HICC: Humoral Immune Correlates for COVID19: Defining protective responses and critical readouts for Clinical Trials of Vaccines and Therapeutics

A critical gap in knowledge is our understanding of immune correlates of protection from COVID-19, and the fine specificity of protective immune responses to SARS-CoV-2. Thisgap is a huge impediment to an entire spectrum of major health care issues, ranging from return to work policies for NHS staff and recovered patients to guiding therapeutic interventions, vaccine development and clinical trials. The WHO cautions that simple antibody tests do not correlate with immunity. In fact robust responses correlate with disease severity, while lower titre responses are associated with accelerated viral clearance (Tan et al, medRxiv https://doi.org/10.1101/2020.03.24.20042382). It isessential to have more specific, qualitative humoral assays and Immunoglobulin (Ig) teststhat clearly identify protective immunity, and distinguish from deleterious responses to be avoided by vaccination.We will characterise the; fine-specificity of anti-SARS-CoV-2 antigen (i.e. S, RBD, N) specific Ig, cross-reactivity (i.e. of anti-S2) to other circulating human Coronaviruses (HCoV), correlation of Ig Fc-binding glycosylation patterns with Fc-gamma receptors used, with Immunoglobulin effector functions such as Neutralisation, Antibody dependent enhancement (ADE) and Antibody dependent cellular cytotoxicity (ADCC). The powerful combination of diagnostic, high throughput MS and comprehensive functional analysis will be applied to 3 clinical cohorts; 1) severe COVID-19 (progressors), 2) survivors(moderate) and 3) mild or asymptomatic cases. This study has already been initiated with the aim of; quickly providing essential data for critical clinical decisions for management of NHS staff, while providing standardised testsfor intervention therapies, vaccine development and immune benchmarks for clinical trials.