Interferon 1beta-1a ring prophylaxis to reduce household transmission of SARS-CoV-2

Introduction/Aim: Accumulating evidence indicates that an early, robust type 1 interferon (IFN) response to SARS-CoV-2 is critical for COVID-19 outcomes. Our objective was to examine the prophylactic potential of IFN treatment to limit viral transmission Methods: A cluster-randomised clinical trial was undertaken to determine effects of IFNbeta-1a treatment on SARS-CoV-2 household transmission (clinicaltrials.gov: NCT04552379). Index cases were identified from confirmed SARS-CoV-2 cases in Santiago, Chile, with 341 index cases and 831 household contacts enrolled. Households received 125 mug subcutaneous pegylated-IFNbeta-1a on days 1, 6, & 11 (172 households, 607 participants), or standard care (169 households, 565 participants). Primary outcomes included: (1) duration of viral shedding in infected cases (IC-INF), (2) transmission to treatment-eligible household contacts (EHC-ITT) at day 11. Result(s): Of 1172 individuals randomised, 53 individuals withdrew from the study (IFNbeta-1a = 35, SOC = 18). Eighty-two households (IFNbeta-1a = 36, SOC = 46) where the index case was SARS-CoV-2 negative on days 1 & 6, or with no SARS-CoV-2 negative contacts at recruitment, were excluded from exploratory analyses. Treatment with IFNbeta-1a: had no effect on duration of viral shedding in the IC-INF population (primary outcome 1), had no effect on transmission of SARS-CoV-2 at day 11 in the EHC-ITT population (primary outcome 2) but an effect was observed in a sensitivity analysis at day 6 (EHC-ITT: OR = 0.493, 95% CI = 0.256-0.949), reduced duration of hospitalisation in the IC-INF population and incidence of hospitalisation in per-protocol index cases (secondary outcome 3). In exploratory frequentist analysis, a significant effect of IFNbeta-1a treatment on SARS-CoV-2 transmission by day 11 (OR = 0.55, 95% CI = 0.36-0.99), and a Bayesian analysis identified a significant reduction in the odds of transmission (OR = -0.85, 95% credible interval = -1.59--0.16). Conclusion(s): Ring prophylaxis with IFNbeta-1a had no effect on duration of viral shedding but reduces the probability of SARS-CoV-2 transmission to uninfected, post-exposure contacts within a household.

Factors Predicting Bacterial Coinfection in Hospitalized COVID-19 Patients

Background. Despite multiple studies indicating a low prevalence of bacterial coinfection in coronavirus disease 2019 (COVID-19) patients, the majority of hospitalized COVID-19 patients receive one or more antibiotics. Patients with coinfection usually have multiple risk factors and poor clinical outcomes. Methods. A retrospective case control study was conducted comparing clinical characteristics and antimicrobial use in hospitalized adult COVID-19 patients with bacterial co-infections vs. randomly selected patients without co-infections (matched on month of admission). The study was conducted at three hospitals within the Montefiore Medical Center, Bronx, NY between March 1, 2020 and October 31, 2020. A multivariable logistic regression model was developed to assess the relationship of each predictor variable with coinfection status. Secondary outcomes included hospital mortality, antibiotic days of therapy (DOT), and C. difficile infection. Results. A total of 150 patients with coinfection and 150 patients without coinfection were included in the analysis. Table 1 summarized baseline characteristics and risk factors. The multivariable logistic regression model indicated that presence of a central line (OR=5.4, 95% CI: 2.7-11.1), prior antibiotic exposure within 30 days (OR=5.3, 95% CI: 2.8-10.0), prior ICU admission (OR=3.6, 95% CI: 1.7-7.6), steroid use (OR=2.7, 95% CI: 1.4-4.9), and any comorbid condition (OR=2.7, 95% CI: 1.4-5.2) were significantly associated with the development of coinfection (table 2). Mortality was higher in patients with coinfection (56% vs. 11%, p < 0.0001) (table 3). Average antibiotic DOT was 10.5 in coinfected patients compared to 4 in noncoinfected patients, (p < 0.0001). Forty-one percent of coinfected patients had a multidrug resistant organism isolated. C. difficile rate was higher in coinfected patients (4% vs. 0%, p=0.03). Conclusion. As the healthcare community contends with a 3rd year of COVID-19 pandemic, understanding risk factors most predictive of bacterial coinfection can guide empiric antimicrobial therapy and targeted stewardship interventions. Ideally, co-infection risk scores are developed which may be useful for future inpatient surges.

Accuracy of the hyphen Zymutest IgG ELISA assay for anti-platelet factor 4 antibody detection after ChAdOx1 nCov-19 vaccination in diagnosing vaccine-induced immune thrombotic thrombocytopenia (VITT)

Background: Vaccine-induced Immune Thrombotic Thrombocytopenia (VITT) is a rare, anti-platelet factor 4 (PF4) antibody-mediated prothrombotic syndrome associated with the AstraZeneca (AZ) Covid-19 vaccination. Diagnostic criteria include thrombosis, thrombocytopenia, appropriate timing post AZ vaccine, and demonstration of an anti-PF4 antibody by enzyme-linked (Table Presented) immunosorbent assay (ELISA). ELISA methods have varying sensitivity and specificity for detecting anti-PF4 antibodies, therefore, functional assays (modified serotonin release and flow cytometry) assist in diagnosis. In Australia, the primary assay for detection of anti-PF4 antibodies is the Asserachrom HPIA IgG ELISA. Aim(s): To assess the accuracy of an alternate ELISA method for suspected VITT compared to the gold standard (clinicopathological diagnosis). Method(s): 96 stored frozen samples from patients with suspected VITT, previously analysed by Asserachrom HPIA IgG ELISA (Stago, Melbourne, Australia), were tested using the Hyphen Biomed Zymutest HIA IgG ELISA (Haematex Research, Sydney, Australia). These patients had confirmed thrombosis within 42 days post first dose of AZ vaccine. Cases were classified as 'serologically confirmed VITT' if clinicopathological criteria were met, and initial ELISA testing and/or functional assays were positive. Results were interpreted as positive or negative for anti-PF4 antibodies using the manufacturer's cut-offs derived for the diagnosis of Heparin-Induced Thrombocytopenia. Result(s): 96 patient samples were tested, including 35 classified as VITT (Table 1). The Hyphen assay had a moderate sensitivity (82%), including 2 probable false negatives on initial testing which were strongly positive by Hyphen assay. The specificity was 93%, including 5 probable false positives on initial ELISA which were negative by Hyphen assay (Table 2). Conclusion(s): The Hyphen ELISA is suitably accurate for the diagnosis of VITT. These data highlight the limitations of using a single ELISA testing method for anti-PF4 antibody detection. In cases with high clinical suspicion, a second ELISA method or functional assay should be considered.

Monitoring the persistence of vaccine-induced immune thrombotic thrombocytopenia (VITT) antibodies and their pathogenicity

Background: The putative mechanism for vaccine-induced immune thrombotic thrombocytopenia (VITT) following ChAdOx1 nCoV-19 vaccination involves pathological anti-PF4 platelet-activating antibodies driving thrombosis and thrombocytopenia. Reports suggest platelet-activating antibodies decline within 12 weeks despite persistence of anti-PF4 by ELISA (Schonborn et al). Optimal duration of anticoagulation remains unclear. The Australian-New Zealand guidance recommends repeat testing of patients with serologically-confirmed VITT at 3, 6 and 12 months. Aim(s): To determine rate of persistence of anti-PF4 ELISA compared with functional platelet-activating tests in VITT. Method(s): We conducted a prospective study of clinicopathological adjudicated VITT patients (thrombocytopenic with D-dimer levels >5x ULN and thrombosis within 4-43 days of ChAdOx1 nCoV-19 vaccination) with a positive functional assay at diagnosis who had follow-up VITT testing. Anti-PF4 antibodies were measured by IgG-specific ELISA (Asserachrom, Stago Diagnostics). Platelet-activating antibodies were assayed using whole blood procoagulant platelet flow cytometry assay (Lee et al) or PF4-serotonin release assay. Result(s): 14 confirmed VITT patients (7 females, 7 males;median age 62.5 years [range, 40-80]) underwent follow-up testing, median follow- up of 12 weeks (range, 3-24). Median time to return a negative functional test was 12 weeks (range, 4-16) with platelet-activating antibodies persistent at 24 weeks in two patients. Median time to negative ELISA was not reached. During follow-up, 9 of 14 patients became negative by functional assay while anti-PF4 antibodies persisted in 8 of 12 (Figure 1). 93% of patients received a documented second vaccination (Comirnaty, median interval 16 weeks [range, 11-28]) and 71% have received an mRNA booster with no reported adverse events. Conclusion(s): Platelet-activating antibodies were persistent in 54% of tested patients at 12 weeks and anti-PF4 ELISA remained positive in the majority. Anti-PF4 antibodies persist longer than functional platelet-activating antibodies in VITT. Whether the decline in platelet-activating antibodies allows withdrawal of anticoagulation in these patients is unclear but could be a useful guide.

Vaccine induced thrombotic thrombocytopenia post dose 2 ChAdOx1 nCoV19 vaccination: Less severe but not void of catastrophic outcomes

Background: Clinical and pathological features of vaccine induced immune thrombotic thrombocytopenia (VITT) following first dose ChAdOx1 nCoV19 vaccination (AZD1222) are well described. VITT post 2nd dose AZD1222 is not widely recognised however its plausible undiagnosed platelet activating antibodies formed after dose 1 may be boosted upon subsequent exposure. (Greinacher et al). Aim(s): We describe the clinicopathological features of suspected VITT post 2nd dose AZD1222 in Australia. Method(s): We conducted a prospective cohort study capturing sequential requests for confirmatory testing for suspected VITT after 2nd dose AZD1222. Testing was based upon key clinicopathological features: Thrombosis within timeframe (4-42 days), thrombocytopenia, D-Dimer >5xULN. High probability VITT (all criteria) underwent immunoassay Asserachrom HPIA IgG (Diagnostica Stago) and functional assay (serotonin release assay or procoagulant flow cytometry). Confirmed VITT cases were compared with those presenting after first dose AZD1222. Descriptive and comparative statistics were performed using SAS studio version 9.4. Result(s): 35 high probability VITT cases presented at a median of 14 days (IQR 9,18) post 2nd dose with platelet count 116 x 109/L (IQR 92, 139) and 14.5 fold increase in D-dimer (IQR 9.4,28.8) were tested. Median dose interval was 84 days (range 25-100), age 70 years (IQR 62, 78) with a male predominance of 66%. Platelet count and D-dimer fold change were less severe compared to cases post 1st dose (Table 1). PF4 antibodies by ELISA were detected in 4 (11%) and antibody mediated platelet activation demonstrable in 19 (54%). These cases were classified as confirmed VITT. Three catastrophic cases including 2 fatalities occurred (Graph 2). Concomitant factors were present in all and influenced outcome severity. Conclusion(s): We describe the largest cohort of suspected VITT post 2nd dose AZD1222. Confirmed cases are similar to those post D1 but platelet count and D-Dimer changes were milder. Similarly, catastrophic cases occurred however concomitant factors were present in all including shorter dosing intervals. (Table Presented).

