ID: 42076068
Title: Advancing Needle-Free Jet Injectors for Global Vaccine Delivery.
Abstract: Background: Global immunization programs continue to rely on needle-based injections despite persistent concerns regarding sharps disposal, accidental injuries, and the technical skill required for accurate intradermal administration. Needle-free jet injectors (NFJIs) are an alternative delivery method in which narrow, high-velocity liquid jets penetrate the skin without a needle. Contemporary designs, ranging from single-use disposable-syringe injectors to digitally controlled electromechanical devices, address historical safety issues and meet current WHO and FDA device expectations. Methods: Evidence from engineering analyses, preclinical modeling, and clinical trials was reviewed to characterize how jet velocity, nozzle structure, and formulation rheology influence skin penetration and drug dispersion. Published vaccine studies were examined for antibody responses, seroconversion, and reactogenicity compared with needle-syringe injection. Field vaccination campaign data from national campaigns and operational reports were evaluated to describe implementation steps, acceptability, and implementation constraints. Results: Published studies evaluating vaccines, including inactivated influenza, hepatitis B, typhoid, rabies, and measles, report antibody titers and seroconversion rates after NFJI administration that are comparable to those achieved with conventional intramuscular or intradermal needle injection. Needle-free delivery was associated with operational advantages in several immunization programs, including reduced sharps waste and improved vaccination rate during high-volume immunization campaigns. Local and systemic reactogenicity follows expected patterns, with slightly higher injection-site responses in some NFJI studies. Imaging and mechanical data confirm that jet performance depends on nozzle geometry and controlled pressure pulses. At the same time, formulation stability remains a critical determinant of successful jet-based vaccine administration, particularly for protein antigens, adjuvanted formulations, and emerging mRNA vaccines that may experience transient shear stress during high-velocity injection. Evidence from vaccination campaigns further indicates that needle-free jet injectors reduce sharps waste, simplify vaccine handling and administration procedures, and support rapid vaccine delivery in large-scale immunization programs. Conclusions: Needle-free jet injectors are a practical alternative to traditional needle-based injections for some vaccines. Their main benefits include enabling intradermal dose-sparing strategies, reducing reliance on sharps disposal methods, and enabling the efficient vaccination of large groups without compromising immunogenicity. Future research should define the physicochemical stability limits of biologic formulations subjected to jet injection and evaluate digitally controlled injectors capable of precise pressure modulation and adjustable delivery parameters. In addition, needle-free jet injection eliminates needle penetration and sharps handling, which may reduce needle-associated anxiety and improve vaccine acceptability among individuals with needle aversion.

ID: 42081324
Title: Enhanced immunogenicity and dose-sparing efficacy of self-amplifying RNA vaccines against seasonal influenza across subtypes.
Abstract: Recent clinical data on seasonal influenza mRNA vaccines have demonstrated suboptimal efficacy against the influenza B virus (IBV). We employed sequence optimization strategies that successfully enhanced the antigen expression of hemagglutinin (HA) and developed mRNA vaccine candidates targeting the WHO-recommended strains. When administered at a low dose (0.1 μg), both mono-and trivalent influenza A mRNA vaccines induced robust humoral immunity and conferred complete protection against homologous viral challenge in murine models, outperforming the quadrivalent inactivated vaccine (QIV, 2 μg). In contrast, IBV mRNA vaccines at an equivalent dose failed to elicit detectable antibodies and offered no protection, consistent with prior evidence of suboptimal immunogenicity in human trials. These findings highlight strain-specific immunogenicity constraints inherent to conventional mRNA platforms. To overcome these limitations, we systematically compared three distinct RNA vaccine modalities: (1) nucleoside-modified mRNA, (2) self-amplifying RNA (saRNA), and (3) circular RNA (circRNA). Notably, a single 0.1 µg dose of the trivalent saRNA vaccine elicited robust humoral immunity and provided complete protection against IBV challenge, whereas mRNA vaccination achieved only 14% survival. Importantly, long-term antibody monitoring over 20 weeks showed that saRNA at the low 0.1 μg dose maintained high antibody levels, with a markedly more durable response to IBV antigens than those of other platforms. Moreover, the trivalent mRNA vaccine exhibited a favourable safety profile, with no obvious abnormal body weight changes or serum biochemical abnormalities observed after immunization. Our findings advocate for strain-adaptive platform selection: conventional mRNA for generating rapid, high-magnitude responses against influenza A and next-generation saRNA vaccines for enhanced dose efficiency, particularly against IBV.

