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.
14/11/2025
Vaccine
TCR bias drives development of dominant vaccine-induced CD8+ T cell responses which can be redirected toward cellular targets
The yellow fever (YF) vaccine is known to elicit strong CD8+ T cell immune responses, predominantly targeting an HLA-A2-restricted immunodominant epitope within the NS4B protein. We aimed to characterize these cells and explore their functional utility when redirected to a target unrelated to YF. We performed single-cell TCR and mRNA sequencing on YF-specific CD8+ T cells from five vaccinated donors, 21 days post-vaccination to characterize their clonal diversity and transcriptional profiles. An HLA-restricted bispecific T cell engager, Redirector of Vaccine-induced Effector Responses (RoVER), was used to redirect YF-specific CD8+ T cells toward target cells including HIV-1-infected CD4+ T cells and CD19+ B cells. The vaccine elicited a robust CD8+ T cell response characterized by a diverse set of differentiated YF-specific cells spanning activated naïve-like, memory and effector phenotypes. Despite biases in the TCR repertoires, antigen-specificity did not promote the development of unique phenotypes following vaccination. Our findings suggest phenotypic overlap causing redundancy in CD8+ T cell immunity across YF epitopes. Using the recombinant RoVER, YF-specific CD8+ T cells could be redirected toward other target cells, leading to efficient target cell elimination. Together, this study enhances our understanding of the cytotoxic T cell response to viral infections and its implications for vaccine development, while also supporting the development of personalised immunotherapies tailored to individual HLA alleles.
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.
04/09/2023
EBioMedicine
Redirector of Vaccine-induced Effector Responses (RoVER) for specific killing of cellular targets
In individuals with malignancy or HIV-1 infection, antigen-specific cytotoxic T lymphocytes (CTLs) often display an exhausted phenotype with impaired capacity to eliminate the disease. Existing cell-based immunotherapy strategies are often limited by the requirement for adoptive transfer of CTLs. We have developed an immunotherapy technology in which potent CTL responses are generated in vivo by vaccination and redirected to eliminate target cells using a bispecific Redirector of Vaccine-induced Effector Responses (RoVER).Following Yellow fever (YF) 17D vaccination of 51 healthy volunteers (NCT04083430), single-epitope YF-specific CTL responses were quantified by tetramer staining and multi-parameter flow cytometry. RoVER-mediated redirection of YF-specific CTLs to kill antigen-expressing Raji-Env cells, autologous CD19+ B cells or CD4+ T cells infected in vitro with a full-length HIV-1-eGFP was assessed in cell killing assays. Moreover, secreted IFN-γ, granzyme B, and TNF-α were analyzed by mesoscale multiplex assays.YF-17D vaccination induced strong epitope-specific CTL responses in the study participants. In cell killing assays, RoVER-mediated redirection of YF-specific CTLs to autologous CD19+ B cells or HIV-1-infected CD4+ cells resulted in 58% and 53% killing at effector to target ratio 1:1, respectively.We have developed an immunotherapy technology in which epitope-specific CTLs induced by vaccination can be redirected to kill antigen-expressing target cells by RoVER linking. The RoVER technology is highly specific and can be adapted to recognize various cell surface antigens. Importantly, this technology obviates the need for adoptive transfer of CTLs.This work was funded by the Novo Nordisk Foundation (Hallas Møller NNF10OC0054577).