Search Results (580)

Multiple sclerosis (MS) is an immune-mediated disease characterized by inflammatory demyelination and axonal degeneration in the central nervous system (CNS) and has been linked to viral infections. Theiler’s murine encephalomyelitis virus (TMEV) infection in SJL/J mice has been widely used as a viral model of MS, since TMEV-infected mice develop MS-like demyelination and axonal degeneration with viral persistence in the CNS. In the TMEV model, we previously demonstrated upregulation of immunoglobulin (Ig) A-related genes in the CNS, as well as IgA deposition and IgA-positive cell infiltration in demyelinating lesions. Although IgA has been implicated in the pathophysiology of MS, its precise role remains unclear. To determine the role of IgA in the TMEV model, we established IgA knockout (KO) mice on the SJL/J background; IgA KO mice lacked serum IgA and exhibited altered gut microbiota compositions. We found that TMEV-infected IgA KO mice developed more severe neurological signs than wild-type (WT) mice. IgA KO mice also had more severe inflammatory demyelination with higher levels of viral persistence and T cell infiltration in the CNS than WT mice. Immunologically, IgA KO mice mounted TMEV-specific lymphoproliferative responses and serum anti-viral antibody isotype titers, except for IgA, which were comparable to WT mice. Interleukin (IL)-17 and IL-10 productions were higher in IgA KO mice than in WT mice. Thus, IgA could play a protective role in the TMEV model in WT mice; IgA deficiency-mediated gut dysbiosis may contribute to enhanced immunopathology in IgA KO mice. Full article

Dengue virus (DENV) serotypes 1–4 cause dengue, a major re-emerging disease in tropical and subtropical regions. This study evaluated the antigenicity of a recombinant DENV-2 premembrane protein (rprM-DENV-2) and its ability to detect anti-DENV human IgA antibodies. The rprM-DENV-2 protein was expressed in Escherichia coli, purified, and assessed for immunogenicity and antigenicity. The recombinant protein induced IgG antibodies in rats, which detected DENV infection in Vero cells. Importantly, in paired saliva and serum samples from patients diagnosed with dengue, IgA antibodies were detected by ELISA using the rprM-DENV-2 antigen, but not in samples from the negative control group (subjects residing in a non-endemic area), with a significant difference (p < 0.0001). These findings demonstrate that rprM-DENV-2 retains antigenic properties similar to the native viral protein; this may be useful for in vitro studies of DENV infection and IgA detection in non-invasive clinical samples. Full article

Toll-like receptors (TLRs) are crucial for eliciting immune responses against pathogens such as bacteria and viruses. TLR activation has also been studied for its potential to drive antitumor activity in immune cells. TLR8 is an intracellular receptor that recognizes single-stranded RNA and promotes antiviral responses, including the release of cytokines such as TNFα and type I IFN. Previously we have shown that TLR8 activation can also modulate the expression of Fcγ receptors (FcγR), which are major drivers of antibody-mediated tumor cell clearance. Hence, TLR8 agonist treatment represents a potential means of overcoming tumor-related immunosuppression and enhancing the efficacy of antibody therapy. In chronic lymphocytic leukemia, the use of therapeutic antibodies against CD20 has become standard for treatment. However, the immune effector cells show suppressed phenotypes and weakened responses compared to their healthy-donor counterparts. Here, we investigated TLR8 agonist treatment as a means to overcome this immune suppression and enhance cellular antibody-mediated responses. Upon stimulation with the agonist TL8-506, primary CLL-patient monocytes showed an increase in the expression of activating FcγR in conjunction with reduced expression of regulatory receptors. Cytokine production was also enhanced and there was a shift in phenotypic markers, suggesting the adoption of a more M1-like state. Treatment with TLR8 agonist also elicited production of IFNγ and Granzyme B and enhanced antibody-dependent cellular cytotoxicity of antibody-coated B cells by NK cells. Agonist treatment also increased the phagocytic activity of neutrophils but did not affect the formation of neutrophil extracellular traps (NETs). Taken together, these results suggest that TLR8 agonists may help counteract the suppressed phenotypes of immune effector cells and may enhance the efficacy of antibody therapy for CLL. Full article

