Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy

Background In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in patients with MS (pwMS) under different DMTs and to identify correlates of reduced protection.Methods This is a prospective Italian multicenter cohort study, long-term clinical follow-up of the CovaXiMS (Covid-19 vaccine in Multiple Sclerosis) study. 1855 pwMS scheduled for SARS-CoV-2 mRNA vaccination were enrolled and followed up to a mean time of 10 months. The cumulative incidence of breakthrough Covid-19 cases in pwMS was calculated before and after December 2021, to separate the Delta from the Omicron waves and to account for the advent of the third vaccine dose.Findings 1705 pwMS received 2 m-RNA vaccine doses, 21/28 days apart. Of them, 1508 (88.5%) had blood assessment 4 weeks after the second vaccine dose and 1154/1266 (92%) received the third dose after a mean interval of 210 days (range 90-342 days) after the second dose. During follow-up, 131 breakthrough Covid-19 infections (33 during the Delta and 98 during the Omicron wave) were observed. The probability to be infected during the Delta wave was associated with SARS-CoV-2 antibody levels measured after 4 weeks from the second vaccine dose (HR=0.57, p < 0.001); the protective role of antibodies was preserved over the whole follow up (HR=0.57, 95%CI=0.43-0.75, p < 0.001), with a significant reduction (HR=1.40, 95%CI=1.01-1.94, p=0.04) for the Omicron cases. The third dose significantly reduced the risk of infection (HR=0.44, 95%CI=0.21-0.90,p=0.025) during the Omicron wave.Interpretation The risk of breakthrough SARS-CoV-2 infections is mainly associated with reduced levels of the virus-specific humoral immune response. Copyright (c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/

Effect of ursodeoxycholic acid on serum enzymes and liver histology in patients with chronic active hepatitis. A 12-month double-blind, placebo-controlled trial.

Abstract: A reduction in serum enzymes has been already observed by administering ursodeoxycholic acid to patients with chronic active hepatitis. The aim of this study was to assess whether the Liver histological activity of inflammation was modified by a 12-month treatment with ursodeoxycholic acid. Thirty-six patients with chronic active hepatitis, fulfilling the inclusion criteria, were admitted to the trial. Patients were randomly allocated to receive double blind either 600 mg/day of ursodeoxycholic acid (Group A: 18 patients) or placebo (Group B: 18 patients). Clinical and biochemical follow-up was performed at 3-month intervals. A percutaneous liver biopsy was performed before and after 1 year of treatment. Histological hepatitis activity was assessed using Knodell's numerical scoring system, while biliary damage was evaluated by an appropriate scoring system. Sixteen and 12 patients in Groups A and B, respectively, completed the clinical and biochemical follow-up. Although a reduction in serum enzymes was found in both groups, multifactorial covariance analysis showed that the reductions in alanine aminotransferase, aspartate aminotransferase and gamma glutamyl transpeptidase were significantly higher in Group A than in Group B. Biochemical remission was not observed in either group. Histological analysis showed a dichotomy between the results from the hepatitis and the biliary components of the disease process. No differences were found in the two groups before or after treatment in histological activity index, which measures the ''hepatitic'' component. Nor were there any significant differences in baseline values. Furthermore, no relationship was found between changes in biochemical parameters and the histological activity indices. In contrast, the ''biliary'' component showed significant improvement after ursodeoxycholic acid treatment for certain cholestatic parameters: ductular metaplasia, bile duct damage and phenotypic cytokeratin changes. These changes were significantly associated with changes in gamma glutamyl transpeptidase serum levels. This study has confirmed that ursodeoxycholic acid administration in patients with chronic active hepatitis reduces transaminases and gamma glutamyl transpeptidase. The morphological substrate of this biochemical improvement can be traced to the biliary component of the process. (C) Journal of Hepatology

TCR repertoire diversity in Multiple Sclerosis: High-dimensional bioinformatics analysis of sequences from brain, cerebrospinal fluid and peripheral blood

BACKGROUND: T cells play a key role in the pathogenesis of multiple sclerosis (MS), a chronic, inflammatory, demyelinating disease of the central nervous system (CNS). Although several studies recently investigated the T-cell receptor (TCR) repertoire in cerebrospinal fluid (CSF) of MS patients by high-throughput sequencing (HTS), a deep analysis on repertoire similarities and differences among compartments is still missing. METHODS: We performed comprehensive bioinformatics on high-dimensional TCR Vβ sequencing data from published and unpublished MS and healthy donors (HD) studies. We evaluated repertoire polarization, clone distribution, shared CDR3 amino acid sequences (CDR3s-a.a.) across repertoires, clone overlap with public databases, and TCR similarity architecture. FINDINGS: CSF repertoires showed a significantly higher public clones percentage and sequence similarity compared to peripheral blood (PB). On the other hand, we failed to reject the null hypothesis that the repertoire polarization is the same between CSF and PB. One Primary-Progressive MS (PPMS) CSF repertoire differed from the others in terms of TCR similarity architecture. Cluster analysis splits MS from HD. INTERPRETATION: In MS patients, the presence of a physiological barrier, the blood-brain barrier, does not impact clone prevalence and distribution, but impacts public clones, indicating CSF as a more private site. We reported a high Vβ sequence similarity in the CSF-TCR architecture in one PPMS. If confirmed it may be an interesting insight into MS progressive inflammatory mechanisms. The clustering of MS repertoires from HD suggests that disease shapes the TCR Vβ clonal profile. FUNDING: This study was partly financially supported by the Italian Multiple Sclerosis Foundation (FISM), that contributed to Ballerini-DB data collection (grant #2015 R02)