Search Results (26,351)

Background/Objectives: It is challenging to develop efficient vaccines against intracellular pathogens such as viruses, and since viral infections are one of the main challenges for farmed salmon, a novel vaccine strategy is needed. mRNA vaccines are optimized and approved for humans, but for fish, the mRNA technology is new, and optimization is required to ensure efficient protein expression. We made an mRNA tailored to salmon and studied the effect of modified nucleosides and the length of the poly(A) tail on protein expression from in vitro-transcribed mRNA in CHSE-214 cells, using enhanced green fluorescent protein (EGFP) as a reporter. Methods: Different lengths of the poly(A) tail were tested, and various modified nucleotides were incorporated in the mRNA during in vitro transcription, including pseudouridine (Ψ), N1-methylpseudouridine (m1Ψ), N6-methyladenosine (m6A), 5-methyluridine (m5U), and 5-methylcytidine (m5C). Protein expression was observed in fluorescence microscopy and quantified using flow cytometry. Results: mRNA containing Ψ resulted in the strongest EGFP expression 1–3 days post-transfection (dpt), while EGFP expression from m5C mRNA was high throughout the experiment (<10 dpt). m5U-containing mRNA had low EGFP expression until 6 dpt, but reached the level of m5C mRNA at 10 dpt. The m5U mRNA, however, expressed EGFP at much higher intensity than all the other mRNAs at all time points. Poly(A) tails with lengths of 40, 100, and >100 were tested, and the one with >100 adenines showed the highest expression. The effects of phosphatase treatment and purification of the mRNA were also investigated. Furthermore, EGFP expression was observed in yolk-sac salmon larvae following micro-injection. Conclusions: Our study provides an important basis for the development of efficient mRNA-based vaccines in the future. Full article

Human adenovirus (HAdV), a double-stranded DNA virus, targets terminally differentiated cells in the upper respiratory tract. As a key platform for gene therapy vectors, elucidating HAdV’s virulence factors is vital for optimizing therapeutic applications and mitigating risks. To achieve productive replication, HAdV strategically neutralizes host immune defenses and induces S-phase pathways essential for viral propagation. This review synthesizes the latest insights into the key pathways through which HAdVs harness these early proteins to enhance virulence, skilfully evading and counteracting host defense mechanisms while propelling viral replication. As foundational platforms for gene therapy vectors (e.g., in oncology and rare disease treatments) and vaccine backbones (e.g., COVID-19 vaccines like ChAdOx1), understanding HAdV’s immunoshadowing—the multifaceted strategies used to cloak innate and adaptive immunity—is crucial for enhancing vector safety and efficacy. Recent insights unveil how early viral proteins—including E1A, E1B-55K, E4orf1, E4orf3, E4orf6, and the E3 complex—participate in these processes. This review critically synthesizes these pathways, evaluating study limitations such as reliance on immortalized cell lines that underestimate the role of these proteins in immunological competent cells, and addresses unresolved controversies, including differential immunoshadowing efficacy across HAdV species that impacts vaccine design. Full article

Hapten-based immunotherapies represent a promising strategy to enhance the immunogenicity of tumor antigens and promote antitumor immune responses. Chemical conjugation of small haptens to antigens generates novel antigenic determinants that increase immune recognition. Mechanistic studies indicate that haptenation enhances antigen uptake, dendritic cell maturation, and the activation of both cellular and humoral immunity. In preclinical models, hapten-modified antigens induce robust immune activation, tumor regression, and durable immune memory. Clinically, dinitrophenyl-modified autologous tumor cell vaccines elicit delayed-type hypersensitivity responses and clonal T-cell expansion, with evidence of clinical activity and a favorable safety profile. However, their clinical benefit remains to be confirmed in larger, randomized studies. Emerging strategies include in situ haptenation and bihaptenized or stressed hapten-modified allogeneic platforms, which aim to expand epitope diversity and enhance immune priming. Hapten-based immunotherapies offer a clinically feasible approach to converting poorly immunogenic tumors into effective immune targets. Full article