Background/Objectives: Healthcare students face an occupational risk of hepatitis B virus (HBV) exposure during clinical training, often many years after receiving their primary vaccination series in infancy or childhood. Progressive waning of anti-hepatitis B surface (anti-HBs) antibody titres, heterogeneous vaccination histories in international student cohorts, high rates of underreported needlestick injuries, and variable occupational health protocols across institutions raise important questions about the adequacy of pre-clinical immunization surveillance in this population. This review aimed to synthesize current evidence on hepatitis B immunization among healthcare students, focusing on occupational exposure risk, seroprotection and immunological memory, clinical management of low or absent anti-HB titres including post-exposure prophylaxis, and the specific challenges posed by multicultural academic settings. Methods: A narrative review was conducted through a systematic literature search of PubMed/MEDLINE and Scopus, covering publications from January 2000 to December 2025, supplemented by key seminal references. After the removal of duplicates and stepwise screening, 49 references were selected for final inclusion. Results: Needlestick and sharps injuries occur at measurable rates during clinical training, with medical students accounting for approximately 30% of occupational exposure events in some series, and with underreporting rates estimated at 19–80% across studies. Pooled seroprotection prevalence at clinical training entry is approximately 73.8% (95% CI 69.1–78.0%), with substantially lower rates among students vaccinated in infancy—as low as 28% at 16–20 years post-vaccination in longitudinal data—compared with adolescence immunization. The majority of students with non-protective titres retain immunological memory, with 90.9% (95% CI 87.7–93.3%) demonstrating an anamnestic response after a single booster dose. Post-exposure prophylaxis pathways depend critically on pre-existing immunological status, reinforcing the operational value of pre-clinical serological screening. International student cohorts present additional complexity due to heterogeneous vaccination schedules, documentation gaps, and variable natural immunity profiles. Conclusions: Systematic pre-clinical serological screening (anti-HBs, HBsAg, and anti-HBc), combined with evidence-based stepwise immunization management and structured educational interventions, is essential to protect healthcare students from occupational HBV exposure. The primary operational goal of screening is the identification of the approximately 5% of true non-responders who require tailored occupational health management. These findings support a proactive, integrated approach to hepatitis B immunization surveillance in healthcare education, aligned with the WHO 2030 viral hepatitis-elimination targets. Full article

Background/Objectives: Classical swine fever (CSF) and pseudorabies (PR), caused by classical swine fever virus (CSFV) and pseudorabies virus (PRV) respectively, are economically significant viral diseases worldwide that severely compromise swine health and constrain international trade. Previously, we generated a recombinant PRV (rPRVTJ-UL44-E2) expressing the CSFV E2 protein that elicited rapid E2-specific antibody responses in rabbits as early as 7 days post-immunization (dpi). However, its immunogenicity and protective efficacy in pigs remain uncharacterized. In this study, we evaluated the protective performance of rPRVTJ-UL44-E2 in pigs via needle-free immunization. Methods: Pigs (n = 5) received a prime immunization with 10⁷ median tissue culture infective doses (TCID₅₀) of rPRVTJ-UL44-E2 via needle-free immunization, followed by a boost immunization with the same dose at 21 dpi, and were then challenged with 10⁵ TCID₅₀ of the virulent CSFV Shimen strain (CSFV-SM) at 33 dpi. Results: Pigs immunized with rPRVTJ-UL44-E2 developed E2-specific antibodies (blocking rates > cutoff value (40%) at 25 dpi) and gB-specific antibodies that were detectable as early as 7 dpi, with anti-CSFV neutralizing antibody titers comparable to those induced by the C-strain vaccine and anti-PRV neutralizing antibody titers also reaching detectable levels at 28 dpi, whereas no specific antibodies were detected in the DMEM control group. All pigs immunized with rPRVTJ-UL44-E2 and C-strain survived the lethal CSFV challenge with no clinical signs or detectable viremia. In contrast all DMEM control pigs succumbed to infection within 9 days post-challenge (dpc). Conclusions: These findings demonstrate that needle-free delivery of rPRVTJ-UL44-E2 confers complete protection against lethal CSFV challenge in pigs. Full article

