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mRNA COVID-19 vaccines have hegemonized the world market, and their administration to the population promises to stop the pandemic. However, the waning of the humoral immune response, which does not seem to last so many months after the completion of the vaccination program, has led us to study the molecular immunological mechanisms of waning immunity in the case of mRNA COVID-19 vaccines. We consulted the published scientific literature and from the few articles we found, we were convinced that there is an immunological memory problem after vaccination. Although mRNA vaccines have been demonstrated to induce antigen-specific memory B cells (MBCs) in the human population, there is no evidence that these vaccines induce the production of long-lived plasma cells (LLPCs), in a SARS-CoV-2 virus naïve population. This obstacle, in our point of view, is caused by the presence, in almost all subjects, of a cellular T and B cross-reactive memory produced during past exposures to the common cold coronaviruses. Due to this interference, it is difficult for a vaccination with the Spike protein alone, without adjuvants capable of prolonging the late phase of the generation of the immunological memory, to be able to determine the production of protective LLPCs. This would explain the possibility of previously and completely vaccinated subjects to become infected, already 4–6 months after the completion of the vaccination cycle.

Innate immune memory (trained immunity) refers to the ability of innate immune cells, such as monocytes and macrophages, to retain a long-term imprint of a prior stimulus through epigenetic and metabolic adaptations, enabling amplified responses upon restimulation. Recent studies have classified innate immune memory into central and peripheral types. Central innate immune memory originates in hematopoietic stem cells (HSCs) within the bone marrow, where epigenetic reprogramming generates a sustained inflammatory bias, contributing to chronic diseases such as atherosclerosis, heart failure, and stroke. Peripheral innate immune memory occurs in monocytes or macrophages that acquire heightened responsiveness after repeated exposure to stimuli in peripheral tissues. This review explores the mechanisms underlying both central and peripheral innate immune memory, their roles in chronic inflammatory diseases, focusing on cardiovascular diseases, and potential strategies to target innate immune memory for therapeutic purposes. Advancing the understanding of these processes could facilitate the development of novel approaches to control inflammatory diseases and immune-related disorders.

Background: No evidence of the possibility to alter a constituent of the immune system without directly affecting one of its associated components has been shown yet. Methods: A schematic model was developed in which two triggers, fasting and splenectomy, were studied for their ability to affect the expression of cell membrane epitopes and the cytokine secretion of out-of-body autogeneic and syngeneic lymphocytes. Results: Fasting decreased expression of CD8 and CD25 and increased TNFα levels. The effect of splenectomy as a trigger was investigated in non-fasting mice by comparing splenectomized and non-splenectomized mice. An increase in the CD8 expression and in TNFα, IFNg, and IL10 secretion was noted. The effect of splenectomy as a trigger was investigated in fasting mice by comparing splenectomized and non-splenectomized mice. Splenectomy had a significant effect on expression of CD25 and CD4 CD25 and on secretion of TNFα, IFNg, and IL10. To determine the effect of keeping the cells in an out-of-body location on the expression of lymphocyte epitopes, tubes kept on top of the cages of the fasting mice were compared with tubes kept on top of empty cages. A significant change in the CD8 expression was noted. To determine the effect of keeping cells in an out-of-body location on cytokine secretion, tubes kept on top of cages were tested for cytokine levels. A significant decrease was noted for the secretion of TNFα and IFNg. Conclusions: The data obtained from this study characterized a system for induction of correlations between two components of the immune system without a transfer of mediators. The study showed that a mouse could affect cells at a distance and alter the expression of surface markers and cytokine secretion following two types of triggers: fasting and/or splenectomy. Thus, an out-of-body correlation can be induced between two components of the immune system.

