SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era

Autoimmunity is a significant feature of idiopathic pulmonary arterial hypertension.

RATIONALE: Autoimmunity is thought to play a role in idiopathic pulmonary arterial hypertension (IPAH). It is not clear if this is causative or a bystander of disease and if it carries any prognostic or treatment significance. OBJECTIVE: To study autoimmunity in IPAH using a large cross-sectional cohort. METHODS: Assessment of the circulating immune cell phenotype was undertaken using flow cytometry and the profile of serum immunoglobulins was generated using a standardised multiplex array of 19 clinically validated autoantibodies in 473 cases and 946 controls. Additional GST-fusion array and ELISA data were used to identify a serum autoantibody to BMPR2. Clustering analyses and clinical correlations were employed to determine associations between immunogenicity and clinical outcomes. MEASUREMENTS AND MAIN RESULTS: Flow cytometric immune profiling demonstrates IPAH is associated with an altered humoral immune response in addition to raised IgG3. Multiplexed autoantibodies were significantly raised in IPAH, and clustering demonstrated three distinct clusters: 'high autoantibody', 'low autoantibody', and a small 'intermediate' cluster exhibiting high levels of RNP-complex. The high autoantibody cluster had worse haemodynamics but improved survival. A small subset of patients demonstrated immunoglobulin reactivity to BMPR2. CONCLUSIONS: This study establishes aberrant immune regulation and presence of autoantibodies as a key feature in the profile of a significant proportion of IPAH patients and is associated with clinical outcomes. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/)