Search Results (1,109)

Background/Objectives: Nipah virus (NiV) is a highly pathogenic zoonotic agent that causes fatal respiratory and neurological diseases, for which no approved vaccines are currently available. To address this unmet need, we developed and evaluated novel mRNA-LNP vaccine candidates. These vaccines employ an epitope- and structure–guided “immune-focusing” strategy, aiming to maximize the exposure of critical neutralizing epitopes on the viral attachment (G) and fusion (F) glycoproteins. Methods: Head-to-head dimeric antigens (2Gs and 2Fs) were engineered by removing subdominant stalk regions and tandemly duplicating epitope-rich globular head domains. Three LNP-encapsulated candidates-NV1 (encoding 2Gs), NV2 (encoding 2Fs), and NV3 (a 1:1 mixture of NV1 and NV2)-were evaluated in BALB/c mice and Syrian hamsters to systematically assess humoral responses, cytokine secretion, BCR/TCR repertoires, and systemic safety. Results: NV1 and NV3 induced potent binding antibodies and strong neutralizing activity against NiV pseudoviruses. Meanwhile, although NV2 lacked neutralizing activity, it induced superior Th1-biased cellular immunity, accompanied by extensive T-cell clonal proliferation. BCR/TCR sequencing revealed unique adaptive immune characteristics that perfectly align with the distinct immunogenic properties described above. Preliminary safety assessments found no toxicity to vital organs, while active germinal center formation confirmed the success of immune mobilization. Conclusions: An epitope-centered dimer design effectively shapes the unique defense mechanisms of the adaptive immune system. NV3 offers a balanced and synergistic strategy that combines potent humoral and cellular immune defenses, providing a highly promising platform for the development of a Nipah virus (NiV) vaccine. Full article

Background/Objectives: Revolutionary small molecule, targeted, tyrosine kinase inhibitors (TKIs) in the clinic have engendered the perception that optimal treatment has already been established for diseases like chronic myeloid leukemia (CML). Addressing BCR::ABL1 oncokinase domain mutations in CML is unlikely to redress disease recrudescence owing to persistent leukemia stem cells (LSCs). Therefore, it is necessary to consider an alternative strategic approach: disrupting LSC interactions with the protective microenvironment and/or immune system. The interaction of the TNF-α superfamily member, CD27, with its upregulated ligand, CD70, initiates survival signaling specifically in CML cells when BCR::ABL1 is inhibited by TKIs and thus represents an attractive target. Previous studies modulating the expression of CD27 on LSCs in a mouse model of advanced phase CML were encouraging. In our study, we explored the CD70/CD27 axis as a therapeutic target in early-phase disease. Methods: Primitive CD34+ cells from treatment-naïve chronic phase (CP) CML patients were drug-exposed in an in vitro co-culture system; combination drug treatments of the therapeutic anti-CD70 antibody and TKIs, nilotinib, were assessed in our CP CML murine model. Results: The blockade of the CD70/CD27 axis in combination with TKIs did not result in greater LSC elimination than with nilotinib as a single agent in our CP CML models. Nonetheless, there was an observed reduction in CD70+ cells with combination treatment. Conclusion: Further preclinical study of the antibody as an adjunct in CD70-expressing hematological malignancy is perhaps warranted. Full article