ITP before and after COVID-19 vaccinations: A national cohort study

Background: Immune thrombocytopenia (ITP) has been reported following COVID-19 vaccination. From a population of over 20 million eligible vaccine recipients in Australia, over 32 million doses have been administered: 19,600,000 Pfizer BNT162b2 (BNT), 12,600,000 AstraZeneca ChAdOx1 nCoV-19 (ChAd), and 397,000 Moderna mRNA-1273. Aim(s): Describe a comprehensive series of ITP after vaccination with clinical outcomes. Method(s): After obtaining IRB approval (2021/ETH00723), we collected data on all ITP cases diagnosed by haematologists in Australia within six weeks of any COVID-19 vaccination. We analysed their outcomes using international consensus definitions of responses and WHO bleeding. Result(s): Demographics (n = 50), treatments, and platelet outcomes (Figures A and B). Bleeding was mostly minor: 35/50 (70%) WHO score <2. Compared to relapses of prior ITP, new presentations of ITP were significantly associated with ChAd over BNT (OR 7.1: 95% CI 1.7 to 25.7, p = 0.0124*). Most patients responded quickly and deeply: Median TTR 4 days (IQR 2-7), median TTCR 7 days (IQR 4-19), overall RR 45/47 (96%), and CR 40/45 (89%). Gender, age, antecedent influenza vaccination and severity of thrombocytopenia had no significant impact on: Bleeding at presentation, response rates, relapse rates, time to response, or the need for ongoing treatments at day 90. No patients presented with thrombosis. PF4 ELISA was positive in one of 18 cases after ChAd (functional testing was negative). Conclusion(s): We diagnosed ITP more frequently after ChAd than BNT vaccination, occurring de novo after 1st doses. Ascertainment bias cannot be excluded due to greater scrutiny for platelet related complications, but almost all patients in this cohort needed treatment. Standard first-line treatments for ITP are highly effective for both de novo and prior ITP (96%), but second-line therapies are often required (34%). Our data reaffirms the safety of vaccinating patients with pre-existing ITP, as bleeding is mild (92% WHO < 2) and platelets respond quickly (TTCR 5 days).

Thrombocytopenia and thrombosis associated with AstraZeneca ChAdOx1 nCoV-19 Vaccination-Results of Australian centralized clinical triage system and functional assay testing system

Background: As a severe, though rare complication of COVID-19 vaccination, vaccine induced immune thrombotic thrombocytopenia (VITT) emerged in 2021 as a public health issue affecting vaccine confidence. Australia pre-emptively instituted a nationally coordinated system for diagnosis and management incorporating state based immunoassays (ELISA) for PF4 antibodies and national centralised functional testing using three functional assays. Aim(s): To evaluate the triage strategy based upon clinical presentation, thrombocytopenia and D-Dimer used to direct VITT testing. Method(s): Consecutive cases presenting between April 1 and June 11, 2021 referred for VITT testing in Australia were assessed regarding clinical classification, immune-assay and functional assay results, thromboses and mortality according to triage category (Table 1). Functional testing proceeded for all triaged as Probable VITT , ELISA positive and unusual site thromboses positive patients if triaged Less likely , and only for quality assurance purposes if Much less likely VITT . Anti-PF4 antibodies were measured by IgG-specific ELISA (Asserachrom, Stago Diagnostics). Platelet-activating antibodies were assayed using whole blood procoagulant platelet flow cytometry assay (Lee et al), PF4-serotonin release assay or multiplate multiple electrode aggregation. Result(s): 92% of 52 patients with a final diagnosis of VITT supported by a positive antibody assay (immunological or functional) were triaged prior to VITT specific testing into the high probability category. 100% ELISA positive individuals within the high and intermediate clinical probability groups were supported by detection of a platelet activating antibody using a functional assay and 0% in the low probability group. 16% of clinical VITT patients without confirmation of anti-PF4 antibodies by ELISA had VITT diagnosis supported by functional assay in a final clinico-pathological adjudication. Conclusion(s): Triage of testing according to clinical probability of VITT based on clinical criteria and standard laboratory tests was helpful in directing testing in resource constrained period. Demonstration of platelet activating antibodies in functional assays significantly contributes to definition of the VITT syndrome. (Table Presented).

Evaluation of Three COVID-19 Monoclonal Antibody Regimens in the Context of Rising B.1.526 Prevalence in New York City

Background. Monoclonal antibodies were given emergency use authorization (EUA) by the Food and Drug Administration for the treatment of high-risk, outpatient COVID-19 infection. In New York City (NYC), the emergence and rapid growth of the B.1.526 variant of concern (VOC) possessing the E484K mutation was first noted in February 2021. In-vitro studies subsequently confirmed attenuated monoclonal antibody neutralization against VOCs. At our institution, bamlanivimab (BAM) alone or with etesevimab (B/E) and casirivimab/imdevimab (C/I) were utilized at different phases of the pandemic. The objective of this study was to assess their comparative efficacies in a highly variant prevalent setting. Methods. This retrospective analysis was conducted at an urban hospital in the Bronx, NY and evaluated adult monoclonal antibody recipients from any of our infusion sites. Patients initially received BAM but given the high prevalence of variants, treatment was transitioned to first B/E and then C/I exclusively. We compared BAM versus combination therapy as well as B/E versus C/I individually. The primary outcome was all-cause hospital admission within 30 days post infusion. Results. From February 1 to March 7, 2021, 358 patients received BAM and from March 17 to May 9, 2021, 86 and 179 patients received B/E and C/I, respectively. Compared to any combination infusion, patients who received BAM were significantly older, more likely to possess ≥ 2 qualifying EUA criteria, and less likely to be vaccinated for COVID-19 prior to infusion (Table 1). Following B/E and C/I, 4.5% of patients were admitted versus 10.1% for BAM, p=0.011. There were no significant differences in admission between B/E and C/I recipients, p=0.485. After excluding fully vaccinated patients (n=14) and adjusting for age and ≥ 2 EUA criteria, combination therapy remained associated with decreased odds of hospitalization compared to BAM (odds ratio, 0.48;95% confidence interval, 0.24-0.94). Conclusion. Combination therapy may be associated with fewer hospital admissions following infusion, although there were no statistically significant differences between the individual combination infusions. We suggest similar studies be conducted by other sites to understand the clinical impact of local SARS-CoV-2 variants on antibody efficacy.