ID: 42083745
Title: Novel vaccine platforms for respiratory viruses: a review of licensed vaccines and candidates in late-stage development.
Abstract: Respiratory infections with influenza, respiratory syncytial virus (RSV), and SARS-CoV-2 are a major cause of global mortality. Vaccination is a cornerstone of disease prevention, though traditional platforms face challenges. Recently, several vaccines utilizing mRNA and adenovirus platforms were brought to the market, with additional vaccines undergoing Phase 3 clinical testing. This review assesses vaccine literature primarily from 2020 to the present, using National Library of Medicine databases. The rapidity of mRNA technology was tested and implemented successfully during the COVID-19 pandemic. Since then, the mRNA RSV vaccine has been licensed as well. mRNA platforms also offer the ability of combining antigens for multivalent vaccines against multiple pathogens. Several combination products have been used in phase III clinical trials. Adenovirus-vectored vaccines for respiratory viruses have the added advantage of mucosal-based delivery and inducing a potentially stronger local immune response. However, both of these platforms have immunogenicity and safety shortcomings. Novel respiratory virus vaccine platforms have demonstrated their importance with both endemic and pandemic pathogens, because of decades of concerted efforts and investment in research. Expediting future vaccine development requires a continuation of these efforts with a focus on pre-clinical models and a better understanding of correlates of protection.

ID: 42090792
Title: Efficacy and Safety of an mRNA Seasonal Influenza Vaccine in Adults.
Abstract: Seasonal influenza causes substantial illness and death in adults 50 years of age or older, even with current vaccines. An investigational messenger RNA (mRNA)-based vaccine called mRNA-1010 encodes hemagglutinin glycoproteins from World Health Organization-recommended influenza strains. In this phase 3, double-blind, active-controlled trial, we randomly assigned adults 50 years of age or older to receive trivalent mRNA-1010 (37.5 μg, which includes 12.5 μg of each strain) or a licensed standard-dose comparator. The primary efficacy end point was relative vaccine efficacy against reverse-transcriptase-polymerase-chain-reaction (RT-PCR)-confirmed, protocol-defined influenza-like illness caused by influenza A or B, from at least 14 days after vaccination through the end of the influenza season. Hypothesis testing was conducted hierarchically to assess noninferiority (lower boundary of the 95% confidence interval [CI], >-10%), superiority (lower boundary of the 95% CI, >0%), and a higher level of superiority (lower boundary of the 95% CI, >9.1%). A total of 40,703 participants received mRNA-1010 (20,350 participants) or the standard-dose comparator (20,353 participants); the median follow-up was 181 days (range, 1 to 227). RT-PCR-confirmed, protocol-defined influenza-like illness was observed in 411 of 20,179 recipients of mRNA-1010 (2.0%) and 557 of 20,124 recipients of the standard-dose comparator (2.8%), which corresponds to a relative vaccine efficacy of 26.6% (95% CI, 16.7 to 35.4), thereby meeting the criteria for noninferiority, superiority, and higher-level superiority. Solicited adverse reactions were more frequent with mRNA-1010 than with the standard-dose comparator (injection-site pain in 65.8% vs. 29.8%, fatigue in 45.1% vs. 20.3%, headache in 37.8% vs. 18.0%, and myalgia in 35.4% vs. 11.6%); most reactions were mild to moderate and transient. Serious adverse events were reported in 2.2% of the recipients of mRNA-1010 (with three events considered by the investigator to be vaccine-related) and in 1.9% of the recipients of the standard-dose comparator (with two events considered by the investigator to be vaccine-related). In this trial, mRNA-1010 was superior to standard-dose licensed vaccines for prevention of RT-PCR-confirmed, protocol-defined influenza-like illness in adults 50 years of age or older. Solicited adverse reactions were more frequent with mRNA-1010. (Funded by Blackstone Life Sciences and Moderna; Fluent ClinicalTrials.gov number, NCT06602024.).