Background/Objectives: Fluorescence in situ hybridization (FISH) is an established component of the diagnostic and prognostic workup of hematologic malignancies. However, most evidence supporting FISH interpretation originates from treatment-naïve diagnostic cohorts, providing limited insight into how cytogenetic findings evolve during longitudinal disease monitoring and therapeutic exposure. We retrospectively analyzed 1357 consecutive FISH assays performed in 1092 patients with hematologic malignancies between 2019 and 2023. Methods: Multivariable logistic regression identified predictors of aberration detection, while longitudinal analyses explored temporal changes in cytogenetic profiles among serially monitored patients. Observed abnormality rates were compared with published diagnostic benchmarks. Results: The cohort had a median age of 68 years and was predominantly composed of patients with myelodysplastic/myeloproliferative neoplasms (27.2%), multiple myeloma (26.9%), and chronic lymphocytic leukemia (21.6%). Overall, 29.2% of informative assays revealed cytogenetic abnormalities. Clinical indication was the strongest predictor of aberration detection. Compared with diagnostic samples, follow-up specimens showed significantly lower odds of abnormal findings (adjusted OR 0.48, 95% CI 0.36–0.64; p < 0.001), whereas relapse samples demonstrated higher odds (adjusted OR 1.82, 95% CI 1.28–2.59; p = 0.001). Increasing age was independently associated with abnormal FISH results (adjusted OR per decade 1.24, 95% CI 1.12–1.38; p < 0.001). Several canonical abnormalities occurred less frequently than expected from historical diagnostic series, including BCR::ABL1 within the chronic myeloid leukemia testing pathway and del(13q14) in both chronic lymphocytic leukemia and multiple myeloma. In contrast, del(17p), involving the TP53 locus, remained consistently represented across disease categories and was enriched in chronic lymphocytic leukemia relative to published diagnostic cohorts. Conclusions: Longitudinal assessment revealed increasing cytogenetic heterogeneity over time, with common lesions progressively declining and rare or complex abnormalities expanding from 16.3% to 36.7% of the observed cytogenetic landscape. The cytogenetic patterns detected by FISH in contemporary hematology practice are strongly associated with clinical context, disease stage, and treatment history; however, the cross-sectional and retrospective design precludes inference of causal influence. The divergence between real-world positivity rates and historical diagnostic benchmarks highlights the need for context-specific interpretation of cytogenetic findings. The persistence of TP53 loss across disease boundaries and the progressive diversification of aberrations over time underscore the dynamic nature of clonal evolution in hematologic malignancies. Full article

Background and Objectives: The outcomes for patients with localised prostate cancer are variable, even within defined tumour grades or clinical risk groups. Identifying features associated with disease aggression is imperative in contemporary PCa research. ISUP 2 PCa is particularly important in this regard as it exhibits a wide range of oncologic behaviour. The aim of this study was to evaluate the relationship between the tumour volume at radical prostatectomy (RP) and metastasis-free survival (MFS) in patients with ISUP 2 PCa. Methods: In this longitudinal multicentre cohort study, we reviewed the data of 809 consecutive patients with ISUP 2 PCa who underwent RP between 1996 and 2021. The tumour volume was estimated by summing the visual percentage involvement and multiplying it by specimen weight. Kaplan–Meier and Cox regression models were used to assess MFS. Linear regression was used to identify the preoperative predictors of the tumour volume (TV), with the appropriate assumption checks. Key Findings: The median TV was 2.9 cc (IQR: 1.4–7.0 cc). The TV categories were <2 cc (37%), 2–20 cc (53%), and >20 cc (11%). The median PSA follow-up was 42 months; 11% experienced biochemical recurrence (BCR). The BCR rates differed significantly across volume categories (p < 0.01). At 120 months, MFS was highest in the <2 cc group (97%) and lowest in the >20 cc group (87%) (p < 0.01). Conclusions and Clinical Implications: Prostate-TV in ISUP-grade group 2 disease is independently associated with MFS. Tumours > 20 cc warrant closer monitoring and may benefit from adjuvant therapy. The improved pre-operative prediction of TV could support more tailored treatment strategies, including suitability for surveillance. What does the study add? We demonstrate for first time that tumour volume at prostatectomy is correlated with metastasis-free survival in ISUP 2 PCa. At 120 months, MFS was highest in the <2 cc group (97%) and lowest in the >20 cc group (87%) (p < 0.01). This has implications for post-operative surveillance. Full article

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated premalignant state defined by somatic mutations in hematopoietic cells at a variant allele frequency (VAF) ≥2% in the absence of overt hematologic malignancy. Among CHIP-associated mutations, JAK2 V617F is of particular interest because it occupies a dual biological and clinical role: it is both the principal driver of BCR::ABL1-negative myeloproliferative neoplasms (MPNs) and a clonal hematopoiesis variant conferring approximately 12-fold cardiovascular risk in selected cohorts, exceeding that reported for common DTA CHIP variants. Quantitative assessment of JAK2 V617F allele burden is therefore clinically relevant across the full disease continuum—from subclinical clonal expansion to MPN diagnosis, prognostic stratification, and therapeutic monitoring—as VAF thresholds correlate with disease phenotype, thrombotic risk, molecular response, and fibrotic progression. Digital PCR platforms, including droplet digital PCR (ddPCR) and chip-based digital PCR, have emerged as highly sensitive and reproducible methods for absolute JAK2 V617F quantification without the need for standard curves, with reported limits of detection as low as 0.01%. In this review, we synthesize current evidence on the molecular biology of JAK2-driven clonal hematopoiesis, the clinical significance of allele burden quantification, and the analytical performance of digital PCR compared with quantitative PCR and next-generation sequencing. We interpret these findings through a systems biology lens that draws together JAK-STAT signaling networks and thrombo-inflammatory pathways including inflammasome-dependent IL-1 signaling, clonal architecture, and bone marrow microenvironmental remodeling. We also discuss published quantitative models in which JAK2 V617F allele burden is treated as a dynamic state variable, while emphasizing that the present review offers a conceptual synthesis rather than a new computational model. We provide a structured comparative synthesis of published digital PCR analytical performance data, a stage-adapted proposal for clinical monitoring, and schematic models to guide future implementation. Overall, the evidence supports digital PCR as a precision tool for monitoring JAK2 V617F clonal dynamics across the CHIP–MPN spectrum, and points to several priorities: assay standardization, harmonized reporting, external quality assessment, and prospective clinical validation. Full article

