Neutralization, effector function and immune imprinting of Omicron variants

Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain$^{1}$ (RBD) of the spike protein. The effects of these mutations on viral infection and transmission and the efficacy of vaccines and therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 and XBB.1.5 variants bind host ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1, XBB.1 and BN.1 RBDs bound to the fragment antigen-binding region of the S309 antibody (the parent antibody for sotrovimab) and human ACE2 explain the preservation of antibody binding through conformational selection, altered ACE2 recognition and immune evasion. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1 and hamsters challenged with XBB.1.5. Vaccine-elicited human plasma antibodies cross-react with and trigger effector functions against current Omicron variants, despite a reduced neutralizing activity, suggesting a mechanism of protection against disease, exemplified by S309. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring the role of persistent immune imprinting

Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages carry distinct spike mutations resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters elicit plasma-neutralizing antibodies against Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5, and that breakthrough infections, but not vaccination alone, induce neutralizing antibodies in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1, BA.2, and BA.4/5 receptor-binding domains, whereas Omicron primary infections elicit B cells of narrow specificity up to 6 months after infection. Although most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant–neutralizing antibody that is a strong candidate for clinical development

Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

SARS-CoV-2 Omicron sublineages carry distinct spike mutations and represent an antigenic shift resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters result in potent plasma neutralizing activity against Omicron BA.1 and BA.2 and that breakthrough infections, but not vaccination-only, induce neutralizing activity in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1 and BA.2 receptor-binding domains whereas Omicron primary infections elicit B cells of narrow specificity. While most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant antibody, that is unaffected by any Omicron lineage spike mutations and is a strong candidate for clinical development

Applying systems thinking to identify enablers and challenges to scale-up interventions for hypertension and diabetes in low-income and middle-income countries: protocol for a longitudinal mixed-methods study.

INTRODUCTION: There is an urgent need to reduce the burden of non-communicable diseases (NCDs), particularly in low-and middle-income countries, where the greatest burden lies. Yet, there is little research concerning the specific issues involved in scaling up NCD interventions targeting low-resource settings. We propose to examine this gap in up to 27 collaborative projects, which were funded by the Global Alliance for Chronic Diseases (GACD) 2019 Scale Up Call, reflecting a total funding investment of approximately US$50 million. These projects represent diverse countries, contexts and adopt varied approaches and study designs to scale-up complex, evidence-based interventions to improve hypertension and diabetes outcomes. A systematic inquiry of these projects will provide necessary scientific insights into the enablers and challenges in the scale up of complex NCD interventions. METHODS AND ANALYSIS: We will apply systems thinking (a holistic approach to analyse the inter-relationship between constituent parts of scaleup interventions and the context in which the interventions are implemented) and adopt a longitudinal mixed-methods study design to explore the planning and early implementation phases of scale up projects. Data will be gathered at three time periods, namely, at planning (TP), initiation of implementation (T0) and 1-year postinitiation (T1). We will extract project-related data from secondary documents at TP and conduct multistakeholder qualitative interviews to gather data at T0 and T1. We will undertake descriptive statistical analysis of TP data and analyse T0 and T1 data using inductive thematic coding. The data extraction tool and interview guides were developed based on a literature review of scale-up frameworks. ETHICS AND DISSEMINATION: The current protocol was approved by the Monash University Human Research Ethics Committee (HREC number 23482). Informed consent will be obtained from all participants. The study findings will be disseminated through peer-reviewed publications and more broadly through the GACD network

Prospective, multicentre study of screening, investigation and management of hyponatraemia after subarachnoid haemorrhage in the UK and Ireland

Background: Hyponatraemia often occurs after subarachnoid haemorrhage (SAH). However, its clinical significance and optimal management are uncertain. We audited the screening, investigation and management of hyponatraemia after SAH. Methods: We prospectively identified consecutive patients with spontaneous SAH admitted to neurosurgical units in the United Kingdom or Ireland. We reviewed medical records daily from admission to discharge, 21 days or death and extracted all measurements of serum sodium to identify hyponatraemia (<135 mmol/L). Main outcomes were death/dependency at discharge or 21 days and admission duration >10 days. Associations of hyponatraemia with outcome were assessed using logistic regression with adjustment for predictors of outcome after SAH and admission duration. We assessed hyponatraemia-free survival using multivariable Cox regression. Results: 175/407 (43%) patients admitted to 24 neurosurgical units developed hyponatraemia. 5976 serum sodium measurements were made. Serum osmolality, urine osmolality and urine sodium were measured in 30/166 (18%) hyponatraemic patients with complete data. The most frequently target daily fluid intake was >3 L and this did not differ during hyponatraemic or non-hyponatraemic episodes. 26% (n/N=42/164) patients with hyponatraemia received sodium supplementation. 133 (35%) patients were dead or dependent within the study period and 240 (68%) patients had hospital admission for over 10 days. In the multivariable analyses, hyponatraemia was associated with less dependency (adjusted OR (aOR)=0.35 (95% CI 0.17 to 0.69)) but longer admissions (aOR=3.2 (1.8 to 5.7)). World Federation of Neurosurgical Societies grade I–III, modified Fisher 2–4 and posterior circulation aneurysms were associated with greater hazards of hyponatraemia. Conclusions: In this comprehensive multicentre prospective-adjusted analysis of patients with SAH, hyponatraemia was investigated inconsistently and, for most patients, was not associated with changes in management or clinical outcome. This work establishes a basis for the development of evidence-based SAH-specific guidance for targeted screening, investigation and management of high-risk patients to minimise the impact of hyponatraemia on admission duration and to improve consistency of patient care