Phase Ib study of BI 836880 (VEGF/Ang2 inhibitor) plus ezabenlimab (BI 754091;anti-PD-1 antibody) in patients (pts) with advanced hepatocellular carcinoma (HCC)

Background: Combination of anti-VEGF compounds and immune checkpoint inhibitors is an approved therapy across multiple solid tumors, including advanced HCC. This phase Ib study (NCT03468426) is assessing BI 836880 (bispecific VEGF/Ang2 nanobody) + ezabenlimab (anti-PD-1 antibody) in pts with advanced solid tumors. The recommended phase 2 dose (RP2D) of BI 836880 720 mg + ezabenlimab 240 mg given IV every 3 weeks was determined in Part 1. In Part 2, RP2D was assessed in 7 expansion cohorts. We report data from cohorts in HCC after prior sorafenib/lenvatinib (cohort F) and untreated unresectable HCC (cohort G). Methods: Pts with locally advanced or metastatic HCC, Child-Pugh class A, not eligible for surgical or locoregional therapies were enrolled. Cohort F enrolled pts who had progressed on or after first-line treatment with sorafenib or lenvatinib or who had discontinued due to poor tolerability after ≥2 weeks of treatment. Cohort G enrolled pts who had received no prior systemic therapy for HCC. Treatment continued until disease progression, undue toxicity or consent withdrawal. Primary endpoint is objective response rate (ORR) by RECIST 1.1. Results: As of Aug 2021, 30/31 pts have been treated in cohorts F/G: 87/77% male;median age 65/64 yrs. Follow-up is ongoing in both cohorts. 9/19 pts in cohorts F/G remain on treatment;median (range) duration of treatment is 175 (42-532)/ 169 (42-336) days in cohorts F/G. All pts were evaluable for response in cohort F: confirmed ORR to date is 40% (1 complete response;11 partial responses [PRs]). Of 28 evaluable pts in cohort G, confirmed ORR to date is 21% (6 PRs). 12 (40%) pts in cohort F and 18 (64%) in cohort G have stable disease. In cohort F, AEs were reported in 28 (93%) pts, most frequently hypertension and proteinuria (each 30%). In cohort G, AEs occurred in 26 (84%) pts, most frequently ascites (26%) and thrombocytopenia (19%). 24 (80%) pts in cohort F and 15 (48%) in cohort G had treatmentrelated AEs (TRAEs). Most frequent TRAEs were proteinuria (27%), infusion-related reactions (IRRs) and hypertension (each 20%) in cohort F, and hypertension (13%), IRRs, hypothyroidism and diarrhea (each 10%) in cohort G. There were 3 pts with G5 AEs in cohort F (COVID-19 pneumonia [n = 1];low Glasgow coma score and dyspnea [n = 1];hepatic cirrhosis [n = 1]) and 1 G5 AE in cohort G (hepatic failure);none were considered related to treatment. AEs leading to discontinuation occurred in 2 pts in cohort F (G3 hepatic encephalopathy and G2 duodenal ulcer) and 3 in cohort G (G5 hepatic failure [n = 1];G2 acute kidney injury and G1 decreased appetite [n = 1];G2 diarrhea [n = 1]). Conclusions: BI 836880 + ezabenlimab had a manageable safety profile and showed promising activity in pts with untreated and second-line post-sorafenib/lenvatinib advanced HCC. Data continue to mature, particularly in cohort G. Cohort F has been expanded by a further 30 pts.

Flow Cytometric Detection of Procoagulant Properties of Plasma from Patients with Clinically Confirmed Vaccine-Induced Immune Thrombotic Thrombocytopenia

Background: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe prothrombotic complication of adenoviral vaccines including ChAdOx1 nCoV-19 (AstraZeneca) vaccine. The putative mechanism involves formation of pathological anti-PF4 antibodies that activate platelets via the FcγRIIa receptor to drive thrombosis and the associated thrombocytopenia. Functional assays are important in the VITT diagnostic pathway as not all detectable PF4 antibodies are pathogenic. Detection of procoagulant platelets (platelets supporting thrombin generation) in presence of PF4 has been proposed as a diagnostic assay for VITT (Althaus et al). Procoagulant platelets are not typically generated in response to low level agonist stimulation;however, combination of ligand binding of G-protein coupled receptors (GPCR) (eg. PAR1) and ITAM linked receptors (eg. GPVI, CLEC2 and FcγRIIa) synergistically induce procoagulant platelet formation. Here, we describe an alternative flow cytometric assay to diagnose VITT. We hypothesized that priming of platelets with a PAR1 agonist at a level sufficient to release PF4, but insufficient to generate a significant procoagulant response in donor platelets, would provide a platform in which procoagulant response would be dependent on presence of FcγRIIa dependent procoagulant antibodies in patient plasma, without requirement for additional PF4. Methods: Our previously established flow cytometry-based procoagulant platelet assay (using cell death marker GSAO and P-selectin) was modified to incorporate exogenous patient plasma and performed on whole blood from healthy donors screened for FcγRIIa responsiveness (aggregation response to anti-CD9 antibody, ALB6), primed with 5 μM SFLLRN. The assay was performed on Australian patients referred for confirmatory VITT testing with probable VITT (confirmed thrombosis within 4-42 days of ChAdOx1 nCov-19 vaccination, D-Dimer > 5x ULN, platelets < 150 x 10 9/L or falling platelet count) after screening on PF4/heparin ELISA (Asserachrom HPIA IgG Assay, Stago Diagnostics). Procoagulant response was also measured in presence of 0.5 U/mL and 100 U/mL heparin, monoclonal FcγRIIa blocking antibody, IV.3, and intravenous immunoglobulin, IVIg. Some plasmas were incubated with ChAdOx1 nCoV-19 or SARS-CoV-2 spike protein. Flow cytometry positive patients were also tested by serotonin release assay (SRA) and multiplate aggregometry. Clinical correlation was obtained. Results: Citrated plasma from 49 unique patients with suspected VITT are reported. Plasma from ELISA+ve patients with clinical picture consistent with VITT (n=31), significantly increased the procoagulant platelet proportions in healthy donors in presence of 5 μM SFLLRN (p<0.0001, Figure 1A). This increase was not seen with plasma from healthy donors (n=14);or individuals exposed to ChAdOx1 nCov-19 vaccine without VITT: thrombocytopenic thrombosis patients who were ELISA-ve and SRA-ve (n=14);or low-level ELISA+ve patients without thrombocytopenia who were negative by either multiplate or SRA (n=4). The procoagulant platelet response induced by VITT positive plasma was reduced with low dose heparin (0.5 U/mL, p<0.01) except for 3 patients who showed a heparin-enhancing effect (Figure 1B). High dose heparin (100 U/mL, p<0.0001), IV.3 (10 µg/mL, p<0.0001) or IVIg (10 mg/mL, p<0.0001) abolished the procoagulant response (Figures 1C-D). The in vitro effect of IVIg was predictive of the in vivo response to IVIg therapy (Figure 1E). Addition of SARS-CoV-2 spike protein had no effect on the procoagulant platelet response. ChAdOx1 nCov-19 had an inconsistent effect on procoagulant platelet formation in presence of VITT plasma. Use of donors without a robust aggregation response to ALB6 resulted in false negative results. Conclusion: Induction of FcγRIIa dependent procoagulant response by patient plasma, suppressible by high dose heparin and IVIg, is highly indicative of VITT in the correct clinical circumstance. This assay modification of priming donor platelets from known FcγRIIa responsive donors ith a GPCR agonist to potentiate the ITAM signaling from platelet activating immune complexes, results in a sensitive and specific assay. This may represent a functional platform that can be adopted into diagnostic laboratories to identify patients with platelet-activating antibodies and potentially predict treatment responses. [Formula presented] Disclosures: No relevant conflicts of interest to declare.