Background: Despite the introduction in 2017 of mandatory vaccination for the hexavalent and the measles–mumps–rubella–varicella vaccines, childhood vaccination coverage in Sicily (Italy) remains below the recommended and safety threshold of 95%. A catch-up vaccination intervention was implemented for the pediatric population of the 2022–2023 birth cohorts residing in a health district of Palermo (Bagheria) where in 2024, 24-month coverage for polio and measles was 77.29% and 77.62%, respectively. Methods: A cross-sectional study with a before–after component was conducted between June 2025 and December 2025, with the aim of evaluating the increase in vaccination coverage. A questionnaire was administered to the parents of non-compliant children to investigate the determinants of infant vaccine hesitancy. Results: Collaboration with primary care pediatricians and the organization of active call sessions and extra vaccination sessions resulted in an increase in vaccination coverage of approximately 10–12 percentage points in both birth cohorts. The investigation of the determinants of vaccination adherence showed some significant associations: “perception of infectious disease risk” (OR: 7.91; p = 0.009) and “expectations of a positive outcome from vaccination” (OR: 8.62; p = 0.003). Vaccine information sources such as the internet and media were associated with refusal of catch-up vaccination (OR 0.47, p < 0.001; and OR 0.13, p = 0.026, respectively). Conclusions: Despite methodological limitations, such as the self-reported nature of the survey data, the study demonstrated the usefulness of local strategies aimed at vaccination catch-up, representing a valuable example of local public health practice and effectively contributing to improved vaccination coverage in the pediatric population. Full article

Tuberculosis (TB) is the leading cause of infectious disease-related death globally. Most TB vaccine strategies have focused on conventional CD4 T cell responses, but to date, these have failed to deliver durable sterilizing protection. Donor unrestricted T cells (DURTs), including CD1-restricted T cells, HLA-E-restricted T cells, MR1-restricted T cells and γδ T cells represent an attractive complementary target for future TB vaccine development. They recognize antigens through conserved, non-polymorphic restricting elements and are therefore broadly targetable across genetically diverse populations. They are also enriched at mucosal sites, have rapid effector and cytotoxic capacities and recognize conserved mycobacterial ligands. Emerging human and animal data support their participation in antimycobacterial immunity and suggest they can be shaped by BCG vaccination and other immunization strategies. Here, we review the evidence for DURT involvement in TB host defense, assess their strengths and current limitations as vaccine targets, and discuss how DURT-directed approaches may help to enable faster, broader, and more durable protection against Mycobacterium tuberculosis. Full article

Background/Objectives: The coronavirus disease 2019 (COVID-19) pandemic profoundly disrupted global respiratory virus circulation, with sharp declines during 2020–2021, followed by a resurgence after the relaxation of public health measures. In South America, post-pandemic respiratory virus dynamics remain insufficiently characterized, particularly in ecologically diverse regions. Arequipa, a high-altitude city in southern Peru, has unique environmental conditions, including marked seasonal temperature variability, that may influence viral transmission. Methods: We performed a cross-sectional analysis of 21,784 nasopharyngeal swabs collected from symptomatic patients at four major hospitals between June 2021 and September 2023. All samples were tested for SARS-CoV-2 by RT-qPCR. Because routine screening for other respiratory viruses was implemented only in SARS-CoV-2-negative cases during the study period, a subset of SARS-CoV-2-negative samples was subsequently analyzed for influenza A virus (IAV), influenza B virus (IBV), and respiratory syncytial virus (RSV) using VIASURE assays. Viral circulation patterns were evaluated by year, month, and epidemiological week. Meteorological data were obtained from the SENAMHI–La Pampilla station. Logistic regression models were used to assess epidemiological and climatic predictors of viral detection. Results: SARS-CoV-2 positivity declined from 20.0% in 2021 to 8.8% in 2023. Conversely, detection of other respiratory viruses among SARS-CoV-2-negative samples increased from 0.8% in 2021 to 29.0% in 2023 (p < 0.01). Temporal increases in detection were observed during 2022–2023, particularly for IAV and RSV. In exploratory analyses, calendar year and relative humidity were associated with IAV and RSV detection, while age and temperature variables were associated with IBV. Conclusions: Climatic and demographic variables were associated with changes in viral detection for IAV, IBV, and RSV during the post-pandemic transition period in Arequipa. These findings describe patterns of viral detection within SARS-CoV-2-negative symptomatic patients and should be interpreted as surveillance-based observations rather than population-level estimates. Strengthened integrated epidemiological and genomic surveillance will be essential for vaccine planning and outbreak preparedness in the post-pandemic era. Full article

