Safety, Tolerability, and Pharmacokinetics of Anti-SARS-CoV-2 Immunoglobulin Intravenous (Human) Investigational Product (COVID-HIGIV) in Healthy Adults: a Randomized, Controlled, Double-Blinded, Phase 1 Study.

Anti-SARS-CoV-2 immunoglobulin (human) investigational product (COVID-HIGIV) is a purified immunoglobulin preparation containing SARS-CoV-2 polyclonal antibodies. This single-center clinical trial aimed to characterize the safety and pharmacokinetics of COVID-HIGIV in healthy, adult volunteers. Participants were enrolled to receive one of three doses of COVID-HIGIV (100, 200, 400 mg/kg) or placebo in a 2:2:2:1 randomization scheme. Between 24 December 2020 and 27 July 2021, 28 participants met eligibility and were randomized with 27 of these 28 (96.4%) being administered either COVID-HIGIV (n = 23) or placebo (n = 4). Only one SAE was observed, and it occurred in the placebo group. A total of 18 out of 27 participants (66.7%) reported 50 adverse events (AEs) overall. All COVID-HIGIV-related adverse events were mild or moderate in severity and transient. The most frequent AEs (>5% of participants) reported in the safety population were headache (n = 6, 22.2%), chills (n = 3, 11.1%), increased bilirubin (n = 2, 7.4%), muscle spasms (n = 2, 7.4%), seasonal allergies (n = 2, 7.4%), pyrexia (n = 2, 7.4%), and oropharyngeal pain (n = 2, 7.4%). Using the SARS-CoV-2 binding IgG immunoassay (n = 22, specific for pharmacokinetics), the geometric means of Cmax (AU/mL) for the three COVID-HIGIV dose levels (low to high) were 7.69, 17.02, and 33.27 AU/mL; the average values of Tmax were 7.09, 7.93, and 5.36 h, respectively. The half-life of COVID-HIGIV per dose level was 24 d (583 h), 31 d (753 h), and 26 d (619 h) for the 100 mg/kg, 200 mg/kg, and 400 mg/kg groups, respectively. The safety and pharmacokinetics of COVID-HIGIV support its development as a single-dose regimen for postexposure prophylaxis or treatment of COVID-19.

Informative Censoring-A Cause of Bias in Estimating COVID-19 Mortality Using Hospital Data.

(1) Background: Several retrospective observational analyzed treatment outcomes for COVID-19; (2) Methods: Inverse probability of censoring weighting (IPCW) was applied to correct for bias due to informative censoring in database of hospitalized patients who did and did not receive convalescent plasma; (3) Results: When compared with an IPCW analysis, overall mortality was overestimated using an unadjusted Kaplan-Meier curve, and hazard ratios for the older age group compared to the youngest were underestimated using the Cox proportional hazard models and 30-day mortality; (4) Conclusions: An IPCW analysis provided stabilizing weights by hospital admission.

The Effect of Convalescent Plasma Therapy on Mortality Among Patients With COVID-19: Systematic Review and Meta-analysis.

To determine the effect of COVID-19 convalescent plasma on mortality, we aggregated patient outcome data from 10 randomized clinical trials, 20 matched control studies, 2 dose-response studies, and 96 case reports or case series. Studies published between January 1, 2020, and January 16, 2021, were identified through a systematic search of online PubMed and MEDLINE databases. Random effects analyses of randomized clinical trials and matched control data demonstrated that patients with COVID-19 transfused with convalescent plasma exhibited a lower mortality rate compared with patients receiving standard treatments. Additional analyses showed that early transfusion (within 3 days of hospital admission) of higher titer plasma is associated with lower patient mortality. These data provide evidence favoring the efficacy of human convalescent plasma as a therapeutic agent in hospitalized patients with COVID-19.

Transfusion reactions associated with COVID-19 convalescent plasma therapy for SARS-CoV-2.

BACKGROUND: Convalescent plasma (CP) for treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown preliminary signs of effectiveness in moderate to severely ill patients in reducing mortality. While studies have demonstrated a low risk of serious adverse events, the comprehensive incidence and nature of the spectrum of transfusion reactions to CP is unknown. We retrospectively examined 427 adult inpatient CP transfusions to determine incidence and types of reactions, as well as clinical parameters and risk factors associated with transfusion reactions. STUDY DESIGN AND METHODS: Retrospective analysis was performed for 427 transfusions to 215 adult patients with coronavirus 2019 (COVID-19) within the Mount Sinai Health System, through the US Food and Drug Administration emergency investigational new drug and the Mayo Clinic Expanded Access Protocol to Convalescent Plasma approval pathways. Transfusions were blindly evaluated by two reviewers and adjudicated by a third reviewer in discordant cases. Patient demographics and clinical and laboratory parameters were compared and analyzed. RESULTS: Fifty-five reactions from 427 transfusions were identified (12.9% incidence), and 13 were attributed to transfusion (3.1% incidence). Reactions were classified as underlying COVID-19 (76%), febrile nonhemolytic (10.9%), transfusion-associated circulatory overload (9.1%), and allergic (1.8%) and hypotensive (1.8%) reactions. Statistical analysis identified increased transfusion reaction risk for ABO blood group B or Sequential Organ Failure Assessment scores of 12 to 13, and decreased risk within the age group of 80 to 89 years. CONCLUSION: Our findings support the use of CP as a safe, therapeutic option from a transfusion reaction perspective, in the setting of COVID-19. Further studies are needed to confirm the clinical significance of ABO group B, age, and predisposing disease severity in the incidence of transfusion reaction events.