Background/Objectives: Quiescent leukemia stem cells (LSCs) are self-renewing, pluripotent cells that present a major obstacle to the successful curative treatment of chronic myeloid leukemia (CML). LSCs function independently of BCR::ABL1 signaling and persist following tyrosine kinase inhibitor treatment. The mechanisms enabling LSC survival are a central focus of current CML research. This review details the complex relationship between signaling pathways and discusses recent advancements in energy metabolism research within the pathogenesis of CML. Discussion: Energy metabolism is critical to the biology of CML LSCs. These cells depend on oxidative phosphorylation (OXPHOS) and mitochondrial homeostasis, utilizing fatty acid oxidation as their primary ATP source. Research highlights significant alterations in signaling networks, marked by a dynamic interplay among dominant pathways within the CML clone. While TGF-β-FOXO signaling maintains the self-renewal capacity of quiescent LSCs, proliferating mature CML cells rely heavily on glycolysis and the PI3K/Akt pathway. Furthermore, unique metabolic traits of LSCs underscore the impact of leukemic cell–microenvironment interactions in fostering a permissive niche. Conclusions: Fatty acid oxidation is critical to the survival and self-renewal of CML LSCs. This adaptation of mitochondrial function is closely linked to signaling alterations and entails an adjustment of mitochondrial respiration alongside stimulated OXPHOS. Emerging research unveils many potential targets within metabolic signaling that can be exploited to overcome these survival mechanisms, highlighting the disruption of mitochondrial energy support as a promising strategy to selectively eradicate CML LSCs. Full article

Organic waste valorisation using black soldier fly larvae (BSFL), Hermetia illucens L., offers a biological strategy to transform biodegradable residues into biomass with potential feed applications. This study evaluated five fruit–vegetable residue mixtures under tropical conditions: 100% fruit (100F), 100% vegetables (100V), 50% fruit–50% vegetables (50F–50V), 70% fruit–30% vegetables (70F–30V) and 30% fruit–70% vegetables (30F–70V), using three independent rearing units per diet. The analysis included initial egg mass, estimated viable larvae, coffee husk input as structural bulking material, tray-level process conditions, larval biomass, dry feed offered and estimated bioconversion indicators. The 100F treatment produced the greatest dry biomass (0.1311 ± 0.0132 kg), while 100V and 50F–50V showed favourable input-normalised responses. Biomass was also expressed relative to estimated viable larvae and dry feed offered to support treatment interpretation under the operational conditions evaluated. Coffee husk improved substrate handling and was incorporated into the dry-matter balance; therefore, adjusted BCR was interpreted as a process balance indicator and complemented with biomass yield per dry feed offered. Estimated protein values ranged from 35.4% to 38.1% in selected composite samples. Salmonella spp. were absent in pooled microbiological samples, Escherichia coli was <10 CFU/g, and screened heavy metals were below the laboratory detection limit in selected composite samples. Overall, the results support the potential of BSFL systems for valorising local fruit and vegetable residues under tropical conditions. Full article

