Hybrid immunity by two COVID-19 mRNA vaccinations and one breakthrough infection provides a robust and balanced cellular immune response as basic immunity against severe acute respiratory syndrome coronavirus 2.

This longitudinal prospective controlled multicenter study aimed to monitor immunity generated by three exposures caused by breakthrough infections (BTI) after COVID-19-vaccination considering pre-existing cell-mediated immunity to common-corona-viruses (CoV) which may impact cellular reactivity against SARS-CoV-2. Anti-SARS-CoV-2-spike-IgG antibodies (anti-S-IgG) and cellular reactivity against Spike-(S)- and nucleocapsid-(N)-proteins were determined in fully-vaccinated (F) individuals who either experienced BTI (F+BTI) or had booster vaccination (F+Booster) compared to partially vaccinated (P+BTI) and unvaccinated (U) from 1 to 24 weeks post PCR-confirmed infection. High avidity anti-S-IgG were found in F+BTI compared to U, the latter exhibiting increased long-lasting pro-inflammatory cytokines to S-stimulation. CoV was associated with higher cellular reactivity in U, whereas no association was seen in F. The study illustrates the induction of significant S-specific cellular responses in F+BTI building-up basic immunity by three exposures. Only U seem to benefit from pre-existing CoV immunity but demonstrated inflammatory immune responses compared to F+BTI who immunologically benefit from enhanced humoral and cellular immunity after BTI. This study demonstrates that individuals with hybrid immunity from COVID-19-vaccination and BTI acquire a stable humoral and cellular immune response that is maintained for at least 6 months. Our findings corroborate recommendations by health authorities to build on basic immunity by three S-protein exposures.

Heterologous and homologous COVID-19 mRNA vaccination schemes for induction of basic immunity show similar immunogenicity regarding long-term spike-specific cellular immunity in healthcare workers.

Healthcare workers (HCWs) are recommended to receive at least three spike-antigen exposures to generate basic immunity and to mediate herd protection of vulnerable patients. So far, less attention has been put on the cellular immune response induced by homologous (three BTN162b2mRNA doses) or heterologous (mRNA-1273 as third dose building on two BTN162bmRNA doses) and the immunological impact of breakthrough infections (BTIs). Therefore, in 356 vaccinated HCWs with or without BTIs the Anti-SARS-CoV-2-Spike-IgG concentrations and avidities and B- and T-cell-reactivity against SARS-CoV-2-Spike-S1- and Nucleocapsid-antigens were assessed with Interferon-gamma-ELISpot and by flow-cytometry. HCWs who had hybrid immunity due to BTIs exhibited strong T-cell-reactivity against the Spike-S1-antigen. A lasso regression model revealed a significant reduction in T-cell immune responses among smokers (p < 0.0001), with less significant impact observed for age, sex, heterologous vaccination, body-mass-index, Anti-Nucleocapsid T-cell reactivity, days since last COVID-19-immunization, and Anti-SARS-CoV-2-Spike-IgG. Although subgroup analysis revealed higher Anti-SARS-CoV-2-Spike-IgG after heterologous vaccination, similar cellular reactivity and percentages of Spike-reactive T- and B-cells were found between homologous and heterologous vaccination. Anti-SARS-CoV-2-Spike-IgG concentrations and avidity significantly correlated with activated T-cells. CD4 + and CD8 + responses correlated with each other. A strong long-term cellular immune response should be considered as baseline for recommendations of booster doses in HCWs with prioritization of smokers. HCWs presented significant T-cellular reactivity towards Spike-S1-antigen with particularly strong responses in hybrid immunized HCWs who had BTIs. HCWs without BTI presented similar percentages of Spike-specific B- and T-cells between homologous or heterologous vaccination indicating similar immunogenicity for both mRNA vaccines, BNT162b2mRNA and mRNA-1273.

Mesenchymal stem cells modulate IL-17 and IL-9 production induced by Th17-inducing cytokine conditions in autoimmune arthritis: an explorative analysis

Abstract Background The importance of proinflammatory T-cells and their cytokine production in patients with autoimmune arthritis has been widely described. Due to their immunomodulatory properties, mesenchymal stem cells (MSCs) have come into focus as a potential therapeutic concept. The aim of this study was to investigate the influence of MSCs on the phenotype, cytokine profile, and functionality of naive and non-naive CD4+ T-cells from healthy donors (HD) and patients with autoimmune arthritis under Th17-cytokine polarizing conditions in an explorative way using a transwell system prohibiting any cell-cell-contact. Methods Magnetically isolated naive and non-naive CD4+ T-cells were stimulated under Th17-polarizing proinflammatory cytokine conditions in presence and absence of bone marrow derived mesenchymal stromal cells (MSCs). After an incubation period of 6 days, the proportions of the T-cell subpopulations TEMRA (CD45RA+CD27−), memory (CD45RA−CD27+), effector (CD45RA−CD27−) and naive cells (CD45RA+CD27+) were determined. Quantitative immunofluorescence intensity was used as a measure for IL-9, IL-17 and IFN-γ production in each subpopulation. Results In isolated naive CD4+ T-cells from HD and patients, MSCs suppressed the differentiation of naive towards an effector phenotype while memory and naive cells showed higher percentages in culture with MSCs. In patients, MSCs significantly decreased the proportion of IL-9 and IL-17 producing effector T-cells. MSCs also reduced IFN-γ production in the naive and memory phenotype from HD. Conclusions The results of the study indicate significant immunomodulatory properties of MSCs, as under Th17-polarizing conditions MSCs are still able to control T-cell differentiation and proinflammatory cytokine production in both HD and patients with autoimmune arthritis.