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

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.