Résilience - COVID-19 - Résilience - Coronavirus disease 2019

Evaluation of IgA neutralizing capacity against SARS-CoV-2 variants – MUCOVID

Evaluating IgA neutralizing capacity against SARS-CoV-2 variants of concern.

Evaluating IgA neutralizing capacity against SARS-CoV-2 variants of concern

Main issues and general objectives

Immunoglobulin A (IgA), the main antibody at mucosal surfaces, plays a crucial role in protecting the human host against infection by neutralizing viruses and impeding their attachment to epithelial cells. Consistent with the fact that SARS-CoV-2 spreads via the nasopharynx, SARS-CoV-2-specific IgA is rapidly produced after infection and efficiently contributes to virus neutralization. Dimeric IgA was reported to be 10 to 15 times more potent than its IgG equivalent, suggesting that this isotype may be of particular interest for the development of novel monoclonal antibodies with virus-neutralizing capacity.The efficacy of natural infection-induced IgA will be compared with that of vaccine-induced IgA, providing important insight into mucosal protection triggered by COVID-19 vaccines. Deciphering the mucosal humoral response in the context of SARS-CoV-2 variants will help to develop suitable vaccine boosters and to identify biomarkers of vaccine efficacy. The secondary objective of this project is to identify biomarkers representative of efficacy and safety of COVID-19 vaccination in patients with autoimmune diseases.

All IgA formats was purified from broncho-alveolar lavages sampled from severe COVID-19 patients. Sécretory IgA neutralization has been compared with paired serum IgA and BAL IgG. Neutralization potential has been assessed using a pseudoneutralization assay.
About 160 lupus patients has been included in this study. Clinical follow-up and immunological data (antibody-secreting cells and B cells analysis, SARS-CoV-2 specific antibodies levels and serum neutralization capacity) has been recorded for 42 days after SARS-CoV-2 vaccination.

Strikingly, mucosal IgA preparations were twice more potent at neutralizing VOCs than paired IgG fractions, reinforcing the view that IgA may exert virus surveillance beyond mutational events. Previous reports showed that SARS-CoV-2-neutralizing IgA persist at mucosal sites up to 73 days after infection. Multivalent IgA, induced by SARS-CoV-2 infection, could therefore constitute an efficient natural barrier against SARS-CoV-2 variants, likely to provide at least partial protection against re-infections. Unexpectedly, we found SARS-CoV-2-specific IgA in breast milk of lactating women suggesting that messenger RNA vaccines elicit multivalent IgA in secretions.

BNT162b2 was well tolerated and no statistically significant variations of BILAG and SLEDAI scores were observed throughout the study in lupus patients with active and inactive disease at baseline. Mycophenolate Mofetil (MMF) and Methotrexate (MTX) treatments were associated with drastically reduced BNT162b2 antibody-response (regression coefficient ß=-78; p=0.007, ß=-122; p< 0.001, respectively). Anti-spike antibody response was positively associated with baseline total IgG serum levels, naïve B cell frequencies (ß=2; p=0.018, ß=2.5; p=0.003) and SARS-CoV-2-specific T cell response (r=0.462; p=0.003). In responders, serum neutralization activity decreased against VOCs bearing the E484K mutation but remained detectable in a majority of patients.

Finally, mucosal IgA would offer broader protection against VOCs as compared to monomeric IgG, whose measure is often taken as the sole surrogate of immune protection. In light of these results we would argue that serum IgG-based parameters might over-estimate the immune evasion potential of VOCs.

MMF, MTX and poor baseline humoral immune status, particularly: low naïve B cell frequencies, are independently associated with impaired BNT162b2 mRNA antibody response, delineating SLE patients who might need adapted vaccine regimens and follow-up.

These results has been published in Annals of Rheumatic Diseases (see press release : www.aphp.fr/contenu/bonne-tolerance-du-vaccin-bnt162b2-pfizer-biontech-et-bonne-efficacite-de-la-reponse)
Results about IgA neutralizing capacity against VOCs are under review.

Immunoglobulin A (IgA), the main antibody at mucosal surfaces, plays a crucial role in protecting the human host against infection by neutralizing viruses and impeding their attachment to epithelial cells. Consistent with the fact that SARS-CoV-2 spreads via the nasopharynx, SARS-CoV-2-specific IgA is rapidly produced after infection and efficiently contributes to virus neutralization. Dimeric IgA was reported to be 10 to 15 times more potent than its IgG equivalent, suggesting that this isotype may be of particular interest for the development of novel monoclonal antibodies with virus-neutralizing capacity.
An exceptional effort started on March 2020 with the Intensive care Unit and Internal Medicine Departments at the Pitié-Salpêtrière Hospital that led to the constitution of a biobank of serum and broncho-alevolar lavages from COVID-19 patients including all pertinent ethical authorizations. Because of the availability of these clinical samples, the goal of the present project is to rapidly evaluate IgA-neutralizing potential against emergent SARS-CoV-2 variants. The efficacy of natural infection-induced IgA will be compared with that of vaccine-induced IgA, providing important insight into mucosal protection triggered by COVID-19 vaccines. Deciphering the mucosal humoral response in the context of SARS-CoV-2 variants will help to develop suitable vaccine boosters and to identify biomarkers of vaccine efficacy.

Project coordination

Delphine Sterlin (Delphine Sterlin)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CIMI-Paris Delphine Sterlin

Help of the ANR 48,600 euros
Beginning and duration of the scientific project: April 2021 - 6 Months

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