Serological analysis reveals an imbalanced IgG subclass composition associated with COVID-19 disease severity

Yates, Jennifer L.; Ehrbar, Dylan; Hunt, Danielle T.; Girardin, Roxanne C.; Dupuis, Alan P.; Payne, Anne F.; Sowizral, Mycroft; Varney, Scott; Kulas, Karen E.; Demarest, Valerie L.; Howard, Kelly M.; Carson, Kyle; Hales, Margaux; Ejemel, Monir; Li, Qi; Wang, Yang; Peredo-Wende, Ruben; Ramani, Ananthakrishnan; Singh, Gurpreet; Strle, Klemen; Mantis, Nicholas J.; McDonough, Kathleen A.; Lee, William T.

doi:10.1016/j.xcrm.2021.100329

Cited by 73 publications

(98 citation statements)

References 40 publications

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“…They may be related to the temporal model of affinity maturation, with the IgG3 response earlier, with a switch to a higher affinity IgG1 antibody response later [ 26 ]. Also, it has been reported that the time-point of donation as well as disease severity are factors influencing the outcome of the antibody profile [ 27 ]. Alternatively, the variations could be due to methodological differences in how the neutralization assays were conducted.…”

Section: Discussionmentioning

confidence: 99%

IgG3 and IgM Identified as Key to SARS-CoV-2 Neutralization in Convalescent Plasma Pools

et al. 2022

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Analysis of convalescent plasma derived from individuals has shown that IgG3 has the most important role in binding to SARS-CoV-2 antigens; however, this has not yet been confirmed in large studies, and the link between binding and neutralization has not been confirmed. By analyzing plasma pools consisting of 247–567 individual convalescent donors, we demonstrated the binding of IgG3 and IgM to Spike-1 protein and the receptor-binding domain correlates strongly with viral neutralization in vitro. Furthermore, despite accounting for only approximately 12% of total immunoglobulin mass, collectively IgG3 and IgM account for approximately 80% of the total neutralization. This may have important implications for the development of potent therapies for COVID-19, as it indicates that hyperimmune globulins or convalescent plasma donations with high IgG3 concentrations may be a highly efficacious therapy.

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Section: Discussionmentioning

confidence: 99%

IgG3 and IgM Identified as Key to SARS-CoV-2 Neutralization in Convalescent Plasma Pools

et al. 2022

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“…We similarly documented elevation in RBD-specific IgG1 and IgG3 levels in the serum of all mothers after the second vaccine dose. Recent studies have described the dominance of IgG1 and IgG3 response over IgG2 and IgG4 following SARS-CoV-2 mRNA vaccination and with natural infection (24)(25)(26). The lower IgM levels after the second vaccine dose may be related to enhanced class switching to IgG and IgA isotypes after this dose.…”

Section: Discussionmentioning

confidence: 99%

Neutralizing Activity and SARS-CoV-2 Vaccine mRNA Persistence in Serum and Breastmilk After BNT162b2 Vaccination in Lactating Women

et al. 2022

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BackgroundThere is limited information on the functional neutralizing capabilities of breastmilk SARS-CoV-2-specific antibodies and the potential adulteration of breastmilk with vaccine mRNA after SARS-CoV-2 mRNA vaccination.MethodsWe conducted a prospective cohort study of lactating healthcare workers who received the BNT162b2 vaccine and their infants. The presence of SARS-CoV-2 neutralizing antibodies, antibody isotypes (IgG, IgA, IgM) and intact mRNA in serum and breastmilk was evaluated at multiple time points using a surrogate neutralizing assay, ELISA, and PCR, over a 6 week period of the two-dose vaccination given 21 days apart.ResultsThirty-five lactating mothers, median age 34 years (IQR 32-36), were included. All had detectable neutralizing antibodies in the serum immediately before dose 2, with significant increase in neutralizing antibody levels 7 days after this dose [median 168.4 IU/ml (IQR 100.7-288.5) compared to 2753.0 IU/ml (IQR 1627.0-4712.0), p <0.001]. Through the two vaccine doses, all mothers had detectable IgG1, IgA and IgM isotypes in their serum, with a notable increase in all three antibody isotypes after dose 2, especially IgG1 levels. Neutralizing antibodies were detected in majority of breastmilk samples a week after dose 2 [median 13.4 IU/ml (IQR 7.0-28.7)], with persistence of these antibodies up to 3 weeks after. Post the second vaccine dose, all (35/35, 100%) mothers had detectable breastmilk SARS-CoV-2 spike RBD-specific IgG1 and IgA antibody and 32/35 (88.6%) mothers with IgM. Transient, low intact vaccine mRNA levels was detected in 20/74 (27%) serum samples from 21 mothers, and 5/309 (2%) breastmilk samples from 4 mothers within 1 weeks of vaccine dose. Five infants, median age 8 months (IQR 7-16), were also recruited - none had detectable neutralizing antibodies or vaccine mRNA in their serum.ConclusionMajority of lactating mothers had detectable SARS-CoV-2 antibody isotypes and neutralizing antibodies in serum and breastmilk, especially after dose 2 of BNT162b2 vaccination. Transient, low levels of vaccine mRNA were detected in the serum of vaccinated mothers with occasional transfer to their breastmilk, but we did not detect evidence of infant sensitization. Importantly, the presence of breastmilk neutralising antibodies likely provides a foundation for passive immunisation of the breastmilk-fed infant.