Infectious pancreatic necrosis (IPN) is a highly contagious viral disease that causes significant economic losses in the global salmon farming industry. Despite the widespread use of vaccines, outbreaks caused by infectious pancreatic necrosis virus (IPNV) continue to occur, even in genetically resistant fish populations. Therefore, the development of alternative vaccination strategies remains a priority for sustainable aquaculture. In this study, we developed a vaccine prototype based on the recombinant IPNV capsid protein VP2 loaded in alginate microparticles for immersion immunization. The VP2 protein was produced using the E. coli pET21b+ expression system and subsequently encapsulated in alginate by ionic gelation with calcium chloride. The immunogenic potential of the VP2-MP formulation was evaluated in salmonids by quantifying specific antibody levels and analyzing the transcription of immune-related genes (ifn-α, ifn-γ, mx, and tbet). Fish immunized with VP2-MP showed induction of antiviral immune responses characterized by increased expression of ifn-γ and mx, together with detectable levels of specific antibodies against IPNV-VP2. Overall, these results indicate that alginate microparticles enhance the immunogenicity of the VP2 antigen and support the feasibility of immersion-based vaccination strategies against IPNV in salmonids. Full article

Background: Elranatamab, a bispecific antibody targeting BCMA and CD3, has demonstrated clinical activity in relapsed/refractory multiple myeloma. Real-world evidence regarding infectious complications and supportive care remains limited. We evaluated the early clinical activity, safety profile, infectious complications, and supportive care practices associated with relapsed/refractory multiple myeloma (RRMM). This study represents one of the first multicenter real-world evaluations of elranatamab in Türkiye. Methods: This multicenter retrospective study included 87 patients with relapsed/refractory multiple myeloma treated with elranatamab. Clinical characteristics, treatment responses, immune-mediated toxicities, infectious complications, and supportive care practices were assessed. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. Multivariable analyses were performed to identify factors associated with treatment response and clinical outcomes. Results: At 3 months, ORR was 47.1% in the ITT population, 54.7% in the mITT population, and 83.7% among evaluable patients; corresponding 6-month ORRs were 31.0%, 42.2%, and 81.8%, respectively. The high proportion of patients without landmark response assessments primarily reflected insufficient follow-up, early death, or disease progression. Elevated LDH remained independently associated with lower response probability and inferior clinical outcomes. Cytokine release syndrome (CRS) occurred in 69% of patients, with grade ≥ 3 events in 5.7%, whereas immune effector cell-associated neurotoxicity syndrome (ICANS) was infrequent (4.6%) and no grade ≥ 3 events occurred. Grade ≥ 3 infections occurred in 39% of patients, including CMV events requiring antiviral treatment in 24.1%. No HBV reactivation occurred among patients receiving antiviral prophylaxis. Median PFS and OS were 8.1 and 10.6 months, respectively. Conclusions: Elranatamab demonstrated early clinical activity and a manageable safety profile in a heavily pretreated real-world RRMM population. Infectious complications, including CMV events, remained clinically relevant, emphasizing the importance of supportive care. Longer follow-up is needed to characterize long-term outcomes. Full article

