key: cord-0688730-2r50zfo6
authors: Wilson, Jeffrey M.; Platts‐Mills, Thomas A. E.; Keshavarz, Behnam
title: Reply to: The antibody response to the glycan α‐Gal correlates with COVID‐19 symptoms
date: 2021-04-23
journal: J Med Virol
DOI: 10.1002/jmv.27022
sha: 748529aa00312f2c0b5ac79bd7c3a71bf7a0be70
doc_id: 688730
cord_uid: 2r50zfo6

We read with interest two recent papers which discussed possible connections between the immune response to galactose-⍺-1,3-galactose (⍺-Gal) and COVID-19(1, 2). This article is protected by copyright. All rights reserved.

Reply to: The antibody response to the glycan α-Gal correlates with COVID-19 symptoms To the Editor:

We read with interest two recent papers which discussed possible connections between the immune response to galactose-α-1,3galactose (α-Gal) and coronavirus disease 2019 (COVID-19). 1,2 First described nearly a hundred years ago by Landsteiner and Miller as a "B-like" blood group substance of non-primate mammals (but not higher primates), work over the last 40 years has made it clear that α-Gal is also expressed on some species of bacteria and multi-cellular parasites, and that all immunocompetent humans produce large quantities of immunoglobulin M (IgM), IgG and IgA antibodies (Ab) specific for the oligosaccharide. 3, 4 More recent research indicates that a subset of the population can also produce IgE specific for α-Gal. IgE sensitization to α-Gal has largely been attributed to tick bites and is an important cause of allergic reactions to mammalian meat and dairy. 5, 6 On this backdrop, Urra et al. reported that patients with COVID-19 had altered levels of anti-α-Gal IgG, IgM, IgA, and IgE Ab as compared to a control cohort. 1 Specifically, they found that levels of α-Gal-specific IgG, IgM, and IgE (but not IgA), were lower in patients hospitalized in an intensive care unit (ICU) with severe COVID-19 as compared to healthy uninfected controls. They also reported that relative amounts of different anti-α-Gal antibody isotypes varied in relation to disease severity.

Interestingly, they noted that IgE represented 14%-45% of the overall repertoire of anti-α-Gal antibody levels, with the highest amount of specific IgE observed in asymptomatic COVID-19 patients. The authors speculate that dysbacteriosis could have caused the reduced antibody response to α-Gal, which in turn translated to greater severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral loads and systemic inflammation. This hypothesis leads to the idea that restoring anti-α-Gal antibodies could be protective against COVID-19. This paper raises some intriguing points, but we think additional commentary is merited.

In our recent investigation of COVID-19, which utilized a quantitative ImmunoCAP-based approach, we did not observe differences in levels of anti-α-Gal IgG when comparing patients with severe COVID-19 to a reference cohort of healthy uninfected controls. 7 The explanation for the discrepancy between our findings and Urra et al. is not clear. One possibility is that inflammatory mediators which are present during acute severe COVID-19 could be interfering with one or both of our assays. However, we would highlight a recent report that used a glycan array and did not find lower anti-α-Gal IgG levels in COVID-19 patients compared to controls. 8 To look at this question in a different light, here we have extended our previous analysis by monitoring anti-α-Gal IgG levels among five patients with severe COVID-19 in which longitudinal data were available. The data indicate that levels were relatively stable across time, including at a follow-up timepoint where the patients had convalesced and recovered from their infection ( Figure 1A) . We also measured IgG to tetanus toxoid as a reference control antigen (to which most individuals are vaccinated) and found little fluctuation in antibody levels across the time points ( Figure 1B ). It is also important to note that the anti-α-Gal antibody levels reported by Urra and F I G U R E 1 Quantitative assessment of antibodies in five patients admitted to the intensive care unit (ICU) with severe COVID-19 using ImmunoCAP. (A) Immunoglobulin G (IgG) levels to galactose-α-1,3-galactose (α-Gal) assessed at day of admission (D0; median 10 days post-symptom onset), Day 7 of admission (D7; median 17 days post-symptom onset) and at a recovery follow-up clinic (median 74 days post-symptom onset). IgE levels to α-Gal were measured at the recovery timepoint, expressed in µg/ml using the same units/axis as for IgG. Two samples in which no IgE was detected were plotted as ×0.5 the technical limit of the assay. Both the IgG and IgE assays used α-Gal-HSA as the assay solid-phase, as previously described. 7 (B) IgG to tetanus toxoid was measured by ImmunoCAP using the commercial assay (Thermo-Fisher/Phadia)

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