Cancer therapies are increasingly reliant on immunotherapeutic interventions; however, the persistent emergence of primary, adaptive, and acquired resistance severely limits durable clinical efficacy. Circular RNAs (circRNAs), distinguished by their extreme structural stability and covalently closed loops, have recently been established as potent orchestrators of this immune evasion. This review systematically synthesizes current advancements detailing how circRNAs undermine anti-tumor immunity across diverse malignancies. Specifically, we delineate their critical roles in post-transcriptionally upregulating immune checkpoint molecules (e.g., PD-L1), mediating intercellular immunosuppression via exosomal transfer, and metabolically reprogramming the tumor microenvironment to drive CD8+ T-cell exhaustion and macrophage polarization. Ultimately, we conclude that translating these molecular insights into clinical practice is paramount. Beyond serving as predictive biomarkers, engineering circRNA-targeted therapies and exploiting tumor-specific circRNAs to develop novel anti-tumor vaccines represent essential, paradigm-shifting strategies to definitively overcome immune checkpoint inhibitor resistance. Full article

Pasteurella multocida (P. multocida) is a significant pathogenic bacterium that causes serious disease and death in the yaks of the Tibetan Plateau, and the existing inactivated vaccines are limited by low protection and reactogenicity. Outer membrane vesicles (OMVs) derived from a yak-origin serogroup B P. multocida isolate were evaluated as a potential vaccine candidate in the present study. The purified OMVs were characterized by transmission electron microscopy and nanoparticle tracking analysis, which demonstrated the presence of typical bilayer vesicles ranging from 20 to 300 nm in diameter. Proteomic profiling revealed 1213 proteins, with many of them being immunologically relevant outer membrane-associated proteins like OmpA, OmpH, Omp16, OmpW, TbpA and PlpP. The functional enrichment analysis showed that these proteins were linked to translation, membrane structure, transport, metabolism, and pathways of adaptation of bacteria. In vitro OMVs were effectively taken up by RAW264.7 macrophages and stimulated robust expression of inflammatory mediators, such as TNF-α, IL-1β, IL-6, iNOS and IL-10, which is indicative of strong innate immunostimulatory capacity. OMV immunization induced significant antigen specific humoral responses in mice and yaks in vivo. In mice, intramuscular immunization was effective in giving full protection against P. multocida challenge but not intranasal immunization. Histopathology also indicated less tissue damage in vaccinated animals, especially in the lung and liver. These findings, taken together, prove that yak-derived P. multocida OMVs have high immunogenicity and protection capabilities, which show their potential as a next-generation vaccine platform to tackle P. multocida infection. Full article

Background: COVID-19 remains a substantial public health challenge in the Netherlands. Next-generation COVID-19 vaccine, mRNA-1283, is approved in the European Union, with potential for higher relative vaccine efficacy compared with originally licensed COVID-19 vaccines. Methods: The potential public health and economic impact of mRNA-1283 in adults ≥ 60 years and high-risk adults aged 18–59 years was modeled versus no vaccination and originally licensed mRNA-1273 and BNT162b2, adapting a published static Markov model with a 1-year time horizon. COVID-19 burden reflected two full post-pandemic seasons. Vaccine efficacy versus mRNA-1273 was based on pivotal phase 3 NextCOVE trial data; efficacy versus BNT162b2 was derived from an indirect treatment comparison. The economically justifiable price (EJP) of mRNA-1283 versus no vaccination and price premiums over existing vaccines were determined at a willingness-to-pay threshold of €50,000/quality-adjusted life-year (QALY) gained. Results: Without COVID-19 vaccination, an estimated 460,000 infections, 23,800 hospitalizations, and 5300 deaths would occur. With current coverage, mRNA-1283 was estimated to prevent 68,000 infections, 5400 hospitalizations, and 1200 deaths, saving 9667 QALYs and over €66.5 million in treatment costs. The EJP was €238 versus no vaccination. Compared with mRNA-1273 and BNT162b2, mRNA-1283 was estimated to prevent additional burden (e.g., 1309 and 1679 hospitalizations, respectively) and was cost-effective at an incremental EJP of €62 versus mRNA-1273 and €80 versus BNT162b2. Conclusions: The results support continued COVID-19 vaccination to mitigate the ongoing health and societal burden of SARS-CoV-2 in the Netherlands. The comparative analyses indicate that mRNA-1283 may be associated with substantial health benefits over originally licensed mRNA vaccines; consequently, its use may further improve health outcomes and economic efficiency within COVID-19 vaccination programs. Full article

