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How immune responses shape the clinical characteristics of COVID-19: a prospective cohort study in patients and their household contacts

English title How immune responses shape the clinical characteristics of COVID-19: a prospective cohort study in patients and their household contacts
Applicant Siegrist Claire-Anne
Number 196732
Funding scheme Special Call on Coronaviruses
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Immunology, Immunopathology
Start/End 01.06.2020 - 31.05.2022
Approved amount 298'200.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Infectious Diseases

Keywords (6)

SARS Coronavirus-2; Disease severity; Innate immunity; Adaptive immunity; Observational study of patients and contacts; COVID-19

Lay Summary (French)

Lead
Comprendre ce que le COVID-19 déclenche comme réponses immunitaires et comment ces réponses immunitaires contribuent à prévenir ou augmenter la gravité de la maladie est essentiel pour identifier des stratégies de prévention ou de traitement qui soient efficaces.
Lay summary
Contenu et objectifs du travail de recherche :

Nous avons lancé mi-mars 2020 une étude clinique aux Hôpitaux Universitaire de Genève pour recruter des patients avec un COVID-19 et leurs contacts proches. En collectant régulièrement des informations sur leur état de santé et des échantillons biologiques, nous voulons déterminer ce qui constitue une réponse immunitaire protégeant ou au contraire aggravant la sévérité du COVID-19.

Notre projet est de recruter 50 patients et 200 contacts suivis à intervalles réguliers. Nous mesurerons la quantité de virus dans le corps, leurs réponses immunitaires immédiates (innées) et celles qui s'installent plus tardivement (anticorps, réponses lymphocytaires B et T). Nous nous intéresserons aussi à l'influence positive ou négative de l'immunité existant au moment de l'exposition au virus du COVID-19.

Les résultats espérés sont de définir ce qui constitue une réponse immunitaire protectrice ou au contraire aggravant la sévérité du COVID-19.

Ces connaissances guideront le développement de vaccins ou de traitements immunomodulateurs spécifiques à donner à un moment précis de l'évolution de la maladie, un défi complexe tant que le COVID-19 est aussi mal connu qu'actuellement.

Contexte scientifique : Biologie et médecine 
Direct link to Lay Summary Last update: 17.05.2020

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Abstract

Background: On March 11th 2020, COVID-19 was declared a pandemic. Despite drastic measures to limit dissemination, it has already lead to a substantial death toll and enormous impact on health-care systems and the world economy. As data are emerging on the clinical manifestations caused by Severe Acute Respiratory Syndrome (SARS)-Coronavirus (CoV)-2, it is critical to understand its immunopathology and put it in perspective of previous SARS epidemics. The immunopathology of SARS disease is poorly understood because of the relatively limited access to patients and because animal studies do not reflect the complexity of human disease. Today, immunological and data analysis tools have progressed enormously and numerous accessible patients exhibit none to critical symptoms, enabling rapid and extensive characterization of SARS-CoV-2 immunopathology. Within 2 weeks of the outbreak of COVID-19 in Geneva, we established a clinical platform recruiting infected patients and used our expertise in clinical research in vaccines, infectious diseases and SARS-specific immunology to start addressing critical questions about COVID-19. In this unique position, we will collect samples before the onset of symptoms, through the monitoring and sampling of household contacts of infected patients, until convalescence. This will establish what constitutes protective or detrimental immune responses to SARS-CoV-2, critical open questions for the development of the numerous vaccines currently in the pipeline. A clinical study has been initiated in the Geneva University Hospitals, planning to include 50 patients (with no, mild, moderate, severe or critical symptoms) and 200 household contacts. All will be followed at regular intervals for clinical evaluation and harvesting of biological samples. We will perform a detailed longitudinal characterization of their immune responses before and after symptom onset.Objectives: 1.Assess the circulating and local innate response induced by SARS-CoV-2 prior to and after the onset of symptoms to determine which specific inflammatory markers (cell types, gene expression, cytokines) are associated with disease outcome. 2.Assess the SARS-CoV-2 specific adaptive responses during the course of COVID-19, which may influence disease outcome through clearance of virus or viral-infected cells and/or enhancement of innate responses.3.Define whether cross-reactive, non-neutralizing antibodies (or memory B cells) to other CoVs may play a role in enhancing disease by skewing the response of macrophages to SARS-CoV-2. 4.Establish prognostic or predictive markers of disease severity by performing a multi-parametric, unsupervised analysis of all parameters (clinical, immunological, viral). Experimental approaches: Innate cell phenotyping by flow cytometry, measure of a broad spectrum of cytokines in plasma and other biological samples, changes in blood gene expression analyses, serological assays and characterization of SARS-CoV-2-specific and cross-reactive B and T cell responses. Expected outcomes: Capturing asymptomatic subjects through the follow-up of household contacts of COVID-19 patients will define “protective” responses (innate and/or linked to rapid generation of SARS-CoV-2-specific immunity); this project will identify the potential role of prior exposure to other coronaviruses as well as protective or detrimental immune responses to SARS-CoV-2, supporting the complex development of COVID-19 vaccines (inducing protective response, avoiding disease enhancement) and immunomodulatory therapies.
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