Global climate change and rapid urbanization have intensified extreme precipitation events, making urban pluvial flood risk management particularly urgent. However, existing research exhibits theoretical and methodological limitations in reconciling pluvial flood resilience within high-density urban development, especially lacking a quantitative framework for human mobility resilience based on natural hydrological units. To address this, this study takes 48 natural catchment areas in Shenzhen as research units. By integrating mobile phone signaling data, remote sensing imagery, and multi-dimensional spatial form indicators, it constructs a post-disaster recovery curve based on population dynamics to quantify human mobility resilience. Using Principal Component Analysis (PCA), Ordinary Least Squares (OLS) regression, and the K-means clustering method, this research analyzes the mechanisms through which green infrastructure, road network structure, and three-dimensional building morphology influence resilience. The results show that three-dimensional building morphology is the core driver of post-disaster recovery capacity, with Floor Area Ratio (FAR), Standard Deviation of Building Height (SDBH), and Building Coverage Ratio (BCR) significantly promoting recovery, while Building Shape Coefficient (BSC) exerts an inhibitory effect. A key comparative analysis reveals that the model based on natural catchment areas has significantly better explanatory power than the model using stormwater management units, and the dominant factors differ: building morphology factors are more prominent in natural hydrological units, whereas road network structure factors are more significant in stormwater management units. This study confirms that natural geographic boundaries can more authentically reveal the intrinsic “morphology–resilience” relationship, providing an important theoretical and empirical basis for optimizing the planning and management units of sponge cities in high-density urban areas. Full article

Background/Objectives: Myeloproliferative neoplasms (MPNs) are chronic myeloid malignancies characterized by substantial genetic heterogeneity. Although routine molecular evaluation focuses on canonical driver alterations (BCR::ABL1, JAK2, CALR, and MPL), additional somatic mutations have important diagnostic and prognostic implications. Methods: We retrospectively analyzed 1209 consecutive patients who underwent peripheral blood next-generation sequencing (NGS) for suspected or established MPNs using a comprehensive 75-gene DNA/RNA panel. Results: Canonical driver alterations were identified in 141 patients, while 1068 were driver-negative. Retrospective analysis demonstrated that 251 patients (21%) harbored at least one additional pathogenic or likely pathogenic mutation that was not routinely reported. Among driver-positive patients, 57 of 141 (40%) carried clinically relevant co-mutations, including high-molecular-risk genes such as ASXL1, TP53, SRSF2, SF3B1, RUNX1, U2AF1, and IDH2. Furthermore, 194 of 1068 (18%) driver-negative patients harbored additional pathogenic mutations, several of which supported clonal hematopoiesis or alternative myeloid neoplasms. Peripheral blood and bone marrow molecular findings demonstrated high concordance (R² = 0.87). Conclusions: These findings indicate that comprehensive NGS performed at the time of initial evaluation provides clinically relevant genomic information beyond canonical driver mutations, improves disease classification and risk stratification, and may facilitate earlier diagnosis and personalized management of patients with suspected MPNs. Full article

Background/Objectives: B-cell receptor (BCR) signalling is implicated in Burkitt lymphoma (BL) lymphomagenesis, although its activation may differ across biological and epidemiological settings. While surface IgM is the predominant immunoglobulin isotype of BCR in BL, cases expressing IgA transcripts or lacking detectable surface immunoglobulin (sIg) expression have been reported, suggesting a more complex pattern of sIg expression than previously recognized. This study aimed to evaluate sIg heavy-chain expression by immunohistochemistry in a relatively large series of BL cases from endemic and sporadic settings and to investigate the mutational landscape of surface immunoglobulin-undetectable (sIg-UND) cases. Methods: sIg heavy-chain expression was assessed by immunohistochemistry in 55 formalin-fixed paraffin-embedded BL samples. Targeted next-generation sequencing was performed on four sIg-UND cases using an Illumina capture-based custom panel covering 74 lymphoma-related genes. KRAS and NRAS hotspot mutations were additionally assessed by real-time PCR. Results: Overall, 41/55 cases showed IgM expression, including 31 IgM-positive and 10 IgM+/UND cases, whereas 8/55 cases showed IgA expression (IgA+/UND). IgA-expressing cases were significantly enriched at mucosal sites, particularly the oral cavity and gastrointestinal tract, consistent with the relevance of these anatomical sites to mucosal IgA production. Six cases lacked detectable sIg expression, showing negativity for all tested immunoglobulin heavy chains in more than 90% of neoplastic cells. Four sIg-UND cases were available for sequencing. These cases harbored mutations affecting genes commonly altered in BL, together with alterations in genes less commonly represented in recurrent BL series, such as MEF2B, CREBBP, PRDM1, PIM1, ARID3A, HIST1H1B, and HIST1H1C. Conclusions: Our study provides a systematic immunohistochemical characterization of surface immunoglobulin heavy-chain expression in a relatively large series of endemic and sporadic BL. We identified a subset of IgA-expressing BL cases enriched at mucosal sites, whereas rarer cases lacked detectable surface immunoglobulin expression. The mutational profile of sIg-UND cases highlights alterations affecting genes involved in epigenetic regulation, chromatin organization, and B-cell differentiation, which may contribute to the biological heterogeneity of these cases. No KRAS or NRAS hotspot mutations were detected in the four sequenced sIg-UND cases, as assessed by targeted NGS and real-time PCR. Further functional studies are needed to clarify the biological and clinical significance of sIg-UND BL cases and to determine the functional relevance of the identified alterations. Full article

