Immunosuppressants exert differential effects on pan-coronavirus infection and distinct combinatory antiviral activity with molnupiravir and nirmatrelvir.

BACKGROUND: Immunocompromised populations, such as organ transplant recipients and patients with inflammatory bowel disease (IBD) receiving immunosuppressive/immunomodulatory medications, may be more susceptible to coronavirus infections. However, little is known about how immunosuppressants affect coronavirus replication and their combinational effects with antiviral drugs. OBJECTIVE: This study aims to profile the effects of immunosuppressants and the combination of immunosuppressants with oral antiviral drugs molnupiravir and nirmatrelvir on pan-coronavirus infection in cell and human airway organoids (hAOs) culture models. METHODS: Different coronaviruses (including wild type, delta and omicron variants of SARS-CoV-2, and NL63, 229E and OC43 seasonal coronaviruses) were used in lung cell lines and hAOs models. The effects of immunosuppressants were tested. RESULTS: Dexamethasone and 5-aminosalicylic acid moderately stimulated the replication of different coronaviruses. Mycophenolic acid (MPA), 6-thioguanine (6-TG), tofacitinib and filgotinib treatment dose-dependently inhibited viral replication of all tested coronaviruses in both cell lines and hAOs. The half maximum effective concentration (EC50) of tofacitinib against SARS-CoV-2 was 0.62 µM and the half maximum cytotoxic concentration (CC50) was above 30 µM, which resulted in a selective index (SI) of about 50. The anti-coronavirus effect of the JAK inhibitors tofacitinib and filgotinib is dependent on the inhibition of STAT3 phosphorylation. Combinations of MPA, 6-TG, tofacitinib, and filgotinib with the oral antiviral drugs molnupiravir or nirmatrelvir exerted an additive or synergistic antiviral activity. CONCLUSIONS: Different immunosuppressants have distinct effects on coronavirus replication, with 6-TG, MPA, tofacitinib and filgotinib possessing pan-coronavirus antiviral activity. The combinations of MPA, 6-TG, tofacitinib and filgotinib with antiviral drugs exerted an additive or synergistic antiviral activity. Thus, these findings provide an important reference for optimal management of immunocompromised patients infected with coronaviruses.

Apolipoprotein-A-I for severe COVID-19-induced hyperinflammatory states: A prospective case study

Viral infections can promote cytokine storm and multiorgan failure in individuals with an underlying immunosuppression or specific genetic background. Hyperinflammatory states, including critical forms of COVID-19, are characterized by a remodeling of the lipid profile including a dramatic decrease of the serum levels of apolipoprotein-A-I (ApoA-I), a protein known for its capacity to reduce systemic and lung inflammation, modulate innate and adaptive immunity, and prevent endothelial dysfunction and blood coagulation. In this study, four immunocompromised patients with severe COVID-19 cytokine storm that progressed despite standard-of-care therapy [Omicron (n = 3) and Delta (n = 1) variants] received 2– 4 infusions (10 mg/kg) of CER-001, an ApoA-I-containing HDL mimetic. Injections were well-tolerated with no serious adverse events. Three patients treated while not on mechanical ventilation had early clinical and biological improvement (oxygen withdrawal and correction of hematological and inflammatory parameters, including serum levels of interleukin-8) and were discharged from the hospital 3–4 days after CER-001 infusions. In the fourth patient who received CER-001 after orotracheal intubation for acute respiratory distress syndrome, infusions were followed by transient respiratory improvement before secondary worsening related to ventilation-associated pneumonia. This pilot uncontrolled exploratory compassionate study provides initial safety and proof-of-concept data from patients with a COVID-19 cytokine storm receiving ApoA-I. Further randomized controlled trial evaluation is now required to ascertain whether ApoA-I has any beneficial effects on patients with a COVID-19 cytokine storm.

Humoral and Cellular Responses to a Delayed Fourth SARS-CoV-2 mRNA-Based Vaccine in Weak Responders to 3 Doses Kidney Transplant Recipients.

