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.
02/02/2026
bioRxiv : the preprint server for biology
Duration of Initial Viremia Modulates Functional Properties of HIV-specific T Cell Receptors
Virus-specific CD8+ T cells are crucial in controlling chronic human viral infections such as HIV-1, but the effect of persistent antigen exposure on T cell repertoire formation is not well understood. In this study, we examined epitope-specific CD8+ T cell repertoires in people living with HIV-1, where duration of viremia following hyperacute infection was modulated by the time of initiation of continuous suppressive antiretroviral therapy (ART). After ART-induced undetectable viremia in persons expressing the same HLA class I allele, we analyzed the impact of early (n=6) versus delayed (n=6) ART initiation on the clonotypic composition, clonotypic cross-reactivity, functional avidity and memory differentiation profile of the HIV-specific T cell repertoire restricted by HLA-B*58:01. Using a panel of barcoded tetramers, we mapped T cell receptor (TCR) clonotypes specific for three dominant epitopes and their variants. Both groups exhibited polyclonal TCR repertoires with evidence of cross-reactivity, which was significantly enriched in donors with prolonged antigen exposure. Within this cohort, broadly cross-reactive clonotypes capable of recognizing all autologous variants were identified, but these were rare (<1%). Early ART initiation preserved repertoires characterized by higher-avidity TCRs and a relative enrichment of transitional memory CD8+ T cell subsets. These functional differences were not associated with differences in TRBV gene sharing, indicating that ART timing shapes repertoire quality and memory differentiation without altering TRBV gene bias. These findings demonstrate how antigen suppression dynamics differentially shape the breadth, functional sensitivity, and memory composition of the HIV-specific TCR repertoire, with implications for T cell-directed immunotherapies and HIV cure strategies.