Background: Sex-related differences in SARS-CoV-2 viral susceptibility, severity, and recovery are prevalent. Factors such as age and biological variation provide some explanation for immune response, yet the use of biological sex as a variable may limit understanding of underlying individual mechanisms related to endocrine–immune function involved in long-term immune memory. Endogenous sex hormone concentrations provide a means to assess the magnitude or durability of antibody persistence and disease recovery. Objective: This study examined salivary concentrations of 17β-estradiol and testosterone, as well as the number of weeks since prior SARS-CoV-2 viral infection. The study aimed to determine whether endogenous sex hormones contributed additional explanatory value to antibody persistence beyond biological sex. Methods: A cross-sectional study included 75 college students (63% female) who reported weeks since previous SARS-CoV-2 infection (M = 15.41, SD = 7.13), confirmed through a positive SARS-CoV-2 anti-N rapid antibody test. Participants provided saliva samples, which were tested for concentration of 17β-estradiol and testosterone. Hierarchical multiple regression analyses examined the effects of biological sex and endogenous sex hormones on the persistence of SARS-CoV-2 antibodies following natural infection. Results: 17β-estradiol was the strongest positive predictor of SARS-CoV-2 antibody persistence (β = 0.63, p < 0.001). Departing from previous findings, biological sex was not a significant predictor of antibodies targeting the SARS-CoV-2 N protein. Conclusions: Findings underscored the role of estradiol on immune recovery in a healthy young adult population. Individual hormone variation appears more informative than sex classification for understanding antibody persistence and immune response. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, with a five-year survival rate of less than 12%. Oncolytic viruses are considered a promising immunotherapeutic approach, but their effectiveness is often limited by the innate interferon response, which is the main antiviral barrier in resistant tumors. A combination of an oncolytic virus with JAK/STAT pathway inhibitors has been proposed to overcome this resistance. Methods: In this study, we investigated the oncolytic and immunotherapeutic potential of the attenuated yellow fever vaccine strain YFV 17D in combination with the JAK1/JAK2 inhibitor ruxolitinib in a panel of six PDAC cell lines with diverse genetic profiles and JAK/STAT signaling activities and in a syngeneic immunocompetent PAN02 mouse model. Results: In vitro, we identified three distinct response patterns: synergistic enhancement of viral replication and cytopathic effect, lack of synergism due to absent interferon signaling, and increased viral replication without cytopathic effect. Despite different cell mutation profiles, the cell response patterns were determined by the basal JAK/STAT activity of each cell line rather than by specific KRAS or TP53 mutation. In vivo, the combination therapy significantly extended median survival compared to YFV 17D monotherapy and the control group and induced tumor regression in 62.5% of animals. Since no difference in intratumoral viral RNA was detected between the combination and monotherapy groups, we suggest that the antitumor effect in vivo was mediated not by enhanced viral replication, but by activation of adaptive immunity. This is indirectly suggested by increased intratumoral IL-12, a fourfold increase in CD8⁺ T cell infiltration, a reduction in CD4⁺ cells, and the generation of virus-neutralizing antibodies. No systemic cytokine surge, neurovirulence, or viral dissemination was observed, suggesting the safety of the proposed regimen. Conclusions: These findings clarify the immune mechanisms determining the efficacy of YFV 17D combined with ruxolitinib and establish the basis for personalized patient stratification by tumor interferon signaling status. Full article

Background/Objectives: Acute respiratory infections represent a global health burden due to their high incidence, morbidity and mortality. Despite advances in prevention and treatment, strategies providing broad protection against respiratory pathogens remain limited. This study evaluated the antiviral activity of nasal spray forms based on an antigen complex from opportunistic bacteria, with or without a mucoadhesive copolymer, and their influence on cellular and humoral components of the immune response. Methods: Antiviral activity was assessed in experimental models of SARS-CoV-2 infection in Syrian hamsters and influenza A pneumonia in mice under prophylactic and therapeutic–prophylactic regimens. Parameters of cellular and humoral immune response were assessed using delayed-type hypersensitivity, antibody-forming cell assays, and leukocyte phagocytic activity. Results: Both forms showed comparable influence on cellular and humoral components of the immune response. In a mouse model of lethal influenza pneumonia induced by A/California/04/2009 (H1N1)pdm09 virus, intranasal administration at 100 µg/kg increased mean survival time and survival rate, and reduced body weight loss. In SARS-CoV-2-infected hamsters, both forms reduced clinical signs, body weight loss, weight lung index, lung pathology, and decreased viral titers. The copolymer-containing form showed the most pronounced effect under the therapeutic–prophylactic regimen, with greater protection against body weight loss and stronger suppression of viral replication. Conclusions: The findings support further investigation of these nasal spray forms as candidates for prophylaxis and adjunctive therapy of respiratory infections, particularly when pathogen variability may limit the effectiveness of pathogen-directed treatments. Further mechanistic studies are needed to clarify the pathways underlying the observed antiviral effect. Full article