While kidney transplant recipients (KTRs) represent a high-risk population for severe SARS-CoV-2 infection, almost half of them do not develop adequate levels of antibodies conferring clinical protection despite 3 doses of the mRNA vaccine. In the present study we retrospectively analyzed the humoral and cellular responses resulting from a fourth dose of vaccine administered to KTRs having an anti-SARS-CoV-2 antibody titer below 142 binding antibody unit (BAU)/mL at 3 months post-third-dose. We observed a significant increase in anti-SARS-CoV-2 antibody concentration from 6.1 (Q1 4.3; Q3 12.7) BAU/mL on the day of the fourth dose to 1054.0 (Q1 739.6; Q3 1649.0) BAU/mL one month later (p = 0.0007), as well as neutralizing antibody titers (from 0.0 (Q1 0.0; Q3 2.0) to 8 (4; 16) IU/mL, p = 0.01) and CD3+ T cell response (from 37.5 (Q1 12.5; Q3 147.5) to 170.0 (Q1 57.5; Q3 510.0) SFUs per 106 PBMCs, p = 0.001). Hence, delaying the fourth dose seems to improve vaccine immunogenicity in KTRs, compared with previously reported data obtained in respect of a fourth dose one month after the third dose. Nevertheless, antibody concentrations seem to remain insufficient to confer clinical protection, especially for Omicron, for which breakthrough infections occur even at very high concentrations.

Can the COVID-19 Pandemic Improve the Management of Solid Organ Transplant Recipients?

Increased mortality due to SARS-CoV-2 infection was observed among solid organ transplant patients. During the pandemic, in order to prevent and treat COVID-19 infections in this context, several innovative procedures and therapies were initiated within a short period of time. A large number of these innovations can be applied and expanded to improve the management of non-COVID-19 infectious diseases in solid organ transplant patients and in the case of a future pandemic. In this vein, the present paper reviews and discusses medical care system adaptation, modification of immunosuppression, adjuvant innovative therapies, the role of laboratory expertise, and the prevention of infections as examples of such innovations.

Cytomegalovirus Management in Solid Organ Transplant Recipients: A Pre-COVID-19 Survey From the Working Group of the European Society for Organ Transplantation.

Infections are leading causes of morbidity/mortality following solid organ transplantation (SOT) and cytomegalovirus (CMV) is among the most frequent pathogens, causing a considerable threat to SOT recipients. A survey was conducted 19 July-31 October 2019 to capture clinical practices about CMV in SOT recipients (e.g., how practices aligned with guidelines, how adequately treatments met patients' needs, and respondents' expectations for future developments). Transplant professionals completed a ∼30-minute online questionnaire: 224 responses were included, representing 160 hospitals and 197 SOT programs (41 countries; 167[83%] European programs). Findings revealed a heterogenous approach to CMV diagnosis and management and, sometimes, significant divergence from international guidelines. Valganciclovir prophylaxis (of variable duration) was administered by 201/224 (90%) respondents in D+/R- SOT and by 40% in R+ cases, with pre-emptive strategies generally reserved for R+ cases: DNA thresholds to initiate treatment ranged across 10-10,000 copies/ml. Ganciclovir-resistant CMV strains were still perceived as major challenges, and tailored treatment was one of the most important unmet needs for CMV management. These findings may help to design studies to evaluate safety and efficacy of new strategies to prevent CMV disease in SOT recipients, and target specific educational activities to harmonize CMV management in this challenging population.

Factors Associated With COVID-19 Vaccine Response in Transplant Recipients: A Systematic Review and Meta-analysis.

BACKGROUND: The rapid development and universal access to vaccines represent a milestone in combating the coronavirus disease 2019 (COVID-19) pandemic. However, there are major concerns about vaccine response in immunocompromised populations in particular transplant recipients. In the present study, we aim to comprehensively assess the humoral response to COVID-19 vaccination in both orthotopic organ transplant and allogeneic hematopoietic stem cell transplant recipients. METHODS: We performed a systematic review and meta-analysis of 96 studies that met inclusion criteria. RESULTS: The pooled rates of seroconversion were 49% (95% confidence interval [CI], 43%-55%) in transplant recipients and 99% (95% CI, 99%-99%) in healthy controls after the second dose of vaccine. The pooled rate was 56% (95% CI, 49%-63%) in transplant recipients after the third dose. Immunosuppressive medication is the most prominent risk factor associated with seroconversion failure, but different immunosuppressive regimens are associated with differential outcomes in this respect. Calcineurin inhibitors, steroids, or mycophenolate mofetil/mycophenolic acid are associated with an increased risk of seroconversion failure, whereas azathioprine or mammalian target of rapamycin inhibitors do not. Advanced age, short interval from receiving the vaccine to the time of transplantation, or comorbidities confers a higher risk for seroconversion failure. CONCLUSIONS: Transplant recipients compared with the general population have much lower rates of seroconversion upon receiving COVID-19 vaccines. Immunosuppressants are the most prominent factors associated with seroconversion, although different types may have differential effects.

