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Open research questions in Immune responses and vaccinations

123 gap statements mined from Immune responses and vaccinations papers in our 4.5M-paper local library, which holds 602 papers on the topic — drawn mostly from each paper's own stated research gap, future-work, challenge and limitation notes, and its abstract. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one.

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What the literature leaves open

  • Most results have been provided by in vitro or animal models, and the durability of trained immunity re-training in humans is not clear (7).

    Immuno-inflammatory-metabolic interactions in cardiovascular diseases: a review from basic mechanisms to clinical translation · 2026 · DOI

  • Second, much of the mechanistic evidence for trained immunity and senescence-driven amplification is extrapolated from obesity and cardiometabolic disease contexts; direct OSO-specific longitudinal and interventional evidence remains limited, and reverse causality and confounding cannot be excluded.

    Immunometabolic mechanisms of osteosarcopenic obesity: chronic inflammation, trained immunity, and systemic immune dysregulation · 2026 · DOI

  • There is a need to investigate the association between BCG vaccination and SARS-CoV-2 infection among healthcare workers.

    BCG vaccination and SARS-CoV-2 infection among healthcare workers: A case-control study in Cape Verde · 2026 · DOI

  • The need for innovative approaches to strengthen host defences against S. pneumoniae infection. The lack of understanding of the mechanisms of protection against S. pneumoniae infection. The need to compare the protective capacity of different BCG substrains against S. pneumoniae infection.

    BCG immunisation through intranasal instillation protects mice against Streptococcus pneumoniae infection by enhancing alveolar macrophage activity · 2026 · DOI

  • Mechanism-guided trials are needed to establish the value of BCG beyond non-muscle-invasive bladder cancer. Clear safety boundaries and clinically anchored endpoints are needed to evaluate the effectiveness of BCG. Future research should focus on optimising antigen strategy, stage selection, and immune monitoring for BCG-based therapies.

    BCG in the fight against cancer: exploring its applications in diverse tumour types and future directions · 2026 · DOI

  • Conditioned immune enhancement is a less explored area of research compared to conditioned immunosuppression. The mechanisms and pathways involved in conditioned immune enhancement are not fully understood.

    The efferent pathway hypothesis—A mini-review on conditioned immune enhancement · 2026 · DOI

  • There is a lack of direct pediatric pneumonia data on CD4+Tim-3. The mechanistic interpretation of Tim-3 is largely extrapolated from other disease contexts.

    Immunopathogenesis of severe pneumonia in children with emphasis on CD4+ T cells, Tim-3 and cytokine-mediated immune dysregulation · 2026 · DOI

  • Unravelling the molecular pathways that activate Tregs during bacterial infection and further investigation of the cellular targets of Tregs are needed to fully understand the interplay between respiratory pathogens and the host, and importantly, novel Treg modulatory therapies to control bacterial shedding and transmission.

    Pneumococcal transmission is driven by TNFR2+ regulatory T-cells · 2026 · DOI

  • This shift reflects a growing recognition that excessive cytokine production can be as detrimental as insufficient immune activation. Consequently, future immunostimulatory strategies are expected to move beyond broad immune stimulation toward the precise regulation of cytokine networks, particularly those involving IFN-γ and IL-6.

    Mechanisms of Immunostimulants in Regulating IFN-γ and IL-6 during inflammatory responses and immune modulation: Implications for therapeutic and vaccine development · 2026 · DOI

  • The exact way by which PMNs inhibit Tregs in response to PCV remains to be elucidated, however multiple mechanisms could be involved. While the effect of PMNs on Tregs has not been investigated in the context of clinically relevant vaccines, several studies have looked at the relationship between Tregs and PMNs in models of inflammation and disease.

    Neutrophils induce effective antibody responses to the pneumococcal conjugate vaccine by inhibiting regulatory T cells · 2026 · DOI

  • Aging is known to alter innate immune function, increasing susceptibility to viral infections, yet its specific effects on influenza B virus (IBV) infection remain poorly characterized.

    Systems-level insights into age-dependent innate immune responses in influenza B infection · 2026 · DOI

  • Although chronic psychosocial stress is a well‐established independent risk factor for cardiovascular disease (CVD), the underlying mechanisms linking stress to CVD remain incompletely understood.

    Stress‐induced trained immunity—A key mechanism linking psychosocial stress, atherosclerosis, and cardiovascular disease · 2026 · DOI

  • Although numerous studies have described cellular and inflammatory alterations in COPD, how EMT–associated transcriptional programs operate within specific cellular contexts to drive disease progression remains incompletely understood.

    Chronic obstructive pulmonary disease reprograms the lung into an immune organ through trained immunity, cell death networks, and immune checkpoint dysregulation · 2026 · DOI

  • Future research should focus on single-cell epigenomic mapping and longitudinal methylation tracking to identify cell populations predisposed to recurrence. Such approaches could form the conceptual foundation of a “periodontal memory clock,” a biological timeline in which aging, inflammation, and healing dynamics can be quantified through epigenetic signatures.