ID: 42196525
Title: Algorithm-Optimized H5 Influenza mRNA Vaccine Induces Broad Immune Responses.
Abstract: The high case fatality rate, cross-species transmission, and ongoing evolution of H5 avian influenza viruses pose an imminent threat of an influenza pandemic, particularly with the currently predominant clade 2.3.4.4b lineage. Existing seasonal influenza vaccines and licensed H5 vaccines provide limited cross-protection against H5 viruses, underscoring an urgent need for the development of broadly protective H5 vaccines. In this study, we analyzed all human-infected H5 hemagglutinin (HA) sequences using bioinformatics approaches and subsequently designed a novel H5 influenza vaccine through algorithm optimization. The predicted structure of this vaccine closely resembles that of the wild-type H5 HA trimer. In animal studies, the algorithm-optimized H5 mRNA vaccine not only induced high levels of neutralizing antibodies against multiple clade 2.3.4.4b H5 viruses but also elicited cross-neutralizing antibodies against clade 2.3.4.4 and clade 2.2.1 H5 viruses, as well as robust cellular immune responses. These findings highlight the potential of algorithm-based approaches in developing broadly protective vaccines against pandemic viruses and suggest that this vaccine candidate could serve as a strategic stockpile for preventing H5 influenza pandemics.

ID: 42236761
Title: Rational design of a modular mRNA vaccine platform for rapid adaptation to SARS-CoV-2 variants.
Abstract: The ongoing emergence of novel SARS-CoV-2 variants due to viral mutations poses a persistent challenge to the efficacy of existing vaccines. To address this challenge, we engineered and comprehensively tested three optimized mRNA vaccine candidates, evaluating the kinetics, quality, and magnitude of antibody responses as well as antigen-specific T cell immunity during a prime-boost vaccination regimen in mice. Among the tested candidates, TP2A encoding secreted receptor-binding domains (RBDs) derived from SARS-CoV-2 wild type (WT), Delta and Omicron variants demonstrated superior immunogenicity, inducing an early IgG2a-dominated antibody response against distinct SARS-CoV-2 spike (S) glycoprotein variants. In addition, TP2A elicited IFN-γ-producing T cells in both spleen and draining lymph nodes and antigen-specific cytotoxic T lymphocytes. Notably, beyond broad immunity induced by the vaccine, TP2A functions as a modular platform, thus enabling flexible antigen assembly and rapid vaccine adaptation to newly emerging variants or even other viral pathogens. These findings position TP2A as a promising next-generation mRNA vaccine candidate.

ID: 42245650
Title: Long-term immune response to mRNA anti-SARS-CoV-2 vaccination in patients with cancer.
Abstract: Patients with cancer are at increased risk of morbidity and mortality from COVID-19 but were underrepresented in pivotal vaccine trials. Data on the magnitude and determinants of immune responses to mRNA SARS-CoV-2 vaccination in this population remain limited. I-SPARC is a prospective, phase IV clinical trial evaluating humoral and cellular immune responses to mRNA SARS-CoV-2 vaccination in 115 patients with cancer, including those receiving systemic therapy and those in remission. Anti-Spike antibody titers were measured longitudinally, and immunophenotyping was performed to assess T and B cell subsets. Clinical outcomes, including SARS-CoV-2 infection, were recorded. All patients developed detectable anti-Spike antibodies, although absolute titers varied by cancer type and treatment. Patients with hematologic malignancies and/or receiving chemotherapy had the lowest anti-Spike antibody levels. Booster doses significantly increased titers, particularly in patients in remission or receiving non-cytotoxic therapies. Prior SARS-CoV-2 infection and the number of vaccine doses were associated with better responses. Immunophenotyping confirmed vaccine-induced expansion of memory T and B lymphocyte subpopulations. SARS-CoV-2 infection occurred in 16% of our cohort, with infrequent severe cases. mRNA SARS-CoV-2 vaccines elicit robust humoral and cellular immune responses in patients with cancer, despite variability according to disease type and treatment. These findings support the use of booster strategies and provide a rationale for tailored vaccination approaches in immunocompromised populations.