Determining the Rate of Anti-PF4 Antibody Positive Results in Patients Presenting with Venous Thrombosis but a Normal Platelet Count Following ChAdOx1 Ncov-19 Astrazeneca Vaccination: An Australian Combined State Testing Centre Experience

Introduction The CHaDOx1 nCov-19 AstraZeneca (AZ) vaccination has been associated with an antibody-mediated prothrombotic syndrome, termed “Thrombosis with Thrombocytopenia Syndrome” (TTS)[1-3]. The current diagnostic criteria for TTS are thrombosis (venous or arterial) within 4-42 days of AZ vaccine, thrombocytopenia and presence of an antibody to platelet factor 4 (PF4)[4, 5]. TTS commonly presents with cerebral venous sinus thrombosis (CVST) or splanchnic vessel thrombosis (SVT), but outside of TTS, CVST and SVT are uncommon, with an overall incidence of less than 0.5 per 100,000 [5-7]. Deep vein thrombosis (DVT) and pulmonary embolism (PE) are also associated with TTS, however the background incidence of venous thromboembolism (VTE) is much higher, with 1-2 events per 1000 patients per year[7, 8]. Therefore, many patients will present with new VTE and a recent exposure to the AZ vaccine, requiring consideration of investigation for TTS. Recent data suggests that PF4 antibodies can be seen in up to 8% of patients without thrombosis but following AZ vaccination[9]. We hypothesised in patients with recent AZ vaccination, new VTE but with a normal platelet count, that the incidence of a PF4 antibody is similar to this background rate of PF4 positivity. If confirmed, then presence of a normal platelet count despite new VTE and recent vaccination may exclude TTS without the need for PF4 antibody testing. We present our preliminary data on the rates of PF4 antibody positivity amongst patients with VTE, recent AZ vaccination and a normal platelet count at presentation. Aim and Methods To assess the incidence of PF4 ELISA positive results in patients with confirmed VTE, recent vaccination (within 4-42 days) with the first dose of AZ vaccine, and platelet count greater than 150x10 9/L. A retrospective audit of cases referred with suspected TTS to Monash Pathology, Melbourne, Victoria, and New South Wales Health Pathology at Royal Prince Alfred Hospital and St George Hospital sites Sydney, New South Wales, Australia, for testing for anti PF4 antibodies from 1 st April to 31 st July 2021. Patient sera were tested for the Anti-PF4 antibody using the STAGO Asserachrom HPIA IgG ELISA (Asnières sur Seine, France). For patients with a positive PF4 antibody test additional testing was sought for either the presence of platelet activating antibodies with a flow cytometry-based assay or the presence of spontaneous serotonin release without heparin in the serotonin release assay. Results From April 1 st to July 31 st 350 tests were run on 332 patients. 91 patients met our criteria, of whom 51 were female and 40 male, with a median age of 73 years. Median platelet count at presentation was 226x10 9/L, and median D dimer values were 10 times the upper limit of normal. 86 patients had either DVT, PE or both, including 2 with upper limb DVT, and 5 patients had PE with concurrent arterial events (1 axillary artery thrombosis, 3 arterial strokes, 1 coronary artery thrombosis). Further details are presented in table 1. 82 patient samples tested negative for anti-PF4 antibodies by ELISA, 5 were positive, and were 4 weak positive/equivocal (see table 2 for further details). Of the positive results, 3 had functional testing available, of which 2 were negative, and 1 showed discordant results, with a positive SRA but negative flow cytometry. None of the weak positive/equivocal cases had functional testing results available. Of the negative ELISA results, 5 patients had functional testing results available, of which 4 were negative. One of these cases had positive testing by flow cytometry, but negative by SRA (case included in table 2). Conclusion In our Australian cohort of patients with their first dose of AZ vaccine and new VTE within 4-42days, but a normal platelet count (therefore not fulfilling the clinical criteria of TTS), the incidence of a positive PF4 antibody test was 9/91 (9.9%, 95% CI 3.7-15.9%) and only one had evidence of platelet activating antibodies. This observed rate is similar to that observed in healthy patients wi hout thrombosis who received AZ vaccination as described by Thiele et. al., 2021. Further confirmation in a larger cohort of VTE patients is required, but if confirmed, then PF4 ELISA testing in patients with VTE and normal platelet count post AZ vaccine may not be required, and should give clinicians confidence to institute routine management. [Formula presented] Disclosures: No relevant conflicts of interest to declare.