Virus-specific antibody responses, including binding antibodies and neutralizing antibodies (nAbs), are important indicators of antiviral immune status after infection or immunization. They provide complementary information on antiviral humoral immunity after infection or vaccination. Antigen-binding antibodies indicate previous exposure and the magnitude of the immune response, whereas receptor-blocking and functional neutralization assays assess whether antibodies interfere with viral entry or infection. Conventional neutralization assays, such as plaque reduction neutralization tests and pseudovirus neutralization tests, provide functional information but are labor-intensive, time-consuming, biosafety-restricted, and difficult to deploy for large-scale or decentralized monitoring. Paper-based biosensors, including lateral flow assays (LFAs), microfluidic paper-based analytical devices (μPADs), and paper-based ELISA, have emerged as promising point-of-care tools owing to their low cost, portability, simple operation, and compatibility with visual or digital readouts. This review critically evaluates these platforms according to whether they measure antigen-binding antibodies, receptor-blocking activity, surrogate neutralization, or functional neutralization and summarizes the applications of these three platforms for monitoring antibody responses against SARS-CoV-2, influenza, dengue, Zika, and monkeypox viruses. Unlike previous reviews that mainly focus on general paper-based biosensor design or conventional nAb assays, this review emphasizes the distinction between antigen-binding, receptor-blocking, and surrogate neutralization readouts, and critically discusses how paper-based signals should be interpreted in relation to functional immunity. We further analyze key translational challenges, including quantitative accuracy, antigen cross-reactivity, standardization, clinical validation, regulatory positioning, and real-world implementation. Future development should combine multiplex detection, standardized calibration, digital and AI-assisted interpretation, and clinically validated assay formats. Paper-based biosensors have considerable potential for decentralized antibody monitoring and public health surveillance, but their clinical utility depends on clear assay positioning and validation against appropriate functional or reference methods. Full article

Functional cure of chronic hepatitis B virus (HBV) infection remains a significant challenge, making viral-entry-blocking antibodies a promising antiviral strategy. Here, we developed a structure-guided computational workflow for affinity-enhancing candidate mutations at the interface between the humanized neutralizing antibody HzKR127 and the HBV preS1 peptide epitope. Based on the crystal structure of the HzKR127–preS1 complex, we performed single-site saturation mutagenesis across the paratope, evaluating variants with a consensus effect score integrated from seven computational models. Benchmarking against published alanine scanning data showed that our consensus score effectively identified major-affinity-loss residues, achieving ROC AUC values of 0.81 and 0.84 for residue-level and site-level predictions, respectively. Mutational profiling revealed distinct asymmetric mutational responses, with broad intolerance on the preS1 side and localized favorable substitutions within antibody CDRs. Multilevel prioritization identified 26 antibody-side candidates, 17 of which showed improved HADDOCK refinement scores compared to the wild type. In particular, the H:D97W/F/Y substitutions presented the strongest structural rationale for enhancing improved interfacial packing through aromatic hydrophobic contacts with preS1 Phe10. These findings provide a prioritized list of candidates for experimental validation and a practical framework for the rational optimization of antibodies targeting functionally constrained viral epitopes. Full article

Background: Dengue fever remains a major mosquito-borne viral disease in tropical and subtropical regions and continues to represent an important public health challenge in the Caribbean. Despite endemic transmission in Trinidad and Tobago, limited laboratory-based studies have evaluated serological markers associated with recent dengue infection. Objective: To evaluate serological and immunological markers associated with recent dengue virus infection through the detection of anti-dengue virus immunoglobulin M (IgM) antibodies in serum samples obtained from Trinidad and Tobago using an enzyme-linked immunosorbent assay (ELISA). Methods: Anti-dengue virus IgM antibodies were detected using a commercial enzyme-linked immunosorbent assay (ELISA). Results were classified as positive, borderline or negative according to manufacturer-recommended criteria. Descriptive statistical analysis was performed to determine seroprevalence in anonymized serum samples. Results: A total of 161 serum samples were analyzed. Twenty samples (12.4%) demonstrated positive anti-dengue IgM reactivity, while 29 samples (18.0%) showed borderline reactivity and 112 samples (69.6%) were negative. Under the conservative analytical approach, the estimated dengue IgM seroprevalence was 12.4% (20/161; 95% CI: 7.7–18.6%). Conclusions: The estimated seroprevalence of dengue IgM in this pilot study was highly dependent on the analytical treatment of borderline ELISA results. Conservative classification provided the most cautious and reproducible estimate of recent dengue infection, while liberal interpretation substantially increased the apparent disease burden. Early viral replication triggers inflammation that progresses to cytokine-driven vascular damage, while cross-reactive humoral responses and host factors ultimately shape dengue severity. Ultimately, understanding the drivers of IgM cross-reactivity is essential for accurate dengue surveillance, outbreak detection, and clinical decision-making. Full article