ID: 42245671
Title: Low effectiveness of influenza vaccines vis-à-vis mechanism of protection by vaccines - potential causes and recommendations to improve control of influenza.
Abstract: Current licensed influenza vaccines primarily protect by eliciting antibodies against the viral hemagglutinin (HA) glycoprotein, thereby blocking viral attachment and fusion with host cells. Unlike most vaccines, influenza vaccines must be administered annually because circulating viruses undergo continuous antigenic drift and population antibody titers wane over time. Despite yearly reformulation, influenza vaccine effectiveness remains highly variable, often below 45%, largely due to antigenic mismatches. These mismatches arise from ongoing HA evolution following strain selection and from egg-adaptation during production or propagation in animal cell cultures, which can alter key HA epitopes relative to circulating strains. Even when an antigenic match is favorable, repeated annual vaccination may elicit immunological phenomena that attenuate protective responses. Serial vaccination in young and older adults can increase regulatory T-cell activation, reducing vaccine-induced antibody titers. In older adults, this may be compounded by age-associated CD4+ T-cell memory populations that have reduced capacity to activate HA-specific B cells. While natural influenza infection induces durable memory B cells, conventional vaccination does not reliably generate such long-lived memory, suggesting a fundamental limitation of current vaccine platforms. Collectively, these observations underscore the need to re-evaluate influenza vaccination strategies, particularly to improve protection in high-risk groups such as older adults. Reducing antigenic mismatch remains essential and can be facilitated by improving the vaccine selection process and expanding the use of recombinant protein and mRNA vaccine production platforms that do not rely on egg- or animal-cell culture technologies. In parallel, the rational selection and development of adjuvants that minimize T-regulatory cell induction while enhancing durable memory B-cell formation and long-lived plasma cells may help overcome the immunological constraints associated with repeated annual vaccination. Beyond active immunization, complementary countermeasures are critical for mitigating severe outcomes, including hospitalizations and deaths. Antiviral drugs and monoclonal antibodies, especially those engineered for extended in vivo half-life, represent important adjuncts for protecting vulnerable populations such as the elderly, young children, and immunocompromised individuals. Strengthening and advancing these modalities should be prioritized as part of an integrated strategy to improve influenza control and reduce the global burden of disease.

ID: 42277158
Title: Does mRNA-based COVID-19 vaccination in the subacute phase lead to microstructural brain changes? A prospective pilot MRI study using T1 relaxometry.
Abstract: Messenger ribonucleic acid (mRNA)-based vaccines delivered via lipid nanoparticles (LNP) were pivotal in managing the severe acute respiratory syndrome coronavirus (SARS-CoV-2) pandemic. While mild systemic reactions are common after vaccination, rare neurological complications have raised concerns about potential structural cerebral changes. This prospective pilot study tested the hypothesis that LNP-mRNA-based SARS-CoV-2 vaccination does not induce significant microstructural cerebral changes in healthy adults. Dedicated 3 Tesla brain MRI was performed at three time points: up to one month before the first vaccination (t1), and 1-2 weeks (t2) and 2-3 months (t3) after the second dose of either BNT162b2 or mRNA-1273. Across 85 MRI scans from 29 initially SARS-CoV-2-seronegative adults, 2D T2-weighted fluid-attenuated inversion recovery, synthetic 3D T1 magnetization prepared rapid acquisition of gradient echoes and 3D quantitative T1 mapping were analyzed. Changes in w matter hyperintensities (WMH) were evaluated visually (Prins scale) and semiquantitatively (Longitudinal Brain Imaging). Microstructural changes of deep and cortical gray matter and white matter were analyzed using qT1 values via paired t-tests or Wilcoxon signed-rank tests. No new or progressive WMH nor significant intraindividual qT1 changes were observed. QT1% deviations were small (mean 0.1%, SD 0.9%; maximum 2.08%) and remained within established scan-rescan variability limits at 3 T. Apart from a 1 mm decrease of a preexisting WMH in one participant, no visually detectable structural brain alterations were observed. Our findings provide no evidence for WMH progression or microstructural cerebral changes after LNP-mRNA-based SARS-CoV-2 vaccination in healthy adults in the subacute phase.

