Antibody affinity maturation and plasma IgA associate with clinical outcome in hospitalized COVID-19 patients

Abstract

Hospitalized COVID-19 patients often present with a large spectrum of clinical symptoms. There is a critical need to better understand the immune responses to SARS-CoV-2 that lead to either resolution or exacerbation of the clinical disease. Here, we examine longitudinal plasma samples from hospitalized COVID-19 patients with differential clinical outcome. We perform immune-repertoire analysis including cytokine, hACE2-receptor inhibition, neutralization titers, antibody epitope repertoire, antibody kinetics, antibody isotype and antibody affinity maturation against the SARS-CoV-2 prefusion spike protein. Fatal cases demonstrate high plasma levels of IL-6, IL-8, TNFα, and MCP-1, and sustained high percentage of IgA-binding antibodies to prefusion spike compared with non-ICU survivors. Disease resolution in non-ICU and ICU patients associates with antibody binding to the receptor binding motif and fusion peptide, and antibody affinity maturation to SARS-CoV-2 prefusion spike protein. Here, we provide insight into the immune parameters associated with clinical disease severity and disease-resolution outcome in hospitalized patients that could inform development of vaccine/therapeutics against COVID-19.

Understanding neutralising antibodies against SARS-CoV-2 and their implications in clinical practice

“…In the case of COVID-19, however, their roles remain less defined, e.g. the predictive value of neutralisation with regard to disease outcome [ 40 , 55 ].…”

“…The absence of NAb response early after disease onset showed the strongest correlation with mortality and delayed viral control—more so than the difference in NAb titre. Almost all patients develop NAb by week 4 of infection, and severely ill patients exhibit higher peak, faster and stronger NAb titres compared to mild cases [ 40 , 55 , 56 ]. Hospitalised patients harbour greater NAb titres than mildly symptomatic and asymptomatic patients whose titres were below the detection limit in half of the cases [ 57 ].…”

Epitope diversity of SARS-CoV-2 hyperimmune intravenous human immunoglobulins and neutralization of variants of concern

“…Recently, we showed that SARS-CoV-2 spike GFPDL can recognize both linear, conformational and neutralizing epitopes in the post-vaccination sera of rabbits and post-SARS-CoV-2 infection sera in adults and the elderly. Adsorption of immune sera with the SARS-CoV-2-S-GFPDL removed >90% of the anti-spike binding antibody in postinfection human sera (Ravichandran et al, 2020(Ravichandran et al, , 2021Tang et al, 2021).…”

“…A gIII display-based phage vector, fSK-9-3, was used where the desired polypeptide can be displayed on the surface of the phage as a gIII-fusion protein. Purified DNA containing spike gene was digested with DNaseI to obtain gene fragments of 50-1,500 bp size range (18-500 amino acids) and used for GFPDL construction (Khurana et al, 2020;Ravichandran et al, 2020;Tang et al, 2021).…”

Pause in immunosuppressive treatment results in improved immune response to SARS-CoV-2 vaccine in autoimmune patient: a case report

“…Neutralisation titres were measured using a pseudovirus neutralisation assay (PsVNA) as described previously. 6 No SARS-CoV-2 neutralising antibodies were detected in plasma at 4 weeks after the second mRNA-1273 vaccination. In the same assay, age-matched (65-77 years old) immunocompetent individuals (healthcare workers who were not on any immunosuppressive drugs and vaccinated with two doses of mRNA-1273 SARS-CoV-2 vaccine in Maryland) generated neutralising antibody titres (PsVNA50: 50% reduction in neutralisation titres) ranging between 1:451 and 1:3293 against the WA-1 strain following mRNA-1273 vaccination.…”