Professor Deborah Dunn-Walters, University of Surrey – Written evidence (COV0024)

Author: Professor Deborah Dunn-Walters, Professor of Immunology, University of Surrey. Expert in B cell development and antibody repertoire.

To assess the efficacy of any vaccine for COVID-19 we need to understand what the correlates of protection (CoP) are. Simple tests of antibody quantity measuring IgG and IgM that are commonly used may not correlate with the functional protection provided due to qualitative differences in: 1. Different levels of antibody (sub)class which have different functions. 2. Different target sites on the pathogen

1. There are several different functions for antibody. Antibodies can encode the same specificity for antigen if they have the same Variable region, but differ in function due to different constant regions encoding different subclasses. Switching the class of antibody from IgM in the first instance, to IgG, IgA, IgE changes some of the antibody functions important for protection. The Fc regions of antibodies bound to pathogen are recognised by Fc receptors on other immune cells which can carry out functions such as cell killing (ADCC, antibody dependent cellular cytotoxicity) or phagocytosis of the pathogen (ADCP, antibody dependent cellular phagocytosis). The subclass of IgG raised in COVID-19 infection is important because the affinity of their Fc region for the Fc receptors varies a lot in the order IgG3>IgG1>IgG4>IgG2. A different type of receptor, FcRn, is found on monocytes and appears to be involved in antigen presentation. The IgG subclasses have equivalent affinity for FcRn. Complement deposition (ADCD) is also important in fighting pathogens and follows a similar pattern of functional variability as for Fc receptor binding. IgM antibody can also activate complement, as well as cross-link pathogens into immune complexes due to its ability to form pentamers. IgA1 can also mediate ADCC via FcR, while IgA2 can exist as a dimer and be secreted across mucosal membranes to protect mucosal tissues such as the lung.

2. In vaccinology people refer to “neutralising antibodies”, a good candidate for CoP. Measured as those that bind to the pathogen in such a way as to prevent the pathogen infecting host cells in a culture system. Non-neutralising antibodies also exist, which might bind to the virus but not in such a way as to interfere with infection of cells. Neutralising capacity depends on the Variable region binding the pathogen in the correct place and is therefore not affected by class switching in the same way as other antibody functions.

Thus, the function and target of different antibodies can have a critical bearing on the protection and pathology of COVID-19. Antibody may not always have a positive effect against infection. Pathogens may use antibody with high affinity for FcR to facilitate entry into cells. While there is no evidence for the antibody dependent enhancement (ADE) as yet it is something to be checked carefully in any vaccine study. Too much complement deposition and or bystander autoimmune antibody could promote thrombosis, too much IgG1 or IgG3 antibody activating macrophages via FcgR could contribute to cytokine storm, both are pathologies reported in severe disease. Not enough focussed functions of ADCP, ADCC, ADCP, neutralisation can delay an effective response enabling the virus to get a foothold. Some asymptomatic infections have yielded functional B cells even when antibodies could not be detected in the blood. While we know that severe COVID-19 disease results in high levels of COVID-19 specific antibody we do not know what proportion of antibody makes a positive contribution, versus what proportion has neutral or negative consequences. We do know that there are numerous age-related changes in B cells and antibodies, including the types of antibody that are made, which could help explain the age-related susceptibility to COVID-19.

Antibody production is not the only function of B cells. We have single cell transcriptome data showing there are 10 major B cell subsets apart from the plasma cells that secrete antibody. Regulatory B cells exist to resolve inappropriate activation of the B cell response. Some memory cells are made in a germinal centre response and are likely to be affinity matured and highly targeted. Some memory cells develop in a T independent fashion and others appear to be directed more towards antigen presentation than antibody production. They vary in their abilities to secrete different cytokines. Almost nothing is known about the roles of these different cell types in COVID-19.

A better understanding of these questions in COVID-19 at different ages and disease severity will inform which measures we need to assess the quality of the vaccines that are being developed.

27 June 2020