ID: 42295617
Title: mRNA Vaccines for Influenza: Hope for a Universal Vaccine?
Abstract: Seasonal influenza epidemics and pandemics remain a persistent public health threat. A universal influenza vaccine is urgently needed. Such a vaccine must accommodate rapid viral evolution, strain diversity-including types A and B and their many subtypes-and the complexities of human immune history and biases. Messenger RNA (mRNA)-formulated lipid-nanoparticles have evolved from an emergency pandemic vaccine experiment into a versatile vaccine platform. This technology has demonstrated potential to address several critical challenges in developing a universal influenza vaccine, including rapid strain updates, the production of high-valent formulations, and the ability to target conserved antigens that may induce broader and longer-lasting protection. This review summarizes recent studies and applications of multivalent antigen selection strategies and self-amplifying and circular RNA vaccine platforms to develop mRNA influenza vaccines to achieve vaccine universality, with an emphasis on immune responses against conserved targets. We also review the latest advances in generating long-term mucosal immunity against influenza through optimized mRNA delivery. Finally, we discuss practical considerations for correlates of protection, manufacturing, and accessibility, pioneering mRNA vaccine candidates heading to clinical trials, and milestones that define vaccine "universality."

ID: 42318873
Title: Bacterial mRNA Vaccines: Programming Immunity Against Antimicrobial Resistance.
Abstract: The relentless rise of antimicrobial resistance poses a critical threat to global health, urgently demanding the development of antibacterial vaccines. Messenger RNA (mRNA) technology, validated during the COVID-19 pandemic, offers a powerful platform of fast development and flexibility. However, its application against bacterial pathogens remains an emerging frontier due to the structural complexity of bacterial antigens, challenges in achieving effective mucosal and cellular delivery, and the need to elicit balanced Th1/Th17-dominated immune responses for durable protection. Progress in antigen design, mRNA engineering, and lipid nanoparticle (LNP) delivery has enabled early preclinical success against Mycobacterium tuberculosis, Pseudomonas aeruginosa, and Streptococcus pneumoniae. Yet, challenges such as complex antigen expression, mucosal targeting, and immune durability persist. This review provides a brief overview of recent advances in bacterial mRNA vaccine design, including antigen selection, mRNA engineering, and delivery platform optimization. Additionally, we summarize current preclinical progress across key bacterial pathogens and highlight emerging strategies that integrate AI-guided antigen discovery, synthetic biology, and next-generation delivery systems to accelerate clinical translation. Finally, we highlight the prospects of bacterial mRNA vaccines by integrating synthetic biology, AI-driven antigen prediction, and advanced delivery systems. These cutting-edge technologies hold the promise of overcoming existing barriers, ultimately establishing mRNA vaccines as a viable and powerful strategy to curb the tide of antibiotic-resistant infections.