Soil pH is a key regulator of cadmium (Cd) mobility, uptake, and translocation under phosphorus (P) fertilization. We hypothesized that P fertilization would enhance Cd phytoextraction by improving photosynthesis and biomass, that foliar KH₂PO₄ would better maintain Cd availability than soil-applied P, and that NH₄H₂PO₄ would promote Cd uptake through acidification, whereas CaHPO₄ would reduce Cd availability by increasing soil pH. A greenhouse pot experiment compared soil-applied KH₂PO₄, CaHPO₄, and NH₄H₂PO₄ with foliar KH₂PO₄ at 0.2%, 0.4%, and 0.8% in grain amaranth grown in Cd-contaminated acidic soil, with four replicates. Soil-applied P increased P availability, photosynthesis, biomass, and plant Cd accumulation by 69.8–139.5%, primarily through biomass promotion rather than greater soil Cd availability; foliar P was less effective. CaHPO₄ increased soil pH, whereas NH₄H₂PO₄ decreased it. Pot-level analyses showed negative relationships between soil pH and CaCl₂-extractable Cd and Cd concentrations in roots, stems, and leaves. NH₄H₂PO₄ produced the highest tissue Cd concentrations, translocation factor, and total Cd accumulation, likely because acidification promoted Cd uptake and root-to-shoot translocation. Overall, the biomass-promoting and acidification hypotheses were supported, whereas the advantage of foliar P was not. However, repeated NH₄H₂PO₄ application may intensify soil acidification and increase heavy-metal mobility, posing ecological risks. Full article

Background/Objectives: Chronic myeloid leukemia (CML) is a hematological malignancy driven by the constitutively active BCR-ABL1 fusion protein. Although current ABL1 tyrosine kinase inhibitors (TKIs) have improved CML management, resistance remains a major challenge, highlighting the need for novel therapeutic strategies. Methods: A chalcone derivative containing naphthalene and toluene moieties (A) was synthesized from 2-acetonaphthone and p-tolualdehyde and subsequently converted into a novel 4,5-dihydro-1H-pyrazole-1-carbothioamide derivative (B) through reaction with thiosemicarbazide. The cytotoxicity of compounds A and B against K562 CML cells was evaluated using the MTT assay. The active compound was further investigated for cytotoxic selectivity using HL-60 acute myeloid leukemia (AML) cells and healthy PBMCs. Apoptotic effects in K562 cells were analyzed using Annexin V/ethidium homodimer staining, whereas ABL1 inhibitory activity was determined using the ADP-Glo kinase assay. The potential interaction between the active compound and ABL1 was assessed by molecular docking analysis. Results: Compound B displayed potent cytotoxic activity against K562 cells with an IC₅₀ value of 6.92 ± 1.14 µM and demonstrated selectivity toward leukemic cells over PBMCs (SI = 5.4). Treatment with compound B markedly induced apoptosis in K562 cells. In addition, compound B inhibited ABL1 activity in a concentration-dependent manner. Molecular docking studies revealed a favorable binding orientation within the ATP-binding pocket of ABL1. Furthermore, in silico absorption, distribution, metabolism, and excretion (ADME) analysis predicted favorable pharmacokinetic properties for compound B. Conclusions: These findings demonstrate that compound B possesses cytotoxic, pro-apoptotic, and ABL1 inhibitory activities against CML cells and may serve as a promising lead structure for the development of novel therapeutic agents targeting CML. Full article

