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

Lead Research Organisation: University of Cambridge
Department Name: UNLISTED

Abstract

SARS-CoV-2 is an emerging virus with very high infectivity and risk of death in those with severe respiratory symptoms. To maximise our success in protecting people against this disease, we urgently need to understand and develop highly accurate tests to identify when a person has developed a protective immune response versus a COVID-19 disease response. We do not understand the antibody response differences between individuals who have mild SARS-CoV-2 infection and high risk patients that progress to life threatening disease. Understanding specific differences will help us develop tests to diagnose the likelihood of severe disease, and vaccines to prevent them. We will use cutting edge, high throughput technologies to identify in detail the functional role of SARS-CoV-2 antibodies in immune protection, their association with disease severity and the duration of immunity after infection. Importantly, we will turn this information into tests which will be used to:

1. Identify when NHS-staff have evidence of protective antibody responses to SARS-CoV-2. This is urgently needed to manage NHS staff returns, guide public health and government policy.
2. Provide clinical tests to assist the development and evaluation of safe vaccines and therapies for the treatment of the sickest patients.

Technical Summary

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. This gap 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 is essential to have more specific, qualitative humoral assays and Immunoglobulin (Ig) tests that 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 tests for intervention therapies, vaccine development and immune benchmarks for clinical trials.

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