ID: 42327741
Title: COVID-19 mRNA vaccines: a prospective outlook from technological innovation to clinical practice.
Abstract: The COVID-19 pandemic established mRNA vaccines as a clinically validated platform for rapid vaccine development and deployment. This review summarizes recent progress in COVID-19 mRNA vaccine technology, clinical performance, immunological mechanisms, and translational applications. First-generation nucleoside-modified mRNA vaccines formulated in lipid nanoparticles demonstrated strong protection against symptomatic disease and, more durably, against severe outcomes, while variant-driven immune escape, waning protection against infection, limited mucosal immunity, and heterogeneous responses in special populations revealed important constraints. The review compares mRNA vaccines with other COVID-19 vaccine platforms and clarifies endpoint-specific correlates of protection, emphasizing the distinct roles of neutralizing antibodies, memory B cells, T-cell responses, and non-neutralizing antibody functions. It further examines unresolved issues associated with repeated vaccination, including immune imprinting and IgG4 class switching, and evaluates technological strategies designed to improve durability, breadth, delivery, and immune programming. Key innovations include optimized RNA chemistry, structure-guided antigen design, advanced lipid nanoparticle formulations, alternative delivery systems, immune-shaping adjuvant approaches, and next-generation RNA formats such as self-amplifying RNA and circular RNA. Finally, the review discusses vaccination strategies for immunocompromised individuals, pregnant and lactating women, older adults, and children, as well as the expansion of mRNA technology into respiratory virus vaccines, cancer immunotherapy, and therapeutic protein expression. These developments define mRNA technology as a modular platform whose clinical impact depends on aligning RNA architecture, delivery system, antigen design, and target population.

ID: 42379196
Title: Safety and efficacy of mRNA vaccines: a mechanistic and public health perspective.
Abstract: mRNA vaccines represent a transformative advance in vaccinology, combining rapid development timelines, scalable manufacturing, and strong immunogenicity with a favourable safety profile. Global deployment of mRNA vaccines during the COVID-19 pandemic provided an unprecedented real-world evaluation of this platform, with billions of doses administered across diverse populations. In this Review, we critically examine the safety and efficacy of mRNA vaccines from mechanistic, preclinical, clinical, and public health perspectives. We outline the biological basis of mRNA vaccines, including their transient cytoplasmic expression, lack of genomic integration, and rapid clearance, distinguishing them clearly from other gene therapies. We synthesise evidence on vaccine components, manufacturing quality controls, and regulatory standards that underpin safety, alongside data from randomised trials, post-authorisation surveillance, and active pharmacovigilance systems. We also review real-world effectiveness across age groups, pregnancy, and populations that are immunocompromised, along with the effects on transmission. Last, we address public perception and vaccine confidence, and discuss implications for next-generation mRNA vaccines, including strategies to reduce reactogenicity, improve breadth and durability of immunity, enhance global access, and support sustainable public trust. Together, the accumulated evidence affirms mRNA vaccines as a safe, effective, and adaptable platform with enduring relevance for future infectious disease prevention and public health preparedness, and for the treatment of cancer and autoimmunity.

ID: 42401363
Title: Cross-neutralization of SARS-CoV-2 BA.3.2.2 lineage by JN.1 mRNA vaccine-induced immunity.
Abstract: The SARS-CoV-2 BA.3.2.2 sublineage has emerged globally as the dominant branch of BA.3.2 by late 2025, yet its antigenic relationship with JN.1 vaccine-induced immunity remains unclear. We evaluated neutralizing antibody responses in 25 JN.1 mRNA vaccinees against eight variants, stratified by anti-nucleocapsid antibody serostatus. Postvaccination titers increased significantly against all variants in both N antibody-negative and -positive groups. Cross-neutralization against BA.3.2.2 was detected in both groups despite lower titers compared to JN.1. Antigenic cartography revealed that BA.3.2.2 was antigenically isolated from all JN.1-descendant variants. AZD3152/sipavibart retained potent neutralization against BA.3.2.2 but completely lost activity against all F456L-harboring JN.1-descendant variants, while VYD222/pemivibart and SA55 maintained broad activity. Retention of wild-type F456 in BA.3.2.2 preserves class 1/2 antibody epitopes, providing a mechanistic basis for cross-neutralization and suggesting a potential therapeutic window for sipavibart should BA.3.2.2 expand globally, pending clinical confirmation.