A High-Throughput Assay for Circulating Antibodies Directed Against the S Protein of Severe Acute Respiratory Syndrome Coronavirus 2.

More than 24 million infections with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were confirmed globally by September 2020. While polymerase chain reaction-based assays are used for diagnosis, there is a need for high-throughput, rapid serologic methods. A Luminex binding assay was developed and used to assess simultaneously the presence of coronavirus disease 2019 (COVID-19)-specific antibodies in human serum and plasma. Clear differentiation was achieved between specimens from infected and uninfected subjects, and a wide range of serum/plasma antibody levels was delineated in infected subjects. All 25 specimens from 18 patients with COVID-19 were positive in the assays with both the trimeric spike and the receptor-binding domain proteins. None of the 13 specimens from uninfected subjects displayed antibodies to either antigen. There was a highly statistically significant difference between the antibody levels of COVID-19-infected and -uninfected specimens (P < .0001). This high-throughput antibody assay is accurate, requires only 2.5 hours, and uses 5 ng of antigen per test.

Convalescent Plasma for the Treatment of Severe COVID-19 Infection in Cancer Patients.

BACKGROUND: Patients with malignancy are particularly vulnerable to infection with Severe Acute Respiratory Disease-Coronavirus-2 (SARS-CoV-2) given their immunodeficiency secondary to their underlying disease and cancer-directed therapy. We report a case series of patients with cancer who received convalescent plasma, an investigational therapy for severe Coronavirus Disease 2019 (COVID-19). METHODS: Patients with cancer were identified who received convalescent plasma. Enrolled patients had confirmed COVID-19 with severe or life-threatening disease and were transfused with convalescent plasma from donors with a SARS-CoV-2 anti-spike antibody titer of ≥ 1:320 dilution. Oxygen requirements and clinical outcomes of interests were captured as well as laboratory parameters at baseline and 3 days after treatment. RESULTS: We identified 24 patients with cancer, 14 of whom had a hematological malignancy, who were treated with convalescent plasma. Fifteen patients (62.5%) were on cancer-directed treatment at the time of COVID-19 infection. After a median of hospital duration of 9 days, 13 patients (54.2%) had been discharged home, 1 patient (4.2%) was still hospitalized, and 10 patients had died (41.7%). Non-intubated patients, particularly those on nasal cannula alone, had favorable outcomes. Three mild febrile non-hemolytic transfusion reactions were observed. C-reactive protein significantly decreased after 3 days of treatment, while other laboratory parameters including ferritin and D-dimer remained unchanged. CONCLUSIONS: Convalescent plasma may be a promising therapy in cancer patients with COVID-19.

Convalescent plasma treatment of severe COVID-19: a propensity score-matched control study.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a new human disease with few effective treatments1. Convalescent plasma, donated by persons who have recovered from COVID-19, is the acellular component of blood that contains antibodies, including those that specifically recognize SARS-CoV-2. These antibodies, when transfused into patients infected with SARS-CoV-2, are thought to exert an antiviral effect, suppressing virus replication before patients have mounted their own humoral immune responses2,3. Virus-specific antibodies from recovered persons are often the first available therapy for an emerging infectious disease, a stopgap treatment while new antivirals and vaccines are being developed1,2. This retrospective, propensity score-matched case-control study assessed the effectiveness of convalescent plasma therapy in 39 patients with severe or life-threatening COVID-19 at The Mount Sinai Hospital in New York City. Oxygen requirements on day 14 after transfusion worsened in 17.9% of plasma recipients versus 28.2% of propensity score-matched controls who were hospitalized with COVID-19 (adjusted odds ratio (OR), 0.86; 95% confidence interval (CI), 0.75-0.98; chi-square test P value = 0.025). Survival also improved in plasma recipients (adjusted hazard ratio (HR), 0.34; 95% CI, 0.13-0.89; chi-square test P = 0.027). Convalescent plasma is potentially effective against COVID-19, but adequately powered, randomized controlled trials are needed.

Treatment with convalescent plasma in solid organ transplant recipients with COVID-19: Experience at large transplant center in New York City.

Solid organ transplant (SOT) recipients may be at higher risk for poor outcomes with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Convalescent plasma is an investigational therapy that may benefit immunosuppressed patients by providing passive immunity. Convalescent plasma was administered to hospitalized patients with coronavirus disease-2019 (COVID-19) at an academic transplant center in New York City. Eligible patients were hospitalized and required to have positive nasopharyngeal polymerase chain reaction (PCR) diagnosis of SARS-CoV-2 infection, be at least 18 years old, and have either dyspnea, blood oxygen saturation ≤ 93% on ambient air, respiratory frequency ≥ 30 breaths/min, partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 300, or lung infiltrates > 50%. Thirteen SOT recipients received convalescent plasma from April 9, 2020, to May 17, 2020. The median time from symptom onset to plasma infusion was 8 days. Eight of 13 patients (62%) had de-escalating oxygenation support by day 7 post-convalescent plasma. Nine (69%) patients were discharged, 1 (7%) patients remain hospitalized, and 3 (23%) patients died. This series supports the need for additional studies on convalescent plasma use in SOT recipients with COVID-19 to better determine efficacy and identify patients who are likely to benefit.

A serological assay to detect SARS-CoV-2 seroconversion in humans.

Here, we describe a serological enzyme-linked immunosorbent assay for the screening and identification of human SARS-CoV-2 seroconverters. This assay does not require the handling of infectious virus, can be adjusted to detect different antibody types in serum and plasma and is amenable to scaling. Serological assays are of critical importance to help define previous exposure to SARS-CoV-2 in populations, identify highly reactive human donors for convalescent plasma therapy and investigate correlates of protection.