Xenophobia in the Time of a Pandemic: Social Media Use, Stereotypes, and Prejudice against Immigrants during the COVID-19 Crisis

This study examines the relationship between social media use, disease risk perception, social and political trust, and out-group stereotyping and prejudice during a social upheaval. Analyses of primary data collected during the COVID-19 outbreak in Singapore found that disease risk perception is positively related to stereotyping and prejudice against Chinese immigrants. Individuals who used social media for news were more likely to stereotype and express prejudice. However, those who engaged in frequent heterogenous discussions, and had more extensive social networks, were less likely to stereotype and express prejudice. Higher social and political trust was also associated with lower stereotyping and prejudice. Finally, moderation effects of network characteristics on the relationship between risk perception, social trust, and prejudice were observed.

Regulating a Quick Fix for Debt Problems

The financial fallout from the COVID-19 pandemic has left many individuals with increasing levels of debt. Studies reveal a greater vulnerability to promises of a quick fix for debt problems when anxiety levels run high over prospects of financial ruin. At the same time, businesses that offer to help resolve problems of unmanageable debt for a fee have been found to pose a significant risk to consumers. This article considers the regulation of debt management firms in the countries that have made significant strides in this burgeoning field, drawing lessons from their experiences. It highlights the key features of regulatory frameworks that contribute to better outcomes for consumers, while revealing the gaps that have allowed predatory businesses to avoid regulation. Specific strategies developed to mitigate risks of consumers being channelled towards unsuitable and unaffordable arrangements provide useful examples to other countries that are seeking to safeguard financially stressed consumers from harm.

An Optimization Framework to Study the Balance Between Expected Fatalities Due to COVID-19 and the Reopening of U.S. Communities

During the COVID-19 pandemic, communities faced two conflicting objectives: 1) minimizing infections among vulnerable populations with higher risk for severe illness and 2) enabling reopening to revive American livelihoods. The U.S. pandemic strategy myopically considered one objective at a time, with lockdowns that addressed the former, but was detrimental to the latter, and phased reopening that pursued the latter, but lost control over the former. How could we prioritize interventions to simultaneously minimize cases of severe illness and fatalities while reopening? A team of researchers anchored by the Center on Stochastic Modeling, Optimization, & Statistics (COSMOS), The University of Texas at Arlington, has formulated a computationally efficient optimization framework, referred to as COSMOS COVID-19 Linear Programming (CC19LP), to study the delicate balance between the expected fatality rate due to cases of severe illness and the level of normalcy in the community. The key to the CC19LP framework is a focus on ``key contacts'' that separate individuals at higher risk from the rest of the population. CC19LP minimizes expected fatalities by optimizing the use of available interventions, namely, COVID-19 testing, personal protective equipment (PPE), COVID-19 vaccines, and social precautions, such as distancing, handwashing, and face coverings. A C3.ai award-winning online CC19LP tool is accessible from the COSMOS COVID-19 project site (https://cosmos.uta.edu/projects/covid-19/) and has been tested for all 3142 U.S. county areas. Results are demonstrated for several metropolitan counties with a deeper investigation for Miami-Dade County in Florida. IEEE

Phase Ib study evaluating BI 836880 (VEGF/Ang2 nanobody) in combination with ezabenlimab (BI 754091;anti-PD-1 antibody) in patients with solid tumours