ID: 42410167
Title: SARS-CoV-2-specific immunity after XBB.1.5 vaccination is not significantly altered by subsequent influenza vaccination in dialysis patients.
Abstract: Annual immunisation against COVID-19 and seasonal influenza before the winter waves is increasingly recommended in routine practice. These vaccines may be administered on the same day or sequentially, yet data on the immunogenicity of consecutive vaccinations in patients on dialysis remain limited. In this real-world observational study, we assessed SARS-CoV-2-specific immune responses in dialysis patients receiving the monovalent XBB.1.5-vaccine followed by a quadrivalent influenza vaccine 14 days later, or either vaccine alone. Antigen-specific antibodies and T cells were quantified using enzyme-linked immunosorbent assays and flow cytometry. Baseline analyses showed that most patients had detectable SARS-CoV-2- and influenza-specific immunity prior to the vaccination season. Both vaccines substantially boosted pre-existing humoral and cellular responses. Among XBB.1.5-vaccinated patients, subsequent influenza vaccination did not alter the magnitude of spike-specific antibody or T-cell responses. Likewise, influenza vaccination had no non-specific effect on SARS-CoV-2-specific immunity. Spike-specific responses remained stable for six months and persisted at levels exceeding those of unvaccinated patients assessed during the same period. Sequential administration of COVID-19 and influenza vaccines in patients on dialysis is feasible and was not associated with compromised immunogenicity of either vaccine. These findings support the use of booster vaccination in these patients and inform future deployment of additional mRNA-based vaccines.

ID: 42412769
Title: A piezoelectric electroporator (Piezopen) for enhanced "naked" RNA vaccine delivery.
Abstract: Despite the success of COVID-19 mRNA vaccines, they still face challenges with high costs, complex manufacturing, off-target biodistribution, and systemic reactogenicity stemming from their inflammatory carriers: lipid nanoparticles (LNPs). While "naked" RNA delivery could in principle solve these issues, studies have suggested that it is infeasible due to rapid degradation by RNases and poor cellular entry, thereby necessitating formulations that enhance intracellular delivery and RNA stability. Now, we challenge this paradigm by showing that a simple and inexpensive (<$1), lighter-derived electroporator with microneedle electrodes (Piezopen) can augment gene expression and immunogenicity to naked mRNA leading to comparable responses to LNPs at low doses. We achieve robust responses in the absence of systemic inflammation and reactogenicity using skin-targeted delivery, administer diverse construct types (i.e., mRNA, self-amplifying RNA (saRNA), circular RNA (circRNA)), and demonstrate cross-species validation in live human skin to derisk subsequent clinical application. Our results introduce Piezopen as an inexpensive, well-tolerated, and efficacious alternative to LNPs for mRNA vaccine delivery, designed to facilitate routine vaccinations and pandemic response.

