Little is known about the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or SARS2) vaccine breakthrough infections (BTIs) on the magnitude and breadth of the T cell repertoire after exposure to different variants. We studied samples from individuals who experienced symptomatic BTIs during Delta or Omicron waves. In the pre-BTI samples, 30% of the donors exhibited substantial immune memory against non-S (spike) SARS2 antigens, consistent with previous undiagnosed asymptomatic SARS2 infections. Following symptomatic BTI, we observed (1) enhanced S-specific CD4 and CD8 T cell responses in donors without previous asymptomatic infection, (2) expansion of CD4 and CD8 T cell responses to non-S targets (M, N, and nsps) independent of SARS2 variant, and (3) generation of novel epitopes recognizing variant-specific mutations. These variant-specific T cell responses accounted for 9%-15% of the total epitope repertoire. Overall, BTIs boost vaccine-induced immune responses by increasing the magnitude and by broadening the repertoire of T cell antigens and epitopes recognized.
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Therapeutic antibodies are an important tool in the arsenal against coronavirus infection. However, most antibodies developed early in the pandemic have lost most or all efficacy against newly emergent strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), particularly those of the Omicron lineage. Here, we report the identification of a panel of vaccinee-derived antibodies that have broad-spectrum neutralization activity. Structural and biochemical characterization of the three broadest-spectrum antibodies reveal complementary footprints and differing requirements for avidity to overcome variant-associated mutations in their binding footprints. In the K18 mouse model of infection, these three antibodies exhibit protective efficacy against BA.1 and BA.2 infection. This study highlights the resilience and vulnerabilities of SARS-CoV-2 antibodies and provides road maps for further development of broad-spectrum therapeutics.
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

To assess the safety of Pfizer-BioNTech COVID-19 mRNA BNT162b2 vaccine (Comirnaty®) among patients with the anamnesis of paediatric inflammatory syndrome temporally associated with COVID-19 (PIMS-TS), we conducted a prospective cohort study of 21 patients with history of PIMS (PIMS group, median age 7.4 years, 71% male) and 71 healthy controls without such an anamnesis (CONTROL group, median age 9.0 years, 39% male) aged 5-18 years. Among them, 85 patients (all PIMS patients and 64 CONTROL patients) completed the two dose schedule of vaccination administered 21 days apart and 7 children in the CONTROL group received a single, age appropriate dose of a COVID-19 mRNA BNT162b2 vaccine during the study period. The frequency and character of reported adverse events (AEs) after each dose and results of flow cytometry (FC) 3 weeks after a second dose were compared between those groups. COVID-19 mRNA BNT162b2 vaccine safety profile was very good and comparable in both groups. No severe AEs were observed. 30% of all patients reported some general AE after any vaccine dose and 46% - some local AE. Frequency of reported AEs did not differ between groups except for local hardening at injection site, more common in PIMS group (20% vs 4% after any vaccine dose, p = 0,02). All AEs were benign, general AEs lasted up to 5 days and localised - up to 6 days after a vaccine dose. COVID-19 mRNA BNT162b2 vaccine did not induce any PIMS-like symptoms in any patient. We did not observe any significant T cells or B cells subset abnormalities in the PIMS group compared to the CONTROL group three weeks after a second dose except for terminally differentiated effector memory T cells that were higher in PIMS group (p < 0.0041). To sum up COVID-19 mRNA BNT162b2 vaccine in children with PIMS-TS was safe. Further studies are required to support our findings.
Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Clinically, xenotransplantation often leads to T-cell-mediated graft rejection. Immunosuppressive agents including polyclonal regulatory T cells (poly-Tregs) promote global immunosuppression, resulting in serious infections and malignancies in patients. Xenoantigen-expanded Tregs (xeno-Tregs) have become a promising immune therapy strategy to protect xenografts with fewer side effects. In this study, we aimed to identify an efficient and stable subset of xeno-Tregs. We enriched CD27+ xeno-Tregs using cell sorting and evaluated their suppressive functions and stability in vitro via mixed lymphocyte reaction (MLR), real-time polymerase chain reaction, inflammatory induction assay, and Western blotting. A STAT5 inhibitor was used to investigate the relationship between the function and stability of CD27+ xeno-Tregs and the JAK3-STAT5 signaling pathway. A humanized xenotransplanted mouse model was used to evaluate the function of CD27+ xeno-Tregs in vivo. Our results show that CD27+ xeno-Tregs express higher levels of Foxp3, cytotoxic T-lymphocyte antigen-4 (CTLA4), and Helios and lower levels of interleukin-17 (IL-17) than their CD27- counterparts. In addition, CD27+ xeno-Tregs showed enhanced suppressive function in xeno-MLR at ratios of 1:4 and 1:16 of Tregs:responder cells. Under inflammatory conditions, a lower percentage of CD27+ xeno-Tregs secretes IL-17 and interferon-γ (IFN-γ). CD27+ xeno-Tregs demonstrated an upregulated JAK3-STAT5 pathway compared with that of CD27- xeno-Tregs and showed decreased Foxp3, Helios, and CTLA4 expression after addition of STAT5 inhibitor. Mice that received porcine skin grafts showed a normal tissue phenotype and less leukocyte infiltration after reconstitution with CD27+ xeno-Tregs. Taken together, these data indicate that CD27+ xeno-Tregs may suppress immune responses in a xenoantigen-specific manner, which might be related to the activation of the JAK3-STAT5 signaling pathway.

The ongoing evolution of SARS-CoV-2 requires monitoring the capability of immune responses to cross-recognize Variants of Concern (VOC). In this cross-sectional study, we examined serological and cell-mediated immune memory to SARS-CoV-2 variants, including Omicron, among a cohort of 18-21-year-old Marines with a history of either asymptomatic or mild SARS-CoV-2 infection 6 to 14 months earlier. Among the 210 participants in the study, 169 were unvaccinated while 41 received 2 doses of mRNA-based COVID-19 vaccines. Vaccination of previously infected participants strongly boosted neutralizing and binding activity and memory B and T cell responses including the recognition of Omicron, compared to infected but unvaccinated participants. Additionally, no measurable differences were observed in immune memory in healthy young adults with previous symptomatic or asymptomatic infections, for ancestral or variant strains. These results provide mechanistic immunological insights into population-based differences observed in immunity against Omicron and other variants among individuals with different clinical histories.