Background: Combining anti-VEGF/Ang2 and anti-PD-1 therapy promotes an immunopermissive state, supportive of T-cell-mediated tumour cell destruction. This phase Ib study is assessing BI 836880 plus ezabenlimab in patients (pts) with advanced solid tumours. In Part 1 (dose escalation in pts with advanced NSCLC), the recommended phase 2 dose (RP2D) was determined as BI 836880 720 mg + ezabenlimab 240 mg IV q3w. Here, we report updated results, including data from Part 2 (expansion cohorts). Methods: Part 2 has 7 cohorts: metastatic (m) NSCLC after checkpoint inhibitor (CPI) monotherapy (Cohort A);mNSCLC after chemotherapy (CT) + CPI (Cohort B);mSCLC after CT ± CPI (Cohort C);recurrent GBM (1st and 2nd recurrence;Cohort D);immunotherapy-resistant m-melanoma (Cohort E);HCC after prior sorafenib or lenvatinib (Cohort F);and previously untreated unresectable HCC (Cohort G). Primary endpoint is objective response rate (complete response [CR] + partial response [PR]). Results: As of March 2021, 215 pts have been treated (Part 1: 14, Part 2: 201 [Cohort A, 35;B, 32;C, 19;D, 31;E, 32;F, 29;G, 23];70% male, median age 62 yrs). Any and ≥G3 AEs (any-cause) were reported in 183 (85%) and 72 (33%) pts. 118 (55%) pts had drug-related AEs, most commonly asthenia (13%) and hypertension (12%). 7 pts had G4 AEs (non-related hyperkalaemia + cardiac arrest, laryngospasm, gastrointestinal perforation;drug-related anaphylactic reaction, cholestatic hepatitis, acute pancreatitis, increased transaminases);9 pts had G5 AEs (non-related COVID-19 pneumonia, epilepsy, intracranial haemorrhage, cardio-respiratory arrest, haemoptysis, hepatic failure, general physical health deterioration, Glasgow coma scale abnormal + shortness of breath;drug-related tracheal haemorrhage). 35 (16%) pts had immune-related AEs and 15 (7%) had AEs leading to discontinuation. 179 pts were evaluable for response: 1 had confirmed CR (Cohort F), 22 had PR (Part 1: 2;Part 2: 20 [Cohort A, 4;C, 5;D, 4;E, 3;F, 3;G, 1]) and 110 had stable disease. 106 pts remain on treatment. Conclusions: BI 836880 plus ezabenlimab had a manageable safety profile, with preliminary activity in a range of tumour types. Clinical trial identification: NCT03468426. Editorial acknowledgement: Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Hannah Simmons MSc, of Ashfield MedComms, an Ashfield Health company, and funded by Boehringer Ingelheim. Legal entity responsible for the study: Boehringer Ingelheim. Funding: Boehringer Ingelheim. Disclosure: N. Girard: Financial Interests, Personal, Advisory Role: Roche, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Novartis, Pfizer, BMS, MSD, Takeda, GSK, AbbVie, Pharmamar, Janssen, Sanofi;Financial Interests, Personal, Funding, Travel/accommodation/expenses: Roche, AstraZeneca, BMS MSD Oncology;Financial Interests, Institutional, Research Grant: Roche, AstraZeneca, Boehringer Ingelheim. M. Wermke: Financial Interests, Personal, Advisory Role: MSD, Novartis, Kite, Heidelberg Pharma, Roche, Boehringer Ingelheim;Financial Interests, Personal, Other, Honoraria: BMS, Merck, Roche, Novartis, Kite, Boehringer Ingelheim, AstraZeneca;Financial Interests, Personal, Funding, Travel/Accommodation/Expenses: Glenmark, BMS, AstraZeneca. E. Ledin: Financial Interests, Personal and Institutional, Research Grant: Boehringer Ingelheim. D. Kim: Financial Interests, Personal, Advisory Role: Health Insurance Review & Assessment Service, Korea;Financial Interests, Personal, Invited Speaker: Korean Association for Lung Cancer, Korean Cancer Association, Korean Society of Medical Oncology, Taiwan Lung Cancer Society;Financial Interests, Institutional, Principal Investigator, Clinical Trial Funding: Alpha Biopharma, Amgen, AstraZeneca/Medimmune, Boehringer-Ingelheim, Bridge BioTherapeutics, Chong Keun Dang, Daiich-Sankyo, GSK, Hanmi, Janssen, Merus, MIrati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeuti;Non-Financial Interests, Person l, Advisory Role: Amgen, AstraZeneca, BMS / ONO Pharmaceuticals, Daiich-Sankyo, GSK, Janssen, Pfizer, SK Biopharm, Takeda, Yuhan;Non-Financial Interests, Personal, Member of the Board of Directors: Asian Thoracic Oncology Research Group, Korean Association for Lung Cancer, Korean Cancer Association, Korean Society of Medical Oncology;Other, Personal, Funding, Travel support for advisory board meeting attendance: Amgen, Daiichi-Sankyo. J. Bennouna: Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb, MSD, AstraZeneca, Roche, Servier, Bayer, AMGEN;Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, MSD, AstraZeneca, Roche;Financial Interests, Institutional, Research Grant: AstraZeneca. T. Lesimple: Financial Interests, Personal, Advisory Role: MSD, Novartis, BMS, Pierre Fabre;Financial Interests, Personal, Speaker’s Bureau: MSD, Novartis;Financial Interests, Institutional, Research Grant: Roche. E. Felip: Financial Interests, Personal, Advisory Board: Amgen;Financial Interests, Personal, Advisory Board: AstraZeneca;Financial Interests, Personal, Advisory Board: BAYER;Financial Interests, Personal, Advisory Board: Beigene;Financial Interests, Personal, Advisory Board: Boehringer-Ingelheim;Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb;Financial Interests, Personal, Advisory Board: Eli Lilly;Financial Interests, Personal, Advisory Board: F. Hoffman-La Roche;Financial Interests, Personal, Advisory Board: Glaxo Smith Kline;Financial Interests, Personal, Advisory Board: Janssen;Financial Interests, Personal, Advisory Board: Medical Trends;Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme;Financial Interests, Personal, Advisory Board: Merck Serono;Financial Interests, Personal, Advisory Board: Peptomyc;Financial Interests, Personal, Advisory Board: Pfizer;Financial Interests, Personal, Advisory Board: Puma;Financial Interests, Personal, Advisory Board: Regeneron;Financial Interests, Personal, Advisory Board: Sanofi;Financial Interests, Personal, Advisory Board: Syneos Health;Financial Interests, Personal, Advisory Board: Takeda;Financial Interests, Personal, Speaker’s Bureau: Amgen;Financial Interests, Personal, Speaker’s Bureau: AstraZeneca;Financial Interests, Personal, Speaker’s Bureau: Bristol-Myers Squibb;Financial Interests, Personal, Speaker’s Bureau: Eli Lilly;Financial Interests, Personal, Speaker’s Bureau: F. Hoffmann-La Roche;Financial Interests, Personal, Speaker’s Bureau: Janssen;Financial Interests, Personal, Speaker’s Bureau: Medscape;Financial Interests, Personal, Speaker’s Bureau: Merck Sharp & Dohme;Financial Interests, Personal, Speaker’s Bureau: Merck Serono;Financial Interests, Personal, Speaker’s Bureau: Peervoice;Financial Interests, Personal, Speaker’s Bureau: Pfizer;Financial Interests, Personal, Speaker’s Bureau: Springer;Financial Interests, Personal, Speaker’s Bureau: Touch Medical;Financial Interests, Personal, Member, Independent Member of the Board: Grífols. D. Berz: Financial Interests, Personal, Other, Honoraria: Oncocyte;Other, Personal, Other, Honoraria: Sun Pharma;Other, Personal, Other, Honoraria: Caris;Other, Personal, Other, Honoraria: Takeda;Other, Personal, Other, Honoraria: Natera;Other, Personal, Other, Honoraria: Jazz Pharma;Other, Personal, Other, Honoraria: Genentech;Financial Interests, Personal, Advisory Role: Oncocyte;Other, Personal, Advisory Role: Sun Pharma;Other, Personal, Advisory Role: Biocept;Other, Personal, Advisory Role: Prelude;Financial Interests, Personal, Speaker’s Bureau: Oncocyte;Other, Personal, Speaker’s Bureau: Caris;Other, Personal, Speaker’s Bureau: Sun Pharma;Other, Personal, Speaker’s Bureau: AstraZeneca;Other, Personal, Speaker’s Bureau: Takeda;Other, Personal, Speaker’s Bureau: Merck;Other, Personal, Speaker’s Bureau: Natera;Other, Personal, Speaker’s Bureau: Jazz Pharma. C. Mascaux: Financial Interests, Personal, Advisory Role: Roche;Financial Interests, Personal, Advisory Role: Astr Zeneca;Financial Interests, Personal, Advisory Role: Kephren;Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb;Financial Interests, Personal, Advisory Role: MSD;Financial Interests, Personal, Advisory Role: Pfizer;Financial Interests, Personal, Other, Honoraria: Roche;Financial Interests, Personal, Other, Honoraria: AstraZeneca;Financial Interests, Personal, Other, Honoraria: Kephren;Financial Interests, Personal, Other, Honoraria: Bristol-Myers Squibb;Financial Interests, Personal, Other, Honoraria: MSD;Financial Interests, Personal, Other, Honoraria: Pfizer;Financial Interests, Personal, Other, travel, accommodations, expenses: Roche;Financial Interests, Personal, Other, travel, accommodations, expenses: AstraZeneca;Financial Interests, Personal, Other, travel, accommodations, expenses: Boehringer Ingelheim;Financial Interests, Personal, Other, travel, accommodations, expenses: Takeda. M. Voskoboynik: Financial Interests, Personal, Advisory Role: AstraZeneca. H.T. Landsteiner: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. V. Chen: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. G. Jayadeva: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. J. Alt: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Boehringer Ingelheim, BMS, Pfizer, Roche, Takeda;Financial Interests, Personal, Advisory Role: AstraZeneca, Boehringer Ingelheim, BMS, Roche;Financial Interests, Personal, Funding, Travel/accommodation/expenses: AstraZeneca, Boehringer Ingelheim, BMS. B. Hackanson: Financial Interests, Personal, Advisory Role: Boehringer Ingelheim, MSD, AstraZeneca, BMS. All other authors have declared no conflicts of interest.