Predictive Factors for Humoral Response After 2-dose SARS-CoV-2 Vaccine in Solid Organ Transplant Patients.

BACKGROUND: A weak immunogenicity has been reported in solid organ transplant (SOT) recipients after 2 doses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. The aim of this retrospective study was to identify the predictive factors for humoral response in SOT patients. METHODS: Three hundred and ninety-three SOT patients from our center with at least 4 wk of follow-up after 2 doses of mRNA-based vaccine were included in this study. Anti-SARS-Cov-2 spike protein antibodies were assessed before and after vaccination. RESULTS: Anti-SARS-CoV-2 antibodies were detected in 34% of the patients: 33.7% of kidney transplant patients, 47.7% of liver transplant patients, and 14.3% of thoracic transplant patients (P = 0.005). Independent predictive factors for humoral response after vaccination were male gender, a longer period between transplantation and vaccination, liver transplant recipients, a higher lymphocyte count at baseline, a higher estimated glomerular filtration rate and receiving the tacrolimus + everolimus ± steroids combination. Conversely, the nondevelopment of anti-SARS-CoV-2 antibodies after vaccination was associated with younger patients, thoracic organ recipients, induction therapy recipients, and tacrolimus + mycophenolic acid ± steroids recipients. CONCLUSIONS: The immunosuppressive regimen is a modifiable predictive factor for humoral response to SARS-CoV-2 vaccine.

Early Administration of Anti-SARS-CoV-2 Monoclonal Antibodies Prevents Severe COVID-19 in Kidney Transplant Patients.

Introduction: Kidney transplant recipients (KTRs) are prone to develop severe COVID-19 and are less well protected by vaccine than immunocompetent subjects. Thus, the use of neutralizing anti-SARS-CoV-2 monoclonal antibody (MoAb) to confer a passive immunity appears attractive in KTRs. Methods: We performed a French nationwide study to compare COVID-19-related hospitalization, 30-day admission to intensive care unit (ICU), and 30-day 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: A total of 80 KTRs received MoAb between February 2021 and June 2021. They were matched to 155 controls. COVID-19-related hospitalization, 30-day admission to ICU, and 30-day death were less frequently observed in the 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 patient required mechanical ventilation in the MoAb group. The number of patients to treat to prevent 1 death was 9.7. Conclusion: The early use of MoAb in KTRs with a mild form of COVID-19 largely improved outcomes in KTRs.

Impact of Casirivimab-Imdevimab on Severe Acute Respiratory Syndrome Coronavirus 2 Delta Variant Nasopharyngeal Virus Load and Spike Quasispecies.

Background: The increasing use of monoclonal antibodies (mAbs) to treat coronavirus disease 2019 raises questions about their impact on the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mAb-resistant variants. We assessed the impact of Casirivimab-Imdevimab on SARS-CoV-2 mutations associated with reduced mAb activity in treated patients. Methods: We measured the nasopharyngeal (NP) viral load and sequenced the haplotypes of spike gene of 50 patients infected with the SARS-CoV-2 delta variant and treated with Casirivimab-Imdevimab using single-molecule real-time sequencing. Results: The NP SARS-CoV-2 viral load of patients treated with Casirivimab-Imdevimab decreased from 8.13 (interquartile range [IQR], 7.06-8.59) log10 copies/mL pretreatment to 3.67 (IQR, 3.07-5.15) log10 copies/mL 7 days later (P < .001). Of the 36 patients for whom follow-up timepoints Spike sequencing were available, none of the Spike mutations that reduced mAb activity were detected. Conclusions: Casirivimab-Imdevimab is an effective treatment for patients infected with the SARS-CoV-2 delta variant. Despite selective pressure on SARS-CoV-2 Spike quasispecies, we detected no key mutations that reduced mAb activity in our patients.

