ABSTRACT
We conducted a post-hoc analysis in seropositive patients who were negative or borderline for functional neutralizing antibodies (nAbs) against SARS-CoV-2 at baseline from a phase 1/2/3 trial of casirivimab and imdevimab (CAS+IMD) treatment in hospitalized COVID-19 patients on low-flow or no supplemental oxygen prior to the emergence of Omicron-lineage variants. Patients were randomized to a single dose of 2.4 g CAS+IMD, 8.0 g CAS+IMD, or placebo. Patients seropositive for anti-SARS-CoV-2 antibodies at baseline were analyzed by their baseline nAb status. At baseline, 20.6% (178/864) of seropositive patients were negative/borderline for nAbs. CAS+IMD reduced viral load in patients who were negative/borderline for nAbs versus placebo, but not in patients who were positive for nAbs. We observed a trend in reduction of the proportion of patients who died or required mechanical ventilation (MV), as well as in all-cause mortality, by day 29 with CAS+IMD versus placebo in patients who were negative/borderline for nAbs. In those who were negative/borderline for nAbs, the proportions who died/needed MV from days 1-29 were 19.1% and 10.9%, and the proportions of patients who died from days 1-29 were 16.2% and 9.1%, in the placebo and CAS+IMD combined dose groups, respectively. No measurable harm or benefit in death/MV or all-cause mortality was observed in patients who were positive for nAbs. In hospitalized COVID-19 patients on low-flow or no supplemental oxygen, CAS+IMD reduced viral load, the risk of death or MV, and all-cause mortality in seropositive patients who were negative/borderline for nAbs. ImportanceThe clinical benefit of CAS+IMD in hospitalized seronegative patients with COVID-19 has previously been demonstrated, although these studies observed no clinical benefit in seropositive patients. As the prevalence of SARS-CoV-2 seropositive individuals rises due to both vaccination and previous infection, it is important to understand whether there is a subset of hospitalized patients with COVID-19, who have antibodies against SARS-CoV-2, who could benefit from anti-SARS-CoV-2 monoclonal antibody treatment. This post-hoc analysis demonstrates that there is a subset of hospitalized, seropositive patients with inadequate SARS-CoV-2 nAbs (ie, those who were negative or borderline for nAbs) who may still benefit from CAS+IMD treatment if infected with a susceptible variant. Therefore, utilizing seronegativity status alone to guide treatment decisions for patients with COVID-19 may fail to identify seropositive patients who could benefit from anti-SARS-CoV-2 monoclonal antibody therapies which retain activity against circulating strains, depending on how effectively their endogenous antibodies neutralize SARS-CoV-2.
ABSTRACT
BackgroundHospitalized patients with COVID-19 experience high mortality rates, ranging from 10% to 30%. Combined casirivimab and imdevimab (CAS+IMD) is authorized for use in outpatients with COVID-19 and in post-exposure prophylaxis. The UK-based platform RECOVERY study reported improved survival in hospitalized seronegative patients treated with CAS+IMD; however, in most of the world, anti-spike monoclonal antibody therapy is currently not approved for hospitalized patients. MethodsIn this phase I/II/III double-blind placebo-controlled trial, patients hospitalized with COVID-19 were randomized (1:1:1) to 2.4 g or 8.0 g of CAS+IMD or placebo, and characterized at baseline for viral load and SARS-CoV-2 endogenous immune response. Results1336 patients on low-flow or no supplemental oxygen were treated. The primary endpoint was met: in seronegative patients, the least squares mean difference (CAS+IMD vs placebo) for time-weighted average change from baseline viral load was -0.28 log10 copies/mL (95% confidence interval [CI] -0.51 to -0.05; P = .0172). The primary clinical analysis of death or mechanical ventilation from day 6 to 29 in patients with high viral load had a strong positive trend but did not reach significance. CAS+IMD numerically reduced all-cause mortality in seronegative patients through day 29 (relative risk reduction, 55.6%; 95% CI 24.2-74.0; nominal P = .0032). No safety concerns were noted. ConclusionsIn hospitalized patients with COVID-19 on low-flow or no oxygen, CAS+IMD treatment reduced viral load and the risk of death or mechanical ventilation as well as all-cause mortality in the overall population, with the benefit driven by seronegative patients and no harm observed in seropositive patients.
ABSTRACT
BackgroundThe efficacy of convalescent plasma (CP) for the treatment of COVID-19 remains unclear. MethodsA matched cohort analysis of hospitalized patients with severe COVID-19. The impact of CP treatment on all cause in-hospital mortality was evaluated using univariate and multivariate Cox proportional-hazards models, and the impact of CP treatment on the time to hospital discharge was assessed using a stratified log-rank analysis. Results64 patients who received CP a median of 7 days after symptom onset were compared to a matched control group of 177 patients. Overall in-hospital mortality was 14.9%. There was no significant difference in the risk of in-hospital mortality between the two groups (adjusted hazard ratio [aHR] 0.93, 95% confidence interval [CI] 0.39 - 2.20). There was also no significant difference in the overall rate of hospital discharge (rate ratio [RR] 1.28, 95% CI 0.91 - 1.81), but a subgroup analysis of patients 65-years-old or greater who received CP demonstrated a significantly increased hospital discharge rate among these patients (RR 1.86, 95% CI 1.03 - 3.36). There was a greater than expected frequency of transfusion reactions in the CP group (2.8% reaction rate observed per unit transfused). ConclusionsThe use of CP in this study was a safe treatment for COVID-19. There was no overall significant reduction of in-hospital mortality or increased rate of hospital discharge associated with the use of CP in this study, although there was a signal for improved outcomes among the elderly. Further adequately powered randomized studies should target this subgroup when assessing the efficacy CP treatment.
ABSTRACT
Talaromyces marneffei is the only dimorphic species in its genus and causes a fatal systemic mycosis named talaromycosis. Our previous study indicated that knockdown of AcuD gene (encodes isocitrate lyase of glyoxylate bypass) of T. marneffei by RNA interference approach attenuated the virulence of T. marneffei, while the virulence of the AcuD knockout strains was not studied. In this study, T. marneffei-zebrafish infection model was successfully established through hindbrain microinjection with different amounts of T. marneffei yeast cells. After co-incubated at 28°C, the increasing T. marneffei inoculum doses result in greater larval mortality; and hyphae generation might be one virulence factor involved in T. marneffei-zebrafish infection. Moreover, the results demonstrated that the virulence of the ΔAcuD was significantly attenuated in this Zebrafish infection model.