Gestalt Processing in Autistic Adolescents

Previous research has documented that individuals with autism preferentially attend to local rather than global elements of a visual scene. We tested another pre-attentive phenomenon - gestalt processing - to investigate whether the global processing deficits seen in autism extend to gestalt processing. We asked 5 individuals with low functioning autism and 13 typically developing individuals to point to the odd item in a four-item display to test ability and speed in using gestalt principles of proximity, similarity and closure. As expected, the control group was significantly faster at responding to gestalt-grouped targets than targets differing in only a single feature. However, individuals with autism did not show a significant difference in reaction time between conditions, implying that parsing gestalt relationships is as taxing as processing single features. Both groups were generally more accurate in the gestalt condition. Taken together, these findings suggest that although the ability to process gestalt relationships appears to be intact in autism, gestalt processing may not be a pre-attentive process for this sample. Implications and future directions are discussed

Protocol for process evaluation of SMART Mental Health cluster randomised control trial:an intervention for management of common mental disorders in India

INTRODUCTION: In India about 95% of individuals who need treatment for common mental disorders like depression, stress and anxiety and substance use are unable to access care. Stigma associated with help seeking and lack of trained mental health professionals are important barriers in accessing mental healthcare. Systematic Medical Appraisal, Referral and Treatment (SMART) Mental Health integrates a community-level stigma reduction campaign and task sharing with the help of a mobile-enabled electronic decision support system (EDSS)—to reduce psychiatric morbidity due to stress, depression and self-harm in high-risk individuals. This paper presents and discusses the protocol for process evaluation of SMART Mental Health. METHODS AND ANALYSIS: The process evaluation will use mixed quantitative and qualitative methods to evaluate implementation fidelity and identify facilitators of and barriers to implementation of the intervention. Case studies of six intervention and two control clusters will be used. Quantitative data sources will include usage analytics extracted from the mHealth platform for the trial. Qualitative data sources will include focus group discussions and interviews with recruited participants, primary health centre doctors, community health workers (Accredited Social Health Activits) who participated in the project and local community leaders. The design and analysis will be guided by Medical Research Council framework for process evaluations, the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework, and the normalisation process theory. ETHICS AND DISSEMINATION: The study has been approved by the ethics committee of the George Institute for Global Health, India and the Institutional Ethics Committee, All India Institute of Medical Sciences (AIIMS), New Delhi. Findings of the study will be disseminated through peer-reviewed publications, stakeholder meetings, digital and social media platforms. TRIAL REGISTRATION NUMBER: CTRI/2018/08/015355

An integrated community and primary healthcare worker intervention to reduce stigma and improve management of common mental disorders in rural India:protocol for the SMART Mental Health programme

Background: Around 1 in 7 people in India are impacted by mental illness. The treatment gap for people with mental disorders is as high as 75–95%. Health care systems, especially in rural regions in India, face substantial challenges to address these gaps in care, and innovative strategies are needed. Methods: We hypothesise that an intervention involving an anti-stigma campaign and a mobile-technology-based electronic decision support system will result in reduced stigma and improved mental health for adults at high risk of common mental disorders. It will be implemented as a parallel-group cluster randomised, controlled trial in 44 primary health centre clusters servicing 133 villages in rural Andhra Pradesh and Haryana. Adults aged ≥ 18 years will be screened for depression, anxiety and suicide based on Patient Health Questionnaire (PHQ-9) and Generalised Anxiety Disorders (GAD-7) scores. Two evaluation cohorts will be derived—a high-risk cohort with elevated PHQ-9, GAD-7 or suicide risk and a non-high-risk cohort comprising an equal number of people not at elevated risk based on these scores. Outcome analyses will be conducted blinded to intervention allocation. Expected outcomes: The primary study outcome is the difference in mean behaviour scores at 12 months in the combined ‘high-risk’ and ‘non-high-risk’ cohort and the mean difference in PHQ-9 scores at 12 months in the ‘high-risk’ cohort. Secondary outcomes include depression and anxiety remission rates in the high-risk cohort at 6 and 12 months, the proportion of high-risk individuals who have visited a doctor at least once in the previous 12 months, and change from baseline in mean stigma, mental health knowledge and attitude scores in the combined non-high-risk and high-risk cohort. Trial outcomes will be accompanied by detailed economic and process evaluations. Significance: The findings are likely to inform policy on a low-cost scalable solution to destigmatise common mental disorders and reduce the treatment gap for under-served populations in low-and middle-income country settings. Trial registration: Clinical Trial Registry India CTRI/2018/08/015355. Registered on 16 August 2018

Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

International audienceSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages carry distinct spike mutations and represent an antigenic shift resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters elicit plasma neutralizing activity against Omicron BA.1, BA.2, BA.2.12.1 and BA.4/5 and that breakthrough infections, but not vaccination-only, induce neutralizing activity in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1, BA.2, and BA.4/5 receptor-binding domains whereas Omicron primary infections elicit B cells of narrow specificity up to 6 months post infection. Although most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant neutralizing antibody, that is a strong candidate for clinical development