    Epigenetic memory in periodontal healing: mechanisms, evidence, and emerging therapeutic perspectives · 2026 · DOI

  • There has been a lack of systematic reviews of comparative ecological studies on childhood vaccinations, especially with a focus on Germany. The existing reviews do not provide a comprehensive overview of the relative historical contributions of different childhood vaccinations. There is a need for a descriptive synthesis of the existing comparative ecological studies to inform public health communication.

    Benefits of childhood vaccines in ecological studies focusing on Germany: a scoping review protocol · 2026 · DOI

  • Preclinical evidence, largely from rodent models, demonstrates its influence on serotonergic signaling, neuroinflammation, and stress-related behaviors; human evidence remains limited to a small number of early-phase and observational studies, which constrains causal inference and limits generalization of preclinical neurobehavioral findings to clinical practice.

    Bridging soil health and human health: Mycobacterium vaccae as a keystone link · 2026 · DOI

  • The functional and clinical significance of these differences remains unknown (12). These observations are compatible with an association between PTB/treatment status and attenuated systems-level molecular changes after vaccination, but the underlying mechanisms and functional significance remain to be established (18).

    Dissociation between humoral and multi-omic immune responses to inactivated COVID-19 vaccination in patients with pulmonary tuberculosis · 2026 · DOI

  • Although immune-evasion mechanisms have been extensively characterized in individual pathogens, their shared architecture across the ESKAPE group remains insufficiently integrated.

    Convergent evolution of immune evasion in ESKAPE pathogens: A cross-pathogen architecture of conserved host-defense checkpoints · 2026 · DOI

  • To investigate the protective capacity of different BCG substrains against S. pneumoniae infection. To determine whether specific substrains confer cross-protection against multiple pneumococcal serotypes. To explore the potential of mucosal immunisation strategies against other respiratory infections.

    BCG immunisation through intranasal instillation protects mice against Streptococcus pneumoniae infection by enhancing alveolar macrophage activity · 2026 · DOI

  • There is profound evidence that prenatal and postnatal inflammatory hits initiate and perpetuate a state of recurrent or sustained immune activation in preterm infants that profoundly affects organ development and neonatal long-term outcome. Thus, effectively targeting inflammation remains a primary therapeutic objective to alleviate the burden of morbidities associated with preterm birth.

    Priming innate immunity and long-term outcome · 2026 · DOI

  • Delivery constraints limited the translation of BCG into durable survival gains in lung and colorectal cancer. Patient selection that mixed minimal residual disease with bulky disease diluted any stage-restricted benefit. Heterogeneous regimens and endpoints were not aligned with immune kinetics or maintenance-like exposure.

    BCG in the fight against cancer: exploring its applications in diverse tumour types and future directions · 2026 · DOI

  • Whether the reversal generalises beyond influenza to other vaccine types could not be established: a systematic search of the public systems-vaccinology record (ImmuneSpace) found no adequately powered non-influenza cohort, so the cross-type question remains open, neither confirmed nor refuted.

    An age-dependent reversal of the baseline-inflammation to vaccine-antibody-response relationship: a meta-analytic replication in ImmuneSignatures2 with independent influenza cohorts · 2026 · DOI

  • Mucosal vaccination has emerged as a distinct immunization strategy with capabilities that cannot be fully replicated by conventional intramuscular approaches.

    Mucosal immunity and vaccine development · 2026 · DOI

  • The past decades have transformed our view of innate immunity from a crude first line of defense to a sophisticated system that orchestrates tissue homeostasis, pathogen clearance, and disease pathogenesis. In this review, we integrate these functional dimensions through a unified recognition-amplification-effector framework.

    Innate immunity: current understandings and future perspectives · 2026 · DOI

  • If sufficient methodological consistency is identified, the feasibility of future systematic reviews or quantitative evidence synthesis will be discussed.

    Benefits of childhood vaccines in ecological studies focusing on Germany: a scoping review protocol · 2026 · DOI

Most-cited papers in Immune responses and vaccinations

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Open questions raised by papers listed on this page include: (1) There is a need to investigate the association between BCG vaccination and SARS-CoV-2 infection among healthcare workers (“BCG vaccination and SARS-CoV-2 infection among healthcare workers: A…”, 2026); (2) The lack of understanding of the mechanisms of protection against S. pneumoniae infection (“BCG immunisation through intranasal instillation protects mice against…”, 2026); (3) Mechanism-guided trials are needed to establish the value of BCG beyond non-muscle-invasive bladder cancer (“BCG in the fight against cancer: exploring its applications in diverse tumour…”, 2026); (4) The mechanisms and pathways involved in conditioned immune enhancement are not fully understood (“The efferent pathway hypothesis—A mini-review on conditioned immune enhancement”, 2026); (5) There is a lack of direct pediatric pneumonia data on CD4+Tim-3 (“Immunopathogenesis of severe pneumonia in children with emphasis on CD4+ T…”, 2026). 123 gap statements have been mined from Immune responses and vaccinations papers in our 4.5M-paper local library, which holds 602 papers on the topic; the gaps come from whichever of those papers state one. They are mostly the research gaps the authors state and the papers' abstracts, plus future-work, limitations and challenges passages. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one, so you can read the original claim in context.

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