Abstract Multisystem inflammatory syndrome in children (MIS-C) can complicate infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but differences in the immune responses during MIS-C compared to coronavirus disease 2019 (COVID-19) are poorly understood. We longitudinally compared the amounts and avidity of plasma anti-nucleocapsid (N) and spike (S) antibodies, phenotypes of B cells, and numbers of virus-specific antibody-secreting cells in circulation of children hospitalized with COVID-19 (n = 10) and with MIS-C (n = 12). N-specific immunoglobulin G (IgG) was higher early after presentation for MIS-C than COVID-19 patients and avidity of N- and S-specific IgG at presentation did not mature further during follow-up as it did for COVID-19. Both groups had waning proportions of B cells in circulation and decreasing but sustained production of virus-specific antibody-secreting cells for months. Overall, B-cell responses were similar, but those with MIS-C demonstrated a more mature antibody response at presentation compared to COVID-19, suggesting a postinfectious entity. 

OUP accepted manuscript

Abstract Multisystem inflammatory syndrome in children (MIS-C) can complicate infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but differences in the immune responses during MIS-C compared to coronavirus disease 2019 (COVID-19) are poorly understood. We longitudinally compared the amounts and avidity of plasma anti-nucleocapsid (N) and spike (S) antibodies, phenotypes of B cells, and numbers of virus-specific antibody-secreting cells in circulation of children hospitalized with COVID-19 (n = 10) and with MIS-C (n = 12). N-specific immunoglobulin G (IgG) was higher early after presentation for MIS-C than COVID-19 patients and avidity of N- and S-specific IgG at presentation did not mature further during follow-up as it did for COVID-19. Both groups had waning proportions of B cells in circulation and decreasing but sustained production of virus-specific antibody-secreting cells for months. Overall, B-cell responses were similar, but those with MIS-C demonstrated a more mature antibody response at presentation compared to COVID-19, suggesting a postinfectious entity.

/pdf/b-cell-responses-in-hospitalized-severe-acute-respiratory-7hgk45hg.pdf

B-Cell Responses in Hospitalized Severe Acute Respiratory Syndrome Coronavirus 2–Infected Children With and Without Multisystem Inflammatory Syndrome

Abstract Antigen-specific class-switched antibodies are detected at the same time or even before IgM in serum of non-vaccinated individuals infected with SARS-CoV-2. These derive from the first wave of plasmablasts formed. Hence, the phenotype and specificity of plasmablasts can reveal information about early B-cell activation. Here we have analyzed B cells and plasmablasts circulating in blood of COVID-19 patients not previously exposed to SARS-CoV-2 during and after disease. We find that during infection with the original Wuhan strain, plasmablasts in blood produce IgA1, IgG1, and IgM, and that most express CCR10 and integrin β1, only some integrin β7, while the majority lack CCR9. Plasmablast-secreted antibodies are reactive to the spike (S) and nucleocapsid (N) proteins of the Wuhan strain as well as later variants of concern, but also bind S proteins from endemic and non-circulating betacoronaviruses. In contrast, after recovery, antibodies produced from memory B cells target variants of SARS-CoV-2 and SARS-CoV-1 but compared to previously non-infected individuals do not show increased binding to endemic coronaviruses. This suggests that the early antibody response to a large extent stems from pre-existing cross-reactive class-switched memory B cells, and that although newly formed memory cells target the novel SARS-CoV-2 virus the numbers of broadly cross-reactive memory B cells do not increase extensively. The observations give insight into the role of pre-existing memory B cells in early antibody responses to novel pathogens and may explain why class-switched antibodies are detected early in the serum of COVID-19 patients.

/pdf/plasmablasts-in-previously-immunologically-naive-covid-19-24c024dv.pdf

Plasmablasts in previously immunologically naïve COVID-19 patients express markers indicating mucosal homing and secrete antibodies cross-reacting with SARS-CoV-2 variants and other beta-coronaviruses

Understanding the development and sustainability of the virus-specific protective immune response to infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remains incomplete with respect to the appearance and disappearance of virus-specific antibody-secreting cells (ASCs) in circulation. Therefore, we performed cross-sectional and longitudinal analyses of peripheral blood mononuclear cells and plasma collected from 55 hospitalized patients up to 4 months after onset of COVID-19 symptoms. Spike (S)- and nucleocapsid (N)-specific IgM and IgG ASCs appeared within 2 weeks accompanied by flow cytometry increases in double negative plasmablasts consistent with a rapid extrafollicular B cell response. Total and virus-specific IgM and IgG ASCs peaked at 3-4 weeks and were still being produced at 3-4 months accompanied by increasing antibody avidity consistent with a slower germinal center B cell response. N-specific ASCs were produced for longer than S-specific ASCs and avidity maturation was greater for antibody to N than S. Patients with more severe disease produced more S-specific IgM and IgG ASCs than those with mild disease and had higher levels of N- and S-specific antibody. Women had more B cells in circulation than men and produced more S-specific IgA and IgG and N-specific IgG ASCs. Flow cytometry analysis of B cell phenotypes showed an increase in circulating B cells at 4-6 weeks with decreased percentages of switched and unswitched memory B cells. These data indicate ongoing antigen-specific stimulation, maturation, and production of ASCs for several months after onset of symptoms in patients hospitalized with COVID-19.

Andy K P Chan

Papers

Continued Virus-Specific Antibody-Secreting Cell Production, Avidity Maturation and B Cell Evolution in Patients Hospitalized with COVID-19.