Functionally impaired antibody response to BNT162b2 booster vaccination in CVID IgG responders

Abstract

Background: Although previous studies described the production of IgG antibodies in a subgroup of patients with common variable immunodeficiency (CVID) following messenger RNA vaccinations with BNT162b2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (CVID responders), the functionality of these antibodies in terms of avidity as measured by the dissociation rate constant (k_dis) and the antibody response to booster immunization has not been studied.

Objective: We sought to analyze in CVID responders and healthy individuals, the avidity of anti-SARS-CoV-2 serum antibodies and their neutralization capacity as measured by surrogate virus-neutralizing antibodies in addition to IgG-, IgM-, and IgA-antibody levels and the response of circulating (peripheral blood) follicular T-helper cells after a third vaccination with BNT162b2 SARS-CoV-2 messenger RNA vaccine.

Methods: Binding IgG, IgA, and IgM serum levels were analyzed by ELISA in patients with CVID responding to the primary vaccination (CVID responders, n = 10) and healthy controls (n = 41). The binding avidity of anti-spike antibodies was investigated using biolayer interferometry in combination with biotin-labeled receptor-binding-domain of SARS-CoV-2 spike protein and streptavidin-labeled sensors. Antigen-specific recall T-cell responses were assessed by measuring activation-induced markers by flow cytometry.

Results: After the third vaccination with BNT162b2, IgG-, IgM-, and IgA-antibody levels, surrogate virus-neutralizing antibody levels, and antibody avidity were lower in CVID responders than in healthy controls. In contrast, anti-SARS-CoV-2 spike protein avidity was comparable in CVID responders and healthy individuals following primary vaccination. Follicular T-helper cell response to booster vaccination in CVID responders was significantly reduced when compared with that in healthy individuals.

Conclusions: Impaired affinity maturation during booster response provides new insight into CVID pathophysiology.

Keywords: BNT162b2 booster vaccination; CVID; antibody avidity; biolayer interferometry; cTfh.

Fig 1

Antibody response following booster immunization with BNT162b2 mRNA vaccine in patients with CVID who responded to primary vaccination (CVID R) and HCs. Anti–SARS-CoV-2 IgG (A), αSpike serum antibody (AB) avidity (B), and sVNT antibody (C) levels were assessed following booster immunization (third vaccine dose) and primary vaccination (inserts, after first 2 doses of BNT162b2 mRNA vaccine). D, Correlation of anti–SARS-CoV-2 IgG (blue dots) and sVNT (black squares) vs serum antibody avidity in HCs (upper panel) and CVID R (lower panel) after booster vaccination. E, Percent of SARS-CoV-2 spike protein–specific cTfh cells after the third vaccination (unstimulated control cells showed below 0.3% Ox40 and CD25 double-positive cells). F, αSpike-IgM (upper panel) and -IgA (lower panel) antibody concentrations in serum after booster vaccination. The dotted lines indicate the cutoff for positivity (IgG, 33 RE/mL; IgM, 20 U/mL; and IgA, a ratio of 1.2). G, αSpike serum antibody (AB) avidity was measured in serum from HCs after the third vaccination (black symbols represent 2 different individuals) and from infection-naive, unvaccinated HCs spiked with a monoclonal αSpike-IgG antibody at 2 different concentrations (triangle: 47 μg/mL, inverted triangle: 24 μg/mL) with or without addition of IVIG (upper panel, final concentration 500 mg/dL), as well as after the third vaccination in healthy individuals (box plot, n = 39) as compared with IgG subclass-deficient patients receiving immunoglobulin replacement therapy (blue dots). RBD, Receptor-binding domain; RE, relative units.