Respiratory infectious diseases encountered early in life may result in life-threatening disease in neonates, which is primarily explained by the relatively naive neonatal immune system. Whereas vaccines are not readily available for all infectious diseases, vaccinations have greatly reduced childhood mortality. However, repeated vaccinations are required to reach protective immunity in infants and not all vaccinations are effective at young age. Moreover, protective adaptive immunity elicited by vaccination wanes more rapidly at young age compared to adulthood. The infant adaptive immune system has previously been considered immature but this paradigm has changed during the past years. Recent evidence shows that the early life adaptive immune system is equipped with a strong innate-like effector function to eliminate acute pathogenic threats. These strong innate-like effector capacities are in turn kept in check by a tolerogenic counterpart of the adaptive system that may have evolved to maintain balance and to reduce collateral damage. In this review, we provide insight into these aspects of the early life’s adaptive immune system by addressing recent literature. Moreover, we speculate that this shift from innate-like and tolerogenic adaptive immune features towards formation of immune memory may underlie different efficacy of infant vaccination in these different phases of immune development. Therefore, presence of innate-like and tolerogenic features of the adaptive immune system may be used as a biomarker to improve vaccination strategies against respiratory and other infections in early life.

The immune response of a host to a pathogen is typically described as either innate or adaptive. The innate form of the immune response is conserved across all organisms, including insects. Previous and recent research has focused on the nature of the insect immune system and the results imply that the innate immune response of insects is more robust and specific than previously thought. Priming of the insect innate immune system involves the exposure of insects to dead or a sublethal dose of microbes in order to elicit an initial response. Comparing subsequent infections in primed insects to non-primed individuals indicates that the insect innate immune response may possess some of the qualities of an adaptive immune system. Although some studies demonstrate that the protective effects of priming are due to a \"loitering\" innate immune response, others have presented more convincing elements of adaptivity. While an immune mechanism capable of producing the same degree of recognition specificity as seen in vertebrates has yet to be discovered in insects, a few interesting cases have been identified and discussed.

For decades, innate immune cells were considered unsophisticated first responders, lacking the adaptive memory of their T and B cell counterparts. However, mounting evidence demonstrates the surprising complexity of innate immunity. Beyond quickly deploying specialized cells and initiating inflammation, two fascinating phenomena – endotoxin tolerance (ET) and trained immunity (TI) – have emerged. ET, characterized by reduced inflammatory response upon repeated exposure, protects against excessive inflammation. Conversely, TI leads to an enhanced response after initial priming, allowing the innate system to mount stronger defences against subsequent challenges. Although seemingly distinct, these phenomena may share underlying mechanisms and functional implications, blurring the lines between them. This review will delve into ET and TI, dissecting their similarities, differences, and the remaining questions that warrant further investigation.

The nonspecific protection provided by the innate immune system can be enhanced through training with stimuli, a phenomenon called ‘trained immunity’. However, it remains unknown if distinct training programs with various functional outcomes can be induced. Here, we show that two training agents, flunisolide and myricetin, distinctively train and modulate the immune response against in vivo Listeria monocytogenes infection. Training with either agent led to significant reduction in pathogen burden but differed in the resulting immune functions. Training with myricetin led to the expansion of myeloid progenitor lineages, rapid cell recruitment, and enhanced phagocytosis. In contrast, training with flunisolide led to expansion of stem cell and multipotent progenitor populations, increase in antigen processing, and faster T cell expansion. We provide preliminary evidence that this divergent training outcomes may arise from agent-specific modulation of transcription factors. This study importantly shows that training can be directed at both the innate response and the onset of the adaptive response, highlighting the potential of modulating distinct training programs to influence protective immune responses.

Macrophages are crucial members of the innate immune response and important regulators. The differentiation and activation of macrophages require the timely regulation of gene expression, which depends on the interaction of a variety of factors, including transcription factors and epigenetic modifications. Epigenetic changes also give macrophages the ability to switch rapidly between cellular programs, indicating the ability of epigenetic mechanisms to affect phenotype plasticity. In this review, we focus on key epigenetic events associated with macrophage fate, highlighting events related to the maintenance of tissue homeostasis, responses to different stimuli and the formation of innate immune memory. Further understanding of the epigenetic regulation of macrophages will be helpful for maintaining tissue integrity, preventing chronic inflammatory diseases and developing therapies to enhance host defense.

[This corrects the article DOI: 10.3389/fimmu.2025.1721553.].

NF-κB signaling is essential to an effective innate and adaptive immune response. Many immune-specific functional and developmental outcomes depend in large on NF-κB. The formidable task of sorting out the mechanisms behind the regulation and outcome of NF-κB signaling remains an important area of immunology research. Here we briefly discuss the role of NF-κB in regulating cell fate decisions at various times in the path of B cell development, activation, and the generation of long-term humoral immunity.