Dengue fever, a rapidly spreading mosquito-borne viral disease, poses a major global health issue, particularly in tropical and subtropical regions. The absence of a universally effective vaccine against all four dengue virus serotypes necessitates continued exploration of novel vaccine strategies. This study evaluated a PrM-derived multiple antigenic peptide (MAP) vaccine candidate in BALB/c mice. Molecular docking analyses predicted favourable interactions of the selected PrM-derived B-cell epitope with both human (human BCR Fab region PDB ID: 5IFH) and mouse (mouse BCR PDB ID: 8EMA) B-cell receptors, supporting its antigenic potential. ChemSketch was used to develop the PrM–MAP vaccine construct, which was then commercially synthesized. Mice received single, double, and triple booster doses of the vaccine, while control groups received either PBS or adjuvant alone. Humoral immune responses were measured by ELISA, and safety was evaluated through in vitro cytotoxicity assays on HEK293 cells and the in vivo histopathological examination of major organs. Mice immunized with a single booster dose produced significant levels of PrM-specific antibodies compared to subsequent booster doses, suggesting variability in the humoral response elicited. Optimal coating concentrations in ELISA demonstrated the importance of antigen concentrations in the sensitivity of the assay. The safety evaluation indicated high cell viability, up to 150 µg/mL of PrM–MAP, in HEK293 cells, and an absence of significant histopathological damage in treated animals. The PrM–MAP vaccine construct elicited a detectable humoral immune response while demonstrating a high safety profile in vitro and in vivo. These findings indicate the potential of MAP-based vaccine platforms as promising candidates for further development against the dengue virus. Full article

Background/Objectives: BCR::ABL1-negative myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are clonal hematopoietic stem cell disorders characterized by chronic systemic inflammation and elevated thrombotic risk. Osteoarthritis (OA), the most prevalent joint disease globally, is common in MPNs and shares a common proinflammatory cytokine milieu with MPNs. However, whether symptomatic OA may independently impact MPN-related symptom burden and thrombotic outcomes remains unexplored. Methods: In this prospective two-center study conducted in Croatia (2021–2023), 107 consecutive MPN patients diagnosed by 2016 World Health Organization criteria underwent orthopedic evaluation and completed the MPN Symptom Assessment Form (MPN-SAF) at enrolment. Symptomatic OA was defined as radiographic grade ≥1 (Kellgren–Lawrence) with concordant symptoms. Patients were subsequently followed for thrombotic events. Multiple linear regression and Cox proportional hazards regression were used for multivariable analyses. Results: Symptomatic OA was identified in 64 patients (59.8%). The total symptom score (TSS) was significantly higher in OA patients (p < 0.001), and in multivariable analysis, OA independently predicted higher TSS (β 10.12, 95% confidence interval-CI 5.38–14.86, p < 0.001), alongside female sex and arterial hypertension. Over a median follow-up of 44 months, 10 thrombotic events occurred. Patients with symptomatic OA had significantly worse time to thrombosis (hazard ratio-HR 3.61, 95% CI 1.02–12.8, p = 0.046). In multivariable Cox regression, OA remained associated with thrombosis (HR 15.55, p = 0.002), while female sex (HR 0.17, p = 0.042) and aspirin use (HR 0.15, p = 0.019) were protective. Conclusions: Symptomatic OA may be associated with higher symptom burden and, in this preliminary analysis, with higher thrombotic risk in MPNs. These findings support systematic OA evaluation in MPNs and multidisciplinary management strategies targeting this frequent and burdensome comorbidity. Full article

Neonates and infants exhibit fundamentally distinct immune responses compared to adults, resulting in increased susceptibility to infectious diseases and reduced vaccine efficacy. These age-specific responses are characterized by developmental constraints affecting both adaptive and innate immunity. T cell-independent (TI) responses to polysaccharide vaccines are severely impaired due to reduced transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) expression on neonatal B cells, while T cell-dependent (TD) responses are compromised by Th2 bias in the CD4+ T cell compartment, and by restricted T follicular helper (Tfh) cell development. Emerging data suggest that cytokines such as IL-6 have completely opposite effects on Tfh cell development between adults and neonates. Germinal center (GC) B cell responses are further constrained by delayed follicular dendritic cell (FDC) maturation, impaired B cell receptor (BCR) signaling, and elevated frequencies of IL-10-producing regulatory B cells. The overall immunosuppressive phenotype associated with early age extends to the neonatal innate immune system as exhibited by altered dendritic cell (DC) subset distribution, decreased IL-12p70 production, lower expression of MHC class II and co-stimulatory molecules, and increased IL-10 secretion. To overcome these immune constraints, various adjuvants that are shown to enhance immune response to vaccines in adults are considered for early age vaccines. Although some of these adjuvants show promising results in animal experiments, mechanistic studies need to be conducted in detail since adult and neonatal in vivo environments may dictate different outcomes between the two age groups, especially because early-life adjuvant exposure may have long-lasting effects on immune system programming. Elucidation of age-specific immune responses to vaccines and adjuvants will help develop age-tailored strategies to develop safe and effective pediatric vaccines. Full article