An Impending "Avalanche": Debt Collection and Consumer Harm After COVID-19

Debt collection activity is expected to rise significantly in 2021, as financial hardship becomes more prevalent due to the economic impact of the COVID-19 pandemic. Consumer advocates have warned of an impending "avalanche in debt collection" and have called for better enforcement of laws designed to protect consumers from harassment as well as unfair, misleading and deceptive conduct by debt collectors. Women's groups have also pointed to a rise in economic abuse, and resulting indebtedness, in the context of a general escalation in family violence during the pandemic. This article examines the legal framework governing the Australian debt collection industry. Drawing on recent case law and a series of focus groups conducted by the authors, it outlines law reform and enforcement measures that would better protect consumers from harmful debt collection practices. These include specific measures to address the financial, social and psychological impacts of family violence and economic abuse.

Phase Ib study of BI 836880 (VEGF/Ang2 nanobody) plus ezabenlimab (BI 754091;anti-PD-1 antibody) in patients (pts) with solid tumors

Background: In preclinical studies, the combination of anti-VEGF/Ang2 and anti-PD-1 therapy has been shown to promote an immunopermissive state, which is supportive of T-cell-mediated tumor cell destruction. BI 836880 is a humanized bispecific nanobody that targets VEGF and Ang2, and ezabenlimab (BI 754091) is an anti-PD-1 antibody. Phase I studies investigating each as monotherapies have reported safety and preliminary antitumor activity. This ongoing Phase Ib study is evaluating the combination of BI 836880 and ezabenlimab in pts with advanced solid tumors. In Part 1 (dose escalation), the combination was feasible in pts with advanced NSCLC, with a recommended Phase II dose (RP2D) of BI 836880 720 mg + ezabenlimab 240 mg IV q3w. Here, we report updated results from Part 2 (expansion phase), which is assessing the antitumor activity and safety of the RP2D. Methods: Seven cohorts are currently recruiting pts in Part 2: metastatic (m) NSCLC after checkpoint inhibitor (CPI) monotherapy (Cohort A);mNSCLC after chemotherapy (CT) + CPI (Cohort B);mSCLC after CT ± CPI (Cohort C);1 and 2nd recurrences of glioblastoma (GBM;Cohort D);immunotherapy-resistant mmelanoma (Cohort E);hepatocellular carcinoma (HCC) after prior sorafenib or lenvatinib ± CPI (Cohort F);and previously untreated/unresectable HCC (Cohort G). Primary endpoint is objective response rate (complete response + partial response [PR]). Results: As of January 2021, 196 pts have received BI 836880 plus ezabenlimab (14 in Part 1, 182 in Part 2 [Cohort A, 26;B, 30;C, 19;D, 31;E, 32;F, 28;G, 16]). 134 (68%) pts were male, median age was 63 years and 102 (52%) had prior CPI use. Any grade and ≥G3 adverse events (AEs;any cause) were reported by 160 (82%) and 62 (32%) pts, most commonly (all%/ ≥G3%) hypertension (20/8), asthenia (20/3), diarrhea, decreased appetite, and nausea (all 11/1). 95 (48%) pts had a drug-related AE, most commonly hypertension and asthenia (both 11%). 6 pts had a G4 AE (non-related: hyperkalemia + cardiac arrest, laryngospasm, gastrointestinal perforation;drug-related: anaphylactic reaction, acute pancreatitis, transaminases increased);8 pts had a G5 AE (non-related: general physical health deterioration, epilepsy, hemoptysis, cardiorespiratory arrest, hepatic failure, intracranial hemorrhage, COVID-19 pneumonia;drugrelated tracheal hemorrhage). 30 (15%) pts had immune-related AEs (3% ≥G3), including hypothyroidism (3%). 11 (6%) pts had an AE leading to discontinuation. Overall, 145 pts were evaluable for response: 9 pts achieved confirmed PR (2 pts in Part 1 and 7 in Part 2 [NSCLC, n = 3;SCLC, n = 1;GBM, n = 1;melanoma, n = 1;and 2 -line HCC, n = 1]), 87 pts had stable disease and 49 pts had progressive disease. 111 pts remain on treatment. Conclusions: BI 836880 plus ezabenlimab had a manageable safety profile. The combination showed preliminary antitumor activity in a range of tumor types.