16/04/2026
Research Square
Hybrid heterologous immunity shapes robust antiviral responses in children and minimizes age-related immunological differences
Background: Understanding how children mount effective antiviral immune responses is critical for preparedness against current and future emerging pathogens. Acute respiratory viral infections provide a tractable human model to dissect age-specific immunity, yet the integration of humoral, cellular, and mucosal responses in children remains incompletely defined. Insights into cross-reactive and durable immune mechanisms are essential to inform vaccination strategies and pandemic readiness. Methods: 182 participants (96 children, 86 adults) from 41 families with newly confirmed SARS-CoV-2 infection were enrolled in the prospective OMI-Kids study (DRKS00029155). Repeated PCR testing, symptom monitoring, saliva sampling, and blood collection 6-8 weeks post household infection enabled detailed immune profiling. Humoral and cellular responses, including neutralization against Hu-1, BA.2, and EG.5.1, as well as HLA-restricted CD8+ T cell responses, were analyzed across distinct immunity profiles. Cytokine autoantibodies were quantified using a multiplex bead-based IgG assay. Findings: Serum and salivary IgG and IgA levels correlated strongly, supporting saliva as a reliable, non-invasive proxy for immune monitoring in children. Antibodies elicited by Hu-1-based infection or vaccination showed partial cross-reactivity to BA.2 but failed to neutralize EG.5.1. Despite limited antibody breadth, T cell-mediated immunity was conserved across variants, with no major age-dependent differences in the magnitude, HLA breadth or functionality of virus-specific T cell responses. Conclusion: These findings highlight fundamental features of antiviral immunity in children, characterized by constrained antibody breadth but robust and conserved cellular responses in the context of SARS-CoV-2 evolution. Cross-reactive T cell immunity may represent a key mechanism of protection against severe disease despite ongoing viral evolution. This work establishes a framework for leveraging acute viral infections as a human model to inform immune protection, surveillance strategies, and vaccine design for future emerging pathogens.
01/03/2026
Nature
Individualized mRNA vaccines evoke durable T cell immunity in adjuvant TNBC
Triple-negative breast cancer (TNBC) is frequently associated with metastatic relapse, even at an early stage1. Here we assessed an individualized neoantigen mRNA vaccine in 14 patients with TNBC following surgery and after neoadjuvant or adjuvant therapy. In peripheral blood of nearly all patients, high-magnitude, vaccine-induced, mostly de novo T cell responses to multiple neoantigens were detected that remained functional for several years. Characterization of individual patients revealed that a large proportion of these T cells developed into two subsets: a late-differentiated phenotype with markers indicative of 'ready-to-act' cytotoxic effector T cells, and T cells with a stem cell-like memory phenotype. Eleven patients remained relapse-free for up to six years post-vaccination. Recurrence occurred in three patients: the individual with the weakest vaccine-induced T cell response relapsed, but achieved complete remission on subsequent anti-PD-1 therapy; another patient had a tumour with low major histocompatibility complex (MHC) class I expression with MHC class I-deficient cells growing out under vaccination; and the third patient was BRCA-positive and had a recurrence from a genetically distinct primary tumour. These findings demonstrate the feasibility of individualized RNA vaccines in TNBC, document persistence of vaccine-induced, functional neoantigen-specific T cells and provide insights into possible immune escape mechanisms that will guide future approaches.
20/02/2024
Cell reports. Medicine
Merkel cell polyomavirus-specific and CD39+CLA+ CD8 TÊcells as blood-based predictive biomarkers for PD-1 blockade in Merkel cell carcinoma
Merkel cell carcinoma is a skin cancer often driven by Merkel cell polyomavirus (MCPyV) with high rates of response to anti-PD-1 therapy despite low mutational burden. MCPyV-specific CD8 TÊcells are implicated in anti-PD-1-associated immune responses and provide a means to directly study tumor-specific TÊcell responses to treatment. Using mass cytometry and combinatorial tetramer staining, we find that baseline frequencies of blood MCPyV-specific cells correlated with response and survival. Frequencies of these cells decrease markedly during response to therapy. Phenotypes of MCPyV-specific CD8 TÊcells have distinct expression patterns of CD39, cutaneous lymphocyte-associated antigen (CLA), and CD103. Correspondingly, overall bulk CD39+CLA+ CD8 TÊcell frequencies in blood correlate with MCPyV-specific cell frequencies and similarly predicted favorable clinical outcomes. Conversely, frequencies of CD39+CD103+ CD8 TÊcells are associated with tumor burden and worse outcomes. These cell subsets can be useful as biomarkers and to isolate blood-derived tumor-specific TÊcells.
20/02/2024
Cell reports. Medicine
Merkel cell polyomavirus-specific and CD39+CLA+ CD8 T cells as blood-based predictive biomarkers for PD-1 blockade in Merkel cell carcinoma
Merkel cell carcinoma is a skin cancer often driven by Merkel cell polyomavirus (MCPyV) with high rates of response to anti-PD-1 therapy despite low mutational burden. MCPyV-specific CD8 T cells are implicated in anti-PD-1-associated immune responses and provide a means to directly study tumor-specific T cell responses to treatment. Using mass cytometry and combinatorial tetramer staining, we find that baseline frequencies of blood MCPyV-specific cells correlated with response and survival. Frequencies of these cells decrease markedly during response to therapy. Phenotypes of MCPyV-specific CD8 T cells have distinct expression patterns of CD39, cutaneous lymphocyte-associated antigen (CLA), and CD103. Correspondingly, overall bulk CD39+CLA+ CD8 T cell frequencies in blood correlate with MCPyV-specific cell frequencies and similarly predicted favorable clinical outcomes. Conversely, frequencies of CD39+CD103+ CD8 T cells are associated with tumor burden and worse outcomes. These cell subsets can be useful as biomarkers and to isolate blood-derived tumor-specific T cells.
23/09/2022
Nature communications
Accumulation of mutations in antibody and CD8 T cell epitopes in a B cell depleted lymphoma patient with chronic SARS-CoV-2 infection
Antibodies against the spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can drive adaptive evolution in immunocompromised patients with chronic infection. Here we longitudinally analyze SARS-CoV-2 sequences in a B cell-depleted, lymphoma patient with chronic, ultimately fatal infection, and identify three mutations in the spike protein that dampen convalescent plasma-mediated neutralization of SARS-CoV-2. Additionally, four mutations emerge in non-spike regions encoding three CD8 T cell epitopes, including one nucleoprotein epitope affected by two mutations. Recognition of each mutant peptide by CD8 T cells from convalescent donors is reduced compared to its ancestral peptide, with additive effects resulting from double mutations. Querying public SARS-CoV-2 sequences shows that these mutations have independently emerged as homoplasies in circulating lineages. Our data thus suggest that potential impacts of CD8 T cells on SARS-CoV-2 mutations, at least in those with humoral immunodeficiency, warrant further investigation to inform on vaccine design.