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Open research questions in Immune responses and vaccinations

51 unresolved questions extracted from the limitations and future-work sections of 111 Immune responses and vaccinations papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Healthcare workers are at high risk of SARS-CoV-2 infection. There is a need for effective prevention and control measures.

    BCG vaccination and SARS-CoV-2 infection among healthcare workers: A case-control study in Cape Verde · 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 study faced challenges in terms of the complexity of the topic and the need for a structured literature-level map. The analysis required the use of specialized software and techniques, such as bibliometrix and text2vec.

    Trained immunity in inflammatory bone disease: a bibliometric and literature-level text-mining analysis · 2026 · DOI

  • The paper identifies the need to understand the molecular pathways responsible for the activation and regulation of core innate immune transcriptional regulators. The paper highlights the importance of studying innate immunity in health and disease.

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

  • Tuberculosis (TB) and chronic obstructive pulmonary disease (COPD) remain global public health challenges, yet the mechanisms underlying their comorbidity remain poorly understood.

    γδ T Cells at the Crossroads of Tuberculosis and COPD: From Early Immunity to Tissue Remodeling · 2026 · DOI

  • A growing body of evidence suggests that TB is not limited to an intramacrophage infection but is accompanied by a disruption of the local immune balance in lung tissue.

    γδ T Cells at the Crossroads of Tuberculosis and COPD: From Early Immunity to Tissue Remodeling · 2026 · DOI

  • The mechanisms behind the role of neutrophils in inducing effective antibody responses to the pneumococcal conjugate vaccine are not well understood. The relationship between Tregs and PMNs in the context of clinically relevant vaccines is not well understood.

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

  • ABSTRACT 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

  • While trained immunity has become a convincing concept to link environmental stimulus to chronic inflammation, several issues remain. 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). Emerging research has refined the trained immunity concept to emphasize dosage/duration-dependent innate immune memory and central/peripheral subtypes, but the clinical relevance of these subtypes in human CVD, as well as the revers- ibility of sustained signal-induced inflammatory memory, remains to be elucidated (8). And it remains unclear if trained immunity uniformly contributes to cardiovascular diseases or might exert context-dependent protective effects. Large longitudinal human studies need to establish causality rather than association (17). Additionally, the translational potential of SCFA derivatives (e.g., 4- PBA) in erasing inflammatory innate immune memory requires further validation in human clinical trials (22). Although NET formation has been found to have a negative influence on plaque and thrombosis, it is not certain whether NETs are causes or a primary factor in inflammation. Furthermore, if NET formation is inhibited pharmacologically, it could potentially impede host defense against infection and safety issues (11). NET- related biomarkers are not standardized, which limits their clini- cal translation. Allostatic load can be an effective integrated model of psycho- social stress and immune dysregulation in many studies but its biological measure is still ambiguous. No standardized biomarkers or prospective validation within cardiovascular groups limits its translational applicability (25). Multi-omics methods provide unprecedented information about immunometabolic networks, but whether the high dimen- sional data provide additional information than the traditional cardiovascular risk score is not clear. Cost and interpretability are also important constraints for clinical implementation (107). Future research should also integrate the study of CHIP and the immunometabolic mechanisms of cardiometabolic drugs (GLP-1 agonists, SGLT2 inhibitors) into multi-omics models to improve risk stratification precision (214, 215).

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

  • Further studies are needed to elucidate the molecular mechanisms underlying the vicious cycle of adipose, muscle, and bone dysregulation in OSO. The development of effective therapeutic strategies targeting shared inflammatory and immune mechanisms across tissues is necessary to disrupt the cycle of OSO and restore systemic homeostasis.

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

  • Current mechanistic interpretations remain largely restricted to single-tissue senescence or isolated metabolic dysfunction, which fail to fully explain the synchronized degeneration of bone, muscle, and adipose tissue. The lack of a systems immunometabolic framework to explain the coordinated deterioration of adipose tissue, skeletal muscle, and bone.

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

  • 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

  • The relationship between trained immunity and osteoimmunology and inflammatory bone disease remains insufficiently characterized. There is a need for a structured literature-level map of trained-immunity-related concepts in osteoimmunology and inflammatory bone disease.

    Trained immunity in inflammatory bone disease: a bibliometric and literature-level text-mining analysis · 2026 · DOI

  • Substantial knowledge gaps remain in understanding the complex interplay between prenatal exposures, postnatal environmental factors, and genetic susceptibility. Prediction of long-term outcomes is challenging due to individual differences between infants.

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

  • The complex interplay between prenatal exposures, postnatal environmental factors, and genetic susceptibility is not fully understood. The role of the microbiome in shaping immune development is an area of ongoing research.

    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

  • 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

  • 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

  • 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

  • Early IAV infection of alveolar cells has been challenging to model both in vitro and in vivo. There is a need for new methods to model IAV infection in alveolar cells.

    Early cell-autonomous and niche-mediated epithelial response to influenza infection in primary alveolar organoids · 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

  • However, direct pediatric pneumonia evidence remains limited, and much of the mechanistic interpretation of Tim-3 is extrapolated from adult sepsis, oncologic, chronic infection and autoimmune literature.

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

  • Investigation of the mechanisms by which TNFR2+ Tregs promote pneumococcal transmission. Development of therapies and vaccines targeting TNFR2+ Tregs. Comparison of transmission dynamics between pneumococcal serotypes.

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

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51 open questions have been extracted from the limitations and future-work passages of 111 Immune responses and vaccinations papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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