Humoral response during the COVID-19 pandemic: from infection to vaccination

Abstract

Coronavirus disease 2019 (COVID-19) is an infec:ous disease caused by the SARSCoV-
2. The disease emerged in Wuhan, China, in late 2019 in a cluster of pa:ents
with pneumonia. COVID-19 was swiKly declared a pandemic by the World Health
Organiza:on (WHO) on March 11, 2020. As of February 11, 2024, more than 774
million COVID-19 cases have been confirmed and around 7 million deaths have been
recorded worldwide.
This unprecedented prolifera:on put considerable pressure on healthcare
infrastructures globally, catalyzing extensive inves:ga:ons to characterize the
physiopathology of the virus and find appropriate treatments. The focal point of this
thesis is the humoral response measurement in infected and/or vaccinated
individuals. Each stage of the pandemic has been documented, from the release of
commercial binding an:body assays in 2020 to the emergence of last variants that
escape vaccine-induced neutralizing an:bodies (NAbs) in late 2023.
Early in the pandemic, and despite the lack of formal regulatory approval, the
healthcare community witnessed the introduc:on of a myriad of commercial assays
designed to measure binding an:bodies, essen:al for diagnosing past-infec:on or
conduc:ng seroprevalence surveys. The first objec:ve was to evaluate and
characterize the humoral response in infected pa:ents. For this purpose, several
binding an:body assays under different formats (total an:bodies, immunoglobulin G
[IgG], IgM, IgA), targe:ng different an:gens (nucleocapsid [N], spike [S], receptorbinding
domain [RBD]), and which could be quan:ta:ve, semi-quan:ta:ve, or
qualita:ve, were carefully evaluated.
Accumula:ng evidence has highlighted the role of NAbs as the best correlate of
protec:on (CoP) against SARS-CoV-2 infec:on. A pseudovirus-neutraliza:on test was
therefore developed by our team and con:nually adapted to accommodate the
emergence of SARS-CoV-2 variants, including one of the most recent (i.e., JN.1) in late
2023.
In response to the pandemic, major efforts have been made to produce and clinically
validate new COVID-19 vaccines at an unprecedented speed. The CRO-VAX HCP
study, a mul:center, prospec:ve, and interven:onal study was designed to evaluate
the humoral response among healthcare professionals having received two doses of
the BNT162b2 messenger ribonucleic acid (mRNA) COVID-19 vaccine. Two hundred
and thirty-one volunteers from three medical centers in Belgium were enrolled.
Samples were collected at regular intervals up to 6 months and kine:c models were
rapidly developed.
Given the decrease of vaccine efficacy (VE) over :me and the emergence of variants
that can escape immunity, a third dose was soon recommended to boost immunity.
A total of 155 volunteers from the CRO-VAX HCP study agreed to receive the booster
and pursue our study. Breakthrough infec:on (BKI) occurrence in volunteers of two
cohorts we followed (BNT162b2 and mRNA-1273) also allowed us to evaluate the
protec:ve role of the humoral response compared to a free-of-infec:on control
group. We also documented the role of the humoral response as a CoP during the
Omicron era.
Faced with a decreased VE correlated with a decline of the humoral response, a
second and adapted booster was proposed by authori:es. On September 2022, 54
par:cipants of the CRO-VAX HCP study received the second and bivalent adapted
BNT162b2 booster. The humoral response was evaluated and the NAbs against
several variants were measured. BKI occurrence due to XBB.1.5 highlighted the
importance of adap:ng vaccine formula:on to circula:ng variants. Moreover, our
study extended to evaluate the cellular response with an interferon gamma (IFNγ)
release assay (IGRA). As compared to the humoral response, which significantly
weakened over :me, the cellular response remained quite stable and could therefore
explained why individuals with low an:body :ters can s:ll be protected against
severe disease.
This dichotomy of kine:cs underscores the complexity of the immune response to
SARS-CoV-2, advoca:ng for con:nued explora:on of CoP against the virus,
par:cularly in the face of emerging variants.

Date of Award	1 Jul 2024
Original language	English
Awarding Institution	University of Namur
Sponsors	Qualiblood, Clinique Saint Luc de Bouge & University of Namur
Supervisor	Jonathan Douxfils (Supervisor), Jean-Michel Dogne (Supervisor), Nicolas Dauby (Jury), Isabelle Desombere (Jury), Nicolas Franco (Jury), Damien Gruson (Jury) & Mario Plebani (Jury)