ID: 42415809
Title: A visualization analysis of Traditional Chinese Medicine for influenza prevention and treatment: advances, hotspots, and future trends.
Abstract: As an acute respiratory infectious disease, influenza continues to impose a substantial public health burden worldwide. This study aims to systematically review the progress of research on the treatment of influenza with Traditional Chinese Medicine (TCM) from 2005 to 2025, identify current research hotspots, and forecast future development trends, in order to provide a clear and systematic reference framework for subsequent research. A bibliometric and scientometric analysis was conducted using the Web of Science Core Collection (WOSCC), PubMed, and Scopus databases. Following the PRISMA 2020 guidelines, the retrieved records underwent a comprehensive deduplication process and stringent quality control checks. By comprehensively applying CiteSpace, VOSviewer, and the R-based Bibliometrix package, metrics and visualization were performed across multiple dimensions, including publication volume, geographical contribution, annual trends, national/regional influence, core authors and institutions, and keywords. A total of 1,527 publications were included in this study. Since 2014, publication output in this field has shown significant growth, with a rapid upward trend emerging after 2020. At the national and institutional level, China ranked first globally in both the number of publications and total citation frequency. Research institutions in China not only serve as the dominant force in this field but also act as hubs for international collaboration. Notable contributions were made by institutions such as the Chinese Academy of Sciences, Beijing University of Chinese Medicine, and the China Academy of Chinese Medical Sciences. Journal analysis revealed that the Journal of Ethnopharmacology is the most influential journal in this domain. In terms of scholarly impact, Yang Zifeng ranked first in both h-index and publication output, establishing them as the most prolific and influential core scholar in the field. Keyword analysis indicated that research focuses on core themes such as "herbal medicine" and "antiviral activity." The evolutionary trajectory demonstrates a shift from traditional clinical practice toward modern mechanistic investigation. Driven by emerging public health events such as COVID-19, the field has rapidly integrated cutting-edge methodologies like network pharmacology, reflecting distinct characteristics of contemporary responsiveness and interdisciplinary convergence. This analysis confirms that TCM for influenza has matured into a structured and interdisciplinary research field. Substantial evidence supports its multi-component and multi-target therapeutic model as a clinically effective strategy against influenza. Future efforts should prioritize the integration of mechanistic insights with standardized clinical translation to enhance global antiviral preparedness.

ID: 42435835
Title: Comparative analysis of non-clinical and clinical safety assessment of COVID 19 vaccines.
Abstract: The aim of this work was to propose a comparative analysis of data from non-clinical studies and from pharmacovigilance evaluation collected following the COVID-19 vaccination campaign in France. Five authorized vaccines were included in the analysis: tozinameran (Comirnaty®), elasomeran (Spikevax®), ChAdOx1-S (Vaxzevria®), Ad26.COV2-S (Jcovden®), and the SARS-CoV-2-S protein with Matrix-M (Nuvaxovid®). Among the four adverse events recognized by the European Medicines Agency the following were analysed: reactogenicity in response to vaccines, myocarditis associated with mRNA vaccines, and vaccine-induced thrombotic thrombocytopenia (VITT) associated with viral vector vaccines. A reactogenicity score was developed from PV data, based on reported symptoms and their intensity showing higher reactogenicity with viral vector vaccines. A parallel score was developed from non-clinical data (biomarkers and histopathological analysis). No correlation was evidenced between clinical outcomes and non-clinical parameters. For rare adverse events, the analysis identified clinical biomarkers such as troponin in the case of myocarditis. These rare events were not predicted by non-clinical studies as expected. While non-clinical studies currently meet regulatory safety requirements, their predictive capacity could be enhanced by integrating a reactogenicity scoring system, harmonizing biomarker monitoring, and adding targeted parameters based on clinical evidence.

ID: 42441816
Title: Optimized seasonal influenza mRNA vaccine compositions demonstrate safety and enhanced immunogenicity in a phase 2 study.
Abstract: Seasonal influenza causes considerable morbidity and mortality, with influenza A and B viruses driving most influenza-associated hospitalizations and deaths. Vaccination remains a key influenza prevention strategy; however, current seasonal influenza vaccines based on traditional platforms provide inconsistent protection. Messenger RNA - based vaccines may offer several key advantages over other vaccines, including the flexibility to optimize antigen expression to enhance immunogenicity without the need for adjuvants. mRNA-1010 is an investigational seasonal influenza vaccine candidate that encodes hemagglutinins (HAs) from WHO-recommended influenza strains. In this randomized, phase 2 study, safety, reactogenicity, and immunogenicity of 3 mRNA-1010 vaccine candidate compositions were evaluated in healthy adults aged 18-49 y in the United States (NCT05868382). Eligible participants were randomly assigned to receive a single dose of one of the mRNA-1010 compositions at several dose levels. The primary objective was the safety and reactogenicity of mRNA-1010 vaccine candidate compositions against vaccine-matched strains; secondary and exploratory objectives included humoral and cellular immunogenicity at evaluable timepoints, respectively. