-doses regimen to further boost protection. Unfortunately, a non-negligible proportion of people treated with immunosuppressive drugs either do not respond or show only a weak response after a third boost and should, therefore, still be considered at risk of severe Covid-19. As of June 2021, we were granted the opportunity to offer a fourth vaccine dose to French solid organ transplant recipients who still showed a weak antibody response after the third dose. In this multicenter study, we demonstrate that that the protection conferred by a fourth dose is adequate for the majority of kidney transplant recipients.

Comparison of infected and vaccinated transplant recipients highlights the role of Tfh and neutralizing IgG in COVID-19 protection (preprint)

Transplant recipients, which receive therapeutic immunosuppression to prevent graft rejection, are characterized by high COVID-19-related mortality and defective response to vaccines. Having observed that previous infection by SARS-CoV-2 but not the standard “2 doses” scheme of vaccination, provided complete protection against COVID-19 to transplant recipients, we undertook this translational study to compare the cellular and humoral immune responses of these 2 groups of patients. Neutralizing anti-Receptor Binding Domain (RBD) IgG were identified as the critical immune effectors associated with protection. Generation of anti-RBD IgG was dependent upon spike-specific T follicular helper (Tfh) CD4+ T cells, which acted as limiting checkpoint. Tfh generation was impeded by high dose mycophenolate mofetil in non-responders to vaccine but not in infected patients, suggesting that increasing immunogenicity of vaccine could improve response rate to mRNA vaccine. This theory was validated in two independent prospective cohorts, in which administration of a 3 rd dose of vaccine resulted in the generation of anti-RBD IgG in half of non-responders to 2 doses. One sentence summary The generation of neutralizing IgG, which protects kidney transplant recipients from COVID-19, requires T follicular helper cells.

Weak anti-SARS-CoV-2 antibody response after the first injection of an mRNA COVID-19 vaccine in kidney transplant recipients (preprint)

Data concerning the anti-SARS-CoV-2 antibody response after mRNA COVID-19 vaccine in kidney transplant recipients (KTRs) are currently lacking. Here, we sought to examine this issue by analyzing the serological response observed in 241 KTRs after a first vaccine injection. Our results indicate that KTRs have a weak anti-SARS-CoV-2 antibody response, ultimately resulting in a low seroconversion rate (26/241, 10.8%). This phenomenon likely stems from a high immunosuppression burden in this clinical population.

In-depth virological assessment of kidney transplant recipients with COVID-19 (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread widely, causing coronavirus disease 2019 (COVID-19) and significant mortality. However, data on viral loads and antibody kinetics in immunocompromised populations are lacking. We aimed to determine nasopharyngeal and plasma viral loads via RT-PCR and SARS-CoV-2 serology via ELISA and study their association with severe forms of COVID-19 and death in kidney transplant recipients. In this study we examined hospitalized kidney transplant recipients with non-severe (n = 21) and severe (n =19) COVID-19. SARS-CoV-2 nasopharyngeal and plasma viral load and serological response were evaluated based on outcomes and disease severity. Ten recipients (25%) displayed persistent viral shedding 30 days after symptom onset. The SARS-CoV-2 viral load of the upper respiratory tract was not associated with severe COVID-19, whereas the plasma viral load was associated with COVID-19 severity (p=0.0087) and mortality (p=0.024). All patients harbored antibodies the second week after symptom onset that persisted for two months. We conclude that plasma viral load is associated with COVID-19 morbidity and mortality, whereas nasopharyngeal viral load is not. SARS-CoV-2 shedding is prolonged in kidney transplant recipients and the humoral response to SARS-CoV-2 does not show significant impairment in this series of transplant recipients.

Cytokine Release Syndrome-Associated Encephalopathy in Patients with COVID-19 (preprint)

Severe disease and uremia are risk factors for neurological complications of coronavirus disease-2019 (COVID-19). An in-depth analysis of a case series was conducted to describe the neurological manifestations of patients with COVID-19 and gain pathophysiological insights that may guide clinical decision-making – especially with respect to the cytokine release syndrome (CRS). Extensive clinical, laboratory, and imaging phenotyping was performed in five patients. Neurological presentation included confusion, tremor, cerebellar ataxia, behavioral alterations, aphasia, pyramidal syndrome, coma, cranial nerve palsy, dysautonomia, and central hypothyroidism. Neurological disturbances were remarkably accompanied by laboratory evidence of CRS. SARS-CoV-2 was undetectable in the cerebrospinal fluid. Hyperalbuminorachy and increased levels of the astroglial protein S100B were suggestive of blood-brain barrier (BBB) dysfunction. Brain MRI findings comprised evidence of acute leukoencephalitis (n = 3, of whom one with a hemorrhagic form), cytotoxic edema mimicking ischemic stroke (n = 1), or normal results (n = 2). Treatment with corticosteroids and/or intravenous immunoglobulins was attempted – resulting in rapid recovery from neurological disturbances in two cases. Patients with COVID-19 can develop neurological manifestations that share clinical, laboratory, and imaging similarities with those of chimeric antigen receptor-T cell-related encephalopathy. The pathophysiological underpinnings appear to involve CRS, endothelial activation, BBB dysfunction, and immune-mediated mechanisms.