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“…More surprising was that, when detected, the MALDI-ToF mass spectra of total IgG3Hc was also significantly higher in the COVID-19 ARDS convalescent plasma (see figure 2). It had been reported that a dominance of anti-SARS-CoV2 IgG3 occurs in the immune responses to SARS-CoV2 in those who died from COVID-19 [14]. We had shown an increase in the mass of IgG3Hc bound to SARS-CoV2 prefusion Spike protein and eluted from magnetic bead to which it was conjugated [13].…”

Section: Discussionmentioning

confidence: 62%

“…infection [14]. The possibility is that elevated glycated albumin along with elevated levels of IgG3 characterised by an increased molecular mass (due to glycation/glycosylation) may act as biomarkers of susceptibility to develop ARDS as a result of SARS-CoV2 infection.…”

Section: Introductionmentioning

confidence: 99%

Direct detection of humoral marker corelates of COVID-19, glycated HSA and hyperglycosylated IgG3, by MALDI-ToF mass spectrometry

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Zmuidinaite

et al. 2021

Preprint

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The prefusion Spike protein of SARS-CoV2 binds advanced glycation end product (AGE) glycated human serum albumin (HSA) and a higher mass, hyperglycosylated/glycated, IgG3, as determined by matrix assisted laser desorption mass spectrometry (MALDI-ToF MS). We set out to investigate if the total blood plasma of patients who had recovered from acute respiratory distress as a result of COVID-19, contained more glycated HSA and higher mass (glycosylated/glycated) IgG3 than those with only clinically mild or asymptomatic infections. A direct dilution and disulphide bond reduction method was development and applied to plasma samples from SARS-CoV2 seronegative (N = 30) and seropositive (N = 31) healthcare workers and 38 convalescent plasma samples from patients who had been admitted with acute respiratory distress syndrome (ARDS) associated with COVID-19.Patients recovering from COVID-19 ARDS had significantly higher mass, AGE-glycated HSA and higher mass IgG3 levels. This would indicate that increased levels and/or ratios of hyper-glycosylation (probably terminal sialic acid) IgG3 and AGE glycated HSA may be predisposition markers for development of ARDS as a result of COVID-19 infection. Furthermore, rapid direct analysis of plasma samples by MALDI-ToF MS for such humoral immune correlates of COVID-19 presents a feasible screening technology for the most at risk; regardless of age or known health conditions.Abstract Figure

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Serological analysis reveals an imbalanced IgG subclass composition associated with COVID-19 disease severity

Cited by 73 publications

References 40 publications

IgG3 and IgM Identified as Key to SARS-CoV-2 Neutralization in Convalescent Plasma Pools

IgG3 and IgM Identified as Key to SARS-CoV-2 Neutralization in Convalescent Plasma Pools

Neutralizing Activity and SARS-CoV-2 Vaccine mRNA Persistence in Serum and Breastmilk After BNT162b2 Vaccination in Lactating Women

Direct detection of humoral marker corelates of COVID-19, glycated HSA and hyperglycosylated IgG3, by MALDI-ToF mass spectrometry

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