Impact of Casirivimab-Imdevimab on SARS-CoV-2 delta variant nasopharyngeal virus load and Spike quasispecies

Objectives The increasing use of monoclonal antibodies (mAbs) to treat COVID-19 raises questions about their impact on the emergence of SARS-CoV-2 mAb-resistant variants. We assessed the impact of Casirivimab-Imdevimab on SARS-CoV-2 mutations associated with reduced mAb activity in treated patients. Patients and methods We measured the nasopharyngeal (NP) viral load and sequenced the haplotypes of spike gene of 50 patients infected with the SARS-CoV-2 delta variant and treated with Casirivimab-Imdevimab using single-molecule real-time sequencing (SMRT). Results The NP SARS-CoV-2 viral load of patients treated with Casirivimab-Imdevimab decreased from 8.13 [IQR, 7.06-8.59] log10 copies/ml pre-treatment to 3.67 [IQR, 3.07-5.15] log10 copies/ml seven days later (p<0.001). Of the 36 patients for whom follow-up time-points Spike sequencing were available, none of the Spike mutations that reduced mAb activity were detected. Conclusion Casirivimab-Imdevimab is an effective treatment for patients infected with the SARS-CoV-2 delta variant. Despite selective pressure on SARS-CoV-2 Spike quasispecies, we detected no key mutations that reduced mAb activity in our patients.

Humoral and Cellular Immune Responses of Solid Organ Transplant Patients on Belatacept to Three Doses of mRNA-Based Anti-SARS-CoV-2 Vaccine.

BACKGROUND: Two doses of anti-SARS-CoV-2 mRNA-based vaccines are poorly immunogenic in solid organ transplant recipients (SOT). METHODS: In total, 68 belatacept-treated SOT recipients followed at the Toulouse University Hospital were investigated. They were given three injections of the BNT162b2 mRNA COVID-19 vaccine. Their humoral response was assessed by determining anti-spike antibodies and neutralizing antibodies. The T-cell responses were assessed using an enzyme-linked immunospot assay that measured the interferon-γ produced by specific SARS-CoV-2 T-cells in a subgroup of 17 patients. RESULTS: Only 23.5% of these patients developed a detectable anti-spike response. Moreover, the cellular and the humoral responses were well correlated. Patients with no humoral response were also without a detectable cellular response. Those belatacept-treated patients who developed an Anti-SARS-CoV-2 humoral response were younger, had been transplanted for longer, and had a higher lymphocyte count and a better glomerular filtration rate than those with no response. Finally, patients on tacrolimus plus belatacept produced a lower immune response. CONCLUSIONS: Belatacept-treated SOT recipients have a reduced immune response to anti-SARS-CoV-2 mRNA vaccination. The vaccine should be given quite separately from the belatacept infusion to improve immunogenicity. Studies to assess whether switching to another immunosuppressive regimen can improve the post-vaccination immune response would be useful.

Anti-SARS-CoV-2 spike protein and neutralizing antibodies at 1 and 3 months after three doses of SARS-CoV-2 vaccine in a large cohort of solid organ transplant patients.

The immunogenicity of the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccine was improved by the administration of a third dose. The aim of our retrospective study was to assess the evolution of binding and neutralizing antibody concentration until 3 months after the third dose in a large cohort of solid organ transplant (SOT) patients (n = 872). At 1 month after the third dose, anti-SARS-CoV-2 antibodies were detected by means of enzyme-linked immunosorbent assay tests in 578 patients (66.3%). In a subgroup of patients, 70% (180 out of 257) had anti-SARS-CoV-2 antibody concentrations ranging from 1.2 to 18 411 binding antibody units (BAU)/ml and 48.5% (115 out of 239) had a neutralizing antibodies titer that can confer clinical protection against SARS-CoV-2. Three-hundred ninety-three patients out of the 416 (94.5%) who were seropositive at month 1 and were tested at 3 months after vaccination remained seropositive. Between months 1 and 3 after vaccination, binding and neutralizing antibodies concentrations decreased significantly. The proportion of protected patients against the SARS-CoV-2 also slightly decreased. In conclusion, this study shows that although two-third of SOT develop anti-SARS-CoV-2 antibodies after three doses, one-third of them remain weak or non-protected. It is important to measure anti-SARS-CoV-2 antibodies to define the strategy that can optimize SOT protection against SARS-CoV-2.