Convalescent human IgG, but not IgM, from COVID-19 survivors confers dose-dependent protection against SARS-CoV-2 replication and disease in hamsters

IntroductionAntibody therapeutic strategies have served an important role during the COVID-19 pandemic, even as their effectiveness has waned with the emergence of escape variants. Here we sought to determine the concentration of convalescent immunoglobulin required to protect against disease from SARS-CoV-2 in a Syrian golden hamster model.MethodsTotal IgG and IgM were isolated from plasma of SARS-CoV-2 convalescent donors. Dose titrations of IgG and IgM were infused into hamsters 1 day prior to challenge with SARS-CoV-2 Wuhan-1.ResultsThe IgM preparation was found to have ~25-fold greater neutralization potency than IgG. IgG infusion protected hamsters from disease in a dose-dependent manner, with detectable serum neutralizing titers correlating with protection. Despite a higher in vitro neutralizing potency, IgM failed to protect against disease when transferred into hamsters.DiscussionThis study adds to the growing body of literature that demonstrates neutralizing IgG antibodies are important for protection from SARS-CoV-2 disease, and confirms that polyclonal IgG in sera can be an effective preventative strategy if the neutralizing titers are sufficiently high. In the context of new variants, against which existing vaccines or monoclonal antibodies have reduced efficacy, sera from individuals who have recovered from infection with the emerging variant may potentially remain an efficacious tool

Kinetics and mechanism of chromium(III)-catalysed oxidation of ethanol by cerium(IV) in aqueous sulphuric acid media

1102-1105The kinetics and mechanism of chromium(III) catalysed oxidation of ethanol by cerium(lV) to acetaldehyde in aqueous sulphuric acid media have been studied at different temperatures (30-40°C) under the conditions, [ethanol]T»[CelV]T»[Cr]T. In 1.0 mol dm-3 sulphuric acid media the experimentally observed rate law conforms to: -dln [CeIV]/dt=kobs =a[ ethanol]T, [Cr]T/ {b+c[Cr]T} where [ethanol]T, and [Cr]T, give the total concentrations of the substrate and catalyst respectively; a, b and c are constants at a particular temperature and fixed [H2SO4], From the [HSO] dependence, Ce(SO4)2 has been found kinetically active. The process is acid catalysed. The proposed mechanism involves the formation of an intermediate involving the oxidant, catalyst and substrate and a Crll/CrlV catalytic cycle operates

Kinetics and mechanism of iridium(III) catalysed oxidation of butan-2-ol by cerium(IV) in aqueous sulphuric acid media

765-768The kinetics and mechanism of Ir(III) catalysed oxidation of butan-Z-ol by Ce(IV) in aqueous sulphuric acid media have been followed at different temperatures (20-35°C) under the conditions, [butan-2-0l]T>>[Ce(IV)]T. >> [Ir]T (ca. 10-6 mol dm-3). In 1.0 mol dm-3 sulphuric acid media, the observed rate law conforms to: -dln[Ce(IV)]ldt=Kobs=a[butan-2-ol]T [Ir]T/(b+c[butan-2-ol]T) where, [butan-z-ol], and [Ir]Tgive the total concentrations of the substrate and catalyst respectively; a, band care constants at a particular temperature and fixed [H2SO4]. From the [HSO4·] dependence, Ce(SO4)2 has been found kinetically active. The proposed mechanism involves a pre-equilibrium interaction between the catalyst and substrate leading to an outer-sphere complex followed by the electron transfer at the rate determining step involving Ce(IV)  and outer-sphere complex formed in pre-equilibrium step. It operates through the Ir(III)/Ir(IV) catalytic cycle. The process is acid catalysed. Activation parameters have been determined to investigate the effect of temperature

Human-Immune-System (HIS) humanized mouse model (DRAGA: HLA-A2.HLA-DR4.Rag1KO.IL-2RγcKO.NOD) for COVID-19

We report a Human Immune System (HIS)-humanized mouse model (“DRAGA”: HLA-A2.HLA-DR4.Rag1KO.IL-2 RγcKO.NOD) for COVID-19 research. DRAGA mice express transgenically HLA-class I and class-II molecules in the mouse thymus to promote human T cell development and human B cell Ig-class switching. When infused with human hematopoietic stem cells from cord blood reconstitute a functional human immune system, as well as human epi/endothelial cells in lung and upper respiratory airways expressing the human ACE2 receptor for SARS-CoV-2. The DRAGA mice were able to sustain SARS-CoV-2 infection for at least 25 days. Infected mice showed replicating virus in the lungs, deteriorating clinical condition, and human-like lung immunopathology including human lymphocyte infiltrates, microthrombi and pulmonary sequelae. Among the intra-alveolar and peri-bronchiolar lymphocyte infiltrates, human lung-resident (CD103+) CD8+ and CD4+ T cells were sequestered in epithelial (CD326+) lung niches and secreted granzyme B and perforin, suggesting anti-viral cytotoxic activity. Infected mice also mounted human IgG antibody responses to SARS-CoV-2 viral proteins. Hence, HIS-DRAGA mice showed unique advantages as a surrogate in vivo human model for studying SARS-CoV-2 immunopathological mechanisms and testing the safety and efficacy of candidate vaccines and therapeutics

A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome

Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: OR(A allele) = 9.87, P = 2.13 × 10(-217); non-Japanese: OR(A allele) = 0.49, P = 2.35 × 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease