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Challenge with specific microbial stimuli induces long lasting epigenetic changes in innate immune cells that result in their enhanced response to a second challenge by the same or unrelated microbial insult, a process referred to as trained immunity. This opens a new avenue in vaccinology to develop (TIbV), defined as vaccine formulations that induce training in innate immune cells. Unlike conventional vaccines, which are aimed to elicit only specific responses to vaccine-related antigens, TIbV aim to stimulate broader responses. As trained immunity is generally triggered by pattern recognition receptors (PRRs), TIbV should be formulated with microbial structures containing suitable PRR-ligands. The TIbV concept we describe here may be used for the development of vaccines focused to promote host resistance against a wide spectrum of pathogens. Under the umbrella of trained immunity, a broad protection can be achieved by: (i) increasing the nonspecific effector response of innate immune cells (e.g., monocyte/macrophages) to pathogens, (ii) harnessing the activation state of dendritic cells to enhance adaptive T cell responses to both specific and nonrelated (bystander) antigens. This capacity of TIbV to promote responses beyond their nominal antigens may be particularly useful when conventional vaccines are not available or when multiple coinfections and/or recurrent infections arise in susceptible individuals. As the set of PRR-ligands chosen is essential not only for stimulating trained immunity but also to drive adaptive immunity, the precise design of TIbV will improve with the knowledge on the functional relationship among the different PRRs. While the TIbV concept is emerging, a number of the current anti-infectious vaccines, immunostimulants, and even vaccine adjuvants may already fall in the TIbV category. This may apply to increase immunogenicity of novel vaccine design approaches based on small molecules, like those achieved by reverse vaccinology.

The mechanisms of trained immunity have been extensively described and the beneficial effects are starting to be deciphered in settings. Prototypical compounds inducing trained immunity, such as β-glucans, act through epigenetic reprogramming and metabolic changes of innate immune cells. The recent advances in this field have opened new areas for the development of Trained immunity-based adjuvants (TIbAs). In this study, we assessed in dogs the potential immune training effects of β-glucans as well as their capacity to enhance the adaptive immune response of an inactivated rabies vaccine (Rabisin ). Injection of β-glucan from was performed 1 month before vaccination with Rabisin supplemented or not with the same β-glucan used as adjuvant. Trained innate immunity parameters were assessed during the first month of the trial. The second phase of the study was focused on the ability of β-glucan to enhance adaptive immune responses measured by multiple immunological parameters. B and T-cell specific responses were monitored to evaluate the immunogenicity of the rabies vaccine adjuvanted with β-glucan or not. Our preliminary results support that adjuvantation of Rabisin vaccine with β-glucan elicit a higher B-lymphocyte immune response, the prevailing factor of protection against rabies. β-glucan also tend to stimulate the T cell response as shown by the cytokine secretion profile of PBMCs re-stimulated Our data are providing new insights on the impact of trained immunity on the adaptive immune response to vaccines in dogs. The administration of β-glucan, 1 month before or simultaneously to Rabisin vaccination give promising results for the generation of new TIbA candidates and their potential to provide increased immunogenicity of specific vaccines.

Respiratory infections remain a major global health threat, and recent epidemics have shown that treating the pathogen alone is not enough. In severe influenza, COVID-19, RSV, and bacterial pneumonia, lung failure often results less from microbial load and more from the host’s overactive immune response. Two key processes, neutrophil extracellular traps (NETs) and trained immunity, sit at the center of this shift toward host-focused intervention. Although both are innate defenses, they are usually discussed in isolation: NETs in the context of acute inflammation and thrombosis, and trained immunity in the context of vaccines, epigenetic reprogramming, and metabolic adaptation. Yet in the lung, these mechanisms function as interconnected elements of early defense. This editorial argues that effective therapies should no longer treat them as separate phenomena but instead co-target NET regulation and trained-immunity pathways as a unified, host-directed strategy to reduce immunopathology and improve outcomes in severe respiratory infections.

Hematopoietic stem and progenitor cell (HSPC) transplantation is a cornerstone for studying hematopoiesis. However, classical conditioning regimens such as irradiation or chemotherapy induce strong inflammation, alter the bone marrow (BM) microenvironment, and severely limit the interpretation of differentiation processes. Moreover, donor HSPC engraftment efficiency in immunocompetent recipients without conditioning is usually very low. In this work, we produced and purified the monoclonal anti-c-Kit antibody ACK2 and tested its capacity to transiently deplete HSPCs in immunocompetent C57BL/6 mice. We defined the in vivo clearance kinetics of the ACK2 antibody from serum, identified the optimal transplantation window, and evaluated donor engraftment efficiency. Intraperitoneal injection of ACK2 induced transient HSPC depletion in the BM, with maximal depletion and complete clearance of circulating antibody at day 4 post-injection. Transplantation of donor HSPCs in ACK2-conditioned recipients at this time point resulted in significantly improved engraftment compared to PBS-treated recipients, particularly in the BM. As a proof of concept, we applied this mouse model to investigate properties of innate immune memory in HSPCs exposed to Candida albicans in vivo . For this, we adoptively transferred HSPCs from infected mice with a non-virulent C. albicans strain and assessed the functional properties of their derived neutrophils in vivo . We found that neutrophils derived from C. albicans -exposed HSPCs displayed an enhanced recruitment to the peritoneal cavity during a secondary C. albicans infection compared to control HSPC-derived neutrophils. In conclusion, here we describe a non-inflammatory, antibody-based conditioning method that enhances adoptive transfer of HSPCs in immunocompetent mice. Consistent with previous reports, ACK2-based conditioning alone does not enable permanent hematopoietic engraftment, but rather facilitates transient donor cell engraftment which provides a versatile methodological tool to study the biology and functional programming of exogenous HSPCs in vivo , including their contribution to trained immunity.

β-Glucans stimulate the immune system, training it to recognize and respond to antigens, which bolsters immunity, including to vaccines. The present study evaluated the capacity of β-glucans to stimulate immunity subsequent to primary vaccination for SARS-CoV-2 with ChAdOx1. Thirty-four SARS-CoV-2-non-immune men (18–49 years) were split into two groups: one receiving 500 mg of oral insoluble yeast β-glucans daily (the glucan group) and the other a placebo (the control group). The supplementation period lasted fourteen days in total, including seven days before and seven days after the initial vaccine dosage. A series of blood samples were collected at three time points: M1 (prevaccination); M2 (30 days after the first vaccination); and M3 (30 days after booster). A lateral flow immunoassay was used to qualitatively identify IgM and IgG against the virus. The levels of antigen-specific IgG anti-spike (S1), receptor-binding domain (RBD), and nucleocapsid (N) were quantified using a LEGENDplex assay. The NeutraLISA assay was used to evaluate the neutralizing antibodies (NAbs). Statistically significant results were defined as those with p < 0.05. Both groups produced similar amounts of NAbs after the first vaccination (M2). However, the glucan group had higher levels in M3, with a more uniform distribution. Furthermore, the levels of anti-S1 IgG in M2 exhibited elevated concentrations, indicating a significant positive correlation with NAbs levels obtained post-second dose (M3). In contrast, individuals who had immunity to common cold human coronaviruses (HCoVs), evidenced by the presence of IgG anti-N in M1 were associated with IgG anti-S1 only in M3, not correlated with NAbs levels. This finding indicates that cross-immunity from other HCoVs did not accelerate or direct the humoral immune response as was observed in the glucan group. Therefore, it can be inferred that the β-glucan supplementation was more effective than immunity from other HCoVs. The capacity of β-glucan to induce trained immunity (TRIM) has the potential to augment immune responses, thereby modifying antibody production in response to the vaccine stimulus. Future studies should evaluate the potential of β-glucan as an adjuvant to vaccines, especially in children, the elderly, and immunocompromised individuals. They should also assess long-term immunity and cross-protection.

In the last decade, a major dogma in the field of immunology has been called into question by the identification of a cell autonomous innate immune memory. This innate immune memory (also named trained immunity) was found to be mostly carried by innate immune cells and to be characterized by an exacerbated inflammatory response with a heightened expression of proinflammatory cytokines, including TNF-α, IL-6 and IL-1β. Unlike the vast majority of cytokines, IL-1β is produced as a proform (pro-IL-1β) and requires a proteolytic cleavage to exert its biological action. This cleavage takes place mainly within complex molecular platforms named inflammasomes. These platforms are assembled upon both the infectious or sterile activation of NOD-like receptors (NLRs), thereby allowing for the recruitment and activation of caspases and the subsequent maturation of pro-IL-1β into IL-1β. The NLRP3 inflammasome has recently been implicated both in western diet-induced trained immunity, and in the detection of microbial virulence factors (effector-triggered immunity (ETI)). Here, we will attempt to link these two immune processes and provide arguments to hypothesize the existence of trained immunity triggered by microbial virulence factors (effector-triggered trained immunity (ETTI)).

Background Bacillus Calmette-Guerin (BCG)-induced trained immunity in the macrophages is characterized by exaggerated inflammatory cytokine production with favourable effects on disease controls. However, how BCG-trained macrophages exert anti-tumor effects and underlying mechanisms remain to be clarified. Methods Pan-anti-tumor activity induced by BCG training was evaluated in mouse models with grafted tumors. The proportion and function of tumor infiltrating macrophages (TAMs) and CD8 + T cells, as well as the level of reactive oxygen species (ROS), were detected by flow cytometry. The secretion of IL-1β and TNF-α were detected by Enzyme-Linked Immunosorbent Assay (ELISA). The expression and activation of NOX2 complex and NF-κB were detected by qRT-PCR, immunoblotting and immunofluorescence. The methylation modification level and chromatin opening level were detected by CUT&RUN and ATAC sequencing. RNA sequencing was used to detect the transcriptome of macrophages and bladder cancer tissues. Results BCG-trained mice exhibited pan-anti-tumor activity where TAMs originated from newly bone marrow hematopoiesis were the predominant effectors. The anti-tumor effects of BCG-trained TAMs were mediated by ROS production in the tumor microenvironment (TME), resulting from the overactivation of NADPH oxidase 2 (NOX2) complex. Epigenetic rewiring of NOX2 complex occurred both in the myeloid progenitor of BCG-trained mice as well as in BCG-trained macrophages marked by increased deposition of H3K4me3 at the promoter regions of NOX2 complex genes, which in turn facilitated the accessibility of transcription factor such as NF-kB and enhanced transcriptional activation. Clinically, NOX2 gene signatures correlated with a favourable prognosis in bladder cancer patients receiving BCG intravesical instillation. Conclusions Our findings reveal that BCG training reprograms TAMs to overproduce ROS through epigenetic rewiring of NOX2-ROS axis. Systemic BCG training becomes an effective and promising strategy to remodel the TME with enhanced pan-anti-tumor activity of infiltrating macrophages.

Pattern recognition receptors (PRRs) function as pivotal components of the innate immune system by orchestrating trained immunity through dynamic epigenetic and metabolic reprogramming. Recent discoveries demonstrate that PRRs not only detect pathogens but also actively regulate immune cell metabolism and transcriptional landscapes, thereby potentiating the speed and magnitude of defensive responses upon secondary challenges. These functional adaptations are coordinated through evolutionarily conserved signaling cascades that establish persistent immunological modifications at cellular and systemic levels. Nevertheless, despite substantial advances in characterizing PRR-driven immune activation, the molecular mechanisms governing their role in innate immune memory formation remain incompletely elucidated. This review systematically explores emerging paradigms of PRR-mediated epigenetic remodeling and metabolic rewiring, with particular emphasis on their mechanistic integration into trained immunity. We critically assess current evidence, identify unresolved questions regarding signal transduction specificity and memory maintenance, and propose novel methodological approaches to decipher the multilayered regulatory networks of innate immune adaptation. By elucidating these processes, our analysis establishes a conceptual framework for developing immunomodulatory therapies and leveraging trained immunity in precision medicine applications.

Trained immunity confers protection against subsequent unrelated infections through metabolic and epigenetic reprogramming. Unlike adaptive immunity, trained innate immunity provides broad, non-specific protection against diverse heterologous pathogens. In addition to potentiating inflammatory responses upon secondary challenge, trained innate immune cells can also acquire anti-inflammatory and tolerogenic phenotypes, a property with important implications for chronic inflammatory diseases such as allergic disorders. Trained immunity-based vaccines (TIbVs) have emerged as promising immunomodulatory strategies capable of attenuating allergic inflammation by inducing immune tolerance. Similarly, allergen-specific immunotherapy (AIT) promotes long-term tolerance to allergens through metabolic and epigenetic reprogramming of innate immune cells. AIT drives the differentiation of monocytes into tolerogenic dendritic cells, thereby reshaping downstream adaptive immune responses. This review summarizes the current understanding of trained immunity and its role in protection against the same and heterologous infections. We discuss the molecular mechanisms underlying trained immunity, with an emphasis on metabolic and epigenetic reprogramming. Furthermore, we highlight the therapeutic potential of TIbVs and AIT as next-generation vaccines for allergic diseases. A deeper understanding of AIT-induced immune tolerance, the identification of predictive biomarkers, and the optimization of delivery platforms—such as lipid nanoparticle-based systems—will be critical for improving the safety and efficacy of future anti-allergy vaccines.

In recent years, the traditional cognition of immunological memory being specific to adaptive immunity has been challenged. Innate immunity can mount enhanced responsiveness upon secondary stimulation, and a phenomenon is termed trained innate immunity. Trained innate immunity is orchestrated by distinct metabolic and epigenetic reprogramming in both circulating myeloid cells and myeloid progenitor cells in bone marrow, leading to long-term resistance to related and non-related pathogens infections. The induction of trained innate immunity can also polarize innate immune cells towards a hyperresponsive phenotype in the tumor microenvironment to exert antitumor effects. This review will discuss the current understanding of innate immune memory and the mechanisms during the induction of innate immunity, including signaling pathways, metabolic changes, and epigenetic rewriting. We also provide an overview of cross-protection against infectious diseases and cancers based on trained innate immunity.