Are SARS-CoV-2 Specific Antibodies a Correlate for Protection?

SARS-CoV-2 has spread at an unprecedented speed and scale since January 2020. Since then,
Belgium has been confronted with >60.000 diagnosed cases and likely many more undiagnosed
with mild or no symptoms. The true seroprevalence of SARS-CoV-2 in the Belgian population is
not known, yet increasing confidence about the performance of several serological assays
paves the way to large-scale serosurveys. These studies will be crucial in assessing
population immunity and evaluating the risk of re-infection. The first, smaller-scaled,
antibody surveys report a range of seroprevalences, i.e. Germany (14%), The Netherlands (4%),
USA (2.49-4.16%) and Belgium (4.7-6.9%). These studies suffer from conceptual and technical
flaws yet are used for easing lockdown measures. A major limitation is that antibody (Ab)
capture assays measure exposure to SARS-CoV-2, rather than subsequent protection, which
requires assessment of the quality of the Abs including their capacity to neutralize the
virus. Also the Ab levels required for protection and their duration are yet unknown. The
proposed project aims to address these pertinent questions in a population at risk of
re-infection during a second epidemic wave. Sero-neutralisation assays are regarded the gold
standard method to measure ex vivo Ab neutralising activity against viruses, including
SARS-CoV-2. A recent Chinese study, using a pseudovirus neutralisation assay, found that nAbs
are detected from day 10-15 after onset of disease and that younger patients typically have
lower levels of nAbs compared to middle-aged and elderly patients. Importantly, in about 1
out of 3 patients the nAb titers were low and in 10 young patients nAbs were absent. A
pseudovirus is an imperfect model for SARS-CoV-2 because of the non-natural embedding of
Spike protein in the pseudovirions and differences in glycosylation. In this study, a whole
virus neutralisation assay will be used that was recently validated using a panel of
SARS-CoV-2 convalescent sera in the lab of the Principal Investigator. Preliminary results of
the study team show a rapid decline in nAb titer within 15-36d after diagnosis in 4/11
patients, while IgG and IgA remain steady and high in ELISA. Older studies with SARS-CoV-1
showed declining IgM and IgA antibody titers within 6 months, declining IgG titers after 1y,
and a complete lack of antigen-specific peripheral memory B-cell (MBC) responses after
recovery. Measuring only circulating Abs can be misleading as it excludes the detection of
the MBC pool, which can exist in the absence of detectable serum Ab levels and is a
pre-requisite to maintain protective immunity in the long term. Upon re-encounter with the
antigen, MBC can rapidly differentiate to produce Abs. So far, little is known about humoral
immune responses against SARS-CoV-2 and their contribution to protection.