Global elimination of hepatitis C virus (HCV) infection requires not only direct-acting antivirals (DAAs) but also the development of a highly effective prophylactic and/or therapeutic vaccine. Background/Objectives: Our aim was to optimize the composition of the candidate vaccine against HCV by combining recombinant non-structural proteins and a DNA construct with a complex adjuvant. Methods: C57BL/6 and DBA/2J mice were immunized three times at 2-week intervals using different schemes. The viral antigens consisted of a mixture of NS3, NS5A, and NS5B proteins and/or recombinant DNA expressing NS3-NS5B polyprotein. As adjuvants, a complex adjuvant, a mixture of Polymuramil^® and Pyrogenalum^® (NOD1/NOD2 and TLR-4 agonists), or a CpG ODN adjuvant (TLR-9 agonist) were used. Results: The most efficient regimen was three subcutaneous administrations of the combined DNA, recombinant protein components, and a new complex adjuvant. This scheme elicited a robust immune response, characterized by high antibody titers, enhanced antigen-specific lymphocyte proliferation, and significant interferon-gamma (IFN-γ) secretion in both mouse lines. Furthermore, the complex adjuvant outperformed CpG ODN in stimulating both humoral and cellular immunity against the HCV antigens. The vaccine composition stimulated the formation of CD4⁺ memory T cells and decreased the relative frequences of suppressive Treg and MDSCs. Conclusions: The presented candidate vaccine induces a strong immune response to HCV proteins. The next step would be to validate the protective effect in cell culture and animal models. This would one the path to preclinical studies of this vaccine composition. Full article

Patients with multiple myeloma (MM) exhibit profound immune dysregulation, predisposing them to severe outcomes following SARS-CoV-2 infection. Current evidence highlights shared immunopathological mechanisms linking MM and COVID-19, with particular emphasis on the interleukin-6 (IL-6) axis as a shared amplifier of inflammation rather than the sole driver of disease. MM is characterized by a baseline pro-inflammatory milieu, in part mediated by IL-6, which is further amplified during SARS-CoV-2 infection, resulting in cytokine escalation, complement activation, coagulopathy, and multi-organ injury. This amplification operates within a broader, redundant network that also includes T-cell exhaustion, NK-cell dysfunction, checkpoint signaling, complement and endothelial injury, and treatment-induced immune defects. This overlap provides a mechanistic basis for the disproportionately high morbidity and mortality observed in this population. Even with advancements in vaccination, antiviral therapy, and clinical practice, patients with MM who exhibit impaired vaccine responses, active disease, or treatment-related immune dysfunction continue to experience considerable vulnerability to COVID-19. In addition, MM patients demonstrate suboptimal vaccine-induced immune responses, contributing to persistent vulnerability to severe and breakthrough infections. Modern MM therapies, including anti-CD38 antibodies, BCMA-directed agents, and bispecific T-cell redirecting antibodies, further reshape antiviral immunity by reducing NK cells, inducing plasma cell aplasia, causing hypogammaglobulinemia, and impairing T-cell function. Emerging treatment approaches targeting this shared pathway have been explored, with a focus on mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs). EVs exhibit multimodal properties, including suppression of pro-inflammatory cytokines, restoration of immune homeostasis, inhibition of viral entry, and promotion of tissue repair and regeneration. Early clinical experience in severe COVID-19 populations suggests a favorable short-term safety profile; reported efficacy, however, derives from small, largely uncontrolled or early-phase studies, and the single randomized trial reporting a mortality benefit did so only in an exploratory post hoc subgroup, with its pre-specified primary endpoint not met. Overall, EVs constitute a biologically plausible but as yet unproven adjunctive strategy that warrants further investigation. Critically, no MM patient has ever been enrolled in an EV trial; current rationale for EV use in MM is therefore extrapolated entirely from non-MM populations, and no MM-specific data exist. Difficulties such as EV heterogeneity, manufacturing variability, uncertain pharmacokinetics, limited targeting efficiency, and potential prothrombotic effects must be resolved before their application in MM-specific clinical settings. Full article