Background: Rabies remains a major zoonotic disease worldwide, particularly in regions with large populations of free-roaming animals. In urban settings, animal-related injuries constitute a substantial healthcare burden and frequently result in the administration of rabies post-exposure prophylaxis (PEP). This study aimed to evaluate the epidemiological characteristics of animal exposures and real-world PEP practices in a metropolitan emergency department. Methods: This retrospective descriptive study included 1960 patients presenting to a tertiary metropolitan emergency department between 1 March and 1 September 2025 with suspected animal exposure. Demographic data, animal species involved, exposure mechanisms, animal ownership and vaccination status, time to presentation, and PEP practices were analyzed using descriptive statistics. Results: Most exposures were cat-related (86.3%) and were caused by scratching (81.5%). Nearly all injuries were superficial (99.8%), while deep injuries were rare (0.2%). The majority of animals were classified as strays (90.1%), and vaccination status was unknown in 81.2% of cases. Rabies immunoglobulin was administered to only 0.6% of patients; however, rabies vaccination was initiated in 98.8% of patients. Approximately 74.5% of patients presented within 24 h. Post-exposure animal observation was documented in only 20.2% of cases. Conclusions: Urban animal exposures in this metropolitan setting were predominantly superficial and cat-related, yet nearly all patients received rabies vaccination. Limited animal observation and incomplete vaccination documentation appear to constrain risk stratification and may contribute to the use of precautionary PEP. Strengthening surveillance systems, improving documentation, and implementing evidence-based risk-stratification strategies are essential for optimizing rabies prophylaxis practices in urban environments. Full article

Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus responsible for sporadic outbreaks of severe disease with high case fatality rates in South and Southeast Asia. Human infection occurs through spillover from natural reservoirs, primarily fruit bats, or via human-to-human transmission, and is characterized by a broad clinical spectrum ranging from asymptomatic infection to acute respiratory disease and fatal encephalitis. Following entry via ephrin-B2 and ephrin-B3 receptors, NiV exhibits marked endothelial and neuronal tropism, leading to systemic vasculitis, disruption of the blood–brain barrier, and direct infection of the central nervous system. Disease progression is driven by a complex interplay between viral replication strategies and host immune responses. NiV effectively counteracts innate immunity through multiple viral proteins that inhibit interferon signaling, while simultaneously inducing dysregulated inflammatory responses that contribute to tissue damage and multi-organ failure. Neurological involvement represents the most severe manifestation, often resulting in acute or relapsing encephalitis with long-term sequelae among survivors. Despite the severity of the disease, no licensed antiviral therapies or human vaccines are currently available. Therapeutic development has focused on neutralizing monoclonal antibodies targeting viral glycoproteins and small-molecule antivirals that inhibit viral RNA synthesis, both of which show promising results in preclinical models, but remain limited by timing and translational challenges. In parallel, several vaccine platforms—including viral vectors, mRNA-based constructs, and recombinant protein subunits—have advanced to early-phase clinical trials, demonstrating encouraging immunogenicity. Beyond biomedical interventions, effective outbreak containment relies on integrated public health strategies. The “Kerala model” highlights the importance of rapid case identification, isolation, contact tracing, and community engagement within a One Health framework to mitigate transmission and reduce mortality. This review synthesizes the current knowledge on NiV pathogenesis, immune evasion, clinical manifestations, and emerging therapeutic and vaccine strategies, while highlighting critical gaps and future directions for improving the preparedness and response to this high-consequence emerging pathogen. Full article

Background/Objectives: In 2020, the World Health Organization (WHO) launched a strategy to eliminate cervical cancer by ensuring high vaccination coverage, effective screening, and access to treatment. This systematic review assesses how this strategy has been implemented in different world regions, what results have been achieved, and what disparities and challenges have been faced. Methods: A systematic search was performed in PubMed, Web of Science, GLOBOCAN, IARC, ASCO, and ESMO for publications issued between November 2020 and December 2024. A total of 721 records were reviewed and assessed, resulting in the inclusion of 47 studies in the final analysis. Results: Considerable regional variations were identified between the regions analyzed. Countries with organized vaccination programs, structured screening systems, and stronger treatment infrastructure generally reported more favorable outcomes. In contrast, several settings in Eastern Europe, parts of Asia, and sub-Saharan Africa remained below the WHO targets, with lower vaccination uptake, limited screening participation, and a persistently high cervical cancer burden. Progress was further constrained by inequalities in access to healthcare, differences in program organization, and limited comparability of available national data. Conclusions: Although many countries demonstrate that eliminating cervical cancer is achievable, global alignment with WHO targets remains uneven. Strengthening health infrastructure, improving vaccination uptake, and ensuring equitable access to screening and treatment are essential to turning this strategy into a realistic global outcome. Full article

Background: In the last decade, a surge of advancements in and approvals of immunotherapies has revolutionized the treatment of non-small-cell lung cancer (NSCLC). Even as an increasing number of immune checkpoint inhibitors and antibody–drug conjugates gained FDA approval for the remarkable response and durable remission they imparted to some patients, persistent challenges of primary and acquired resistance, imperfect predictive biomarkers, and toxicity remain. Methods: This review identifies and summarizes the most significant emerging clinical data being reported for immunotherapies in NSCLC. Results: We found that the most recent clinical trials are centered on antibody–drug conjugates, bispecific and multispecific antibodies, cellular therapies, and immunocytokines, while other ongoing trials continue to explore new monoclonal antibodies as well as a variety of immunotherapy modalities. Conclusions: Immunotherapy in NSCLC remains an area of rapid advancement, with the potential for further improvements in safety and efficacy as monotherapy and in multimodal approaches. Full article

Enteroviruses represent important human pathogens, posing a substantial disease burden, particularly in children under 5 years of age. Enteroviruses are the primary causative agents of hand-foot-and-mouth disease (HFMD) and are strongly associated with acute flaccid myelitis (AFM), with severe cases potentially resulting in significant neurological complications. Inactivated vaccines against EV-A71 based on the C4 genotype are currently available. However, there are no licensed direct antiviral agents for severe cases. By focusing on viral proteins and host factors, researchers have made great strides in the creation of antiviral medications that target enteroviruses. However, several viral candidates failed to progress in clinical development due to limited efficacy or side effects. This review discusses key findings in enterovirus antiviral research, analyzes the advantages and limitations of each drug target, and highlights knowledge gaps that need to be addressed to advance further development in this field. Full article

Metal–organic frameworks (MOFs) are a versatile class of hybrid crystalline materials that have emerged as promising candidates for a broad range of applications. γ-cyclodextrin MOFs (γ-CD-MOFs) represent an innovative subgroup of MOFs constructed from “edible” γ-CD ligands coordinated with biocompatible metal ions to form an extended porous structure. Owing to their unique characteristics such as their “green” origin, biodegradability, and biocompatibility they became a promising platform for drug delivery applications. Structurally, γ-CD-MOF possess a body-centered cubic structure with dual-mode porosity, enabling the simultaneous encapsulation of hydrophilic and hydrophobic drugs. Such structural features contribute to high loading capacity, tunable release behavior, and enhanced stability of incorporated drugs. In this review, we comprehensively discuss the structural features of γ-CD-MOF, synthesis strategies, crystals size and morphology control, activation and drying techniques, and drug encapsulation approaches. We further address computational and simulation approaches used to predict and optimize drug-framework interactions, as well as post- synthetic modifications aimed at enhancing stability and functionality. The diverse pharmaceutical applications of γ-CD-MOFs are examined, including the delivery of small molecules, macromolecules, multi-drug systems, and emerging pulmonary formulations. Additionally, we examine biocompatibility and safety considerations and current limitations related to aqueous stability, industrial-scale production, and reproducibility. Finally, this review highlights recent progress and underlines future perspectives, emphasizing innovations such as fast drug-loaded MOF formation via spray-drying, co-delivery strategies, and vaccine-oriented formulations. Together, these insights highlight the potential of γ-CD-MOFs to shape the next generation of multifunctional drug delivery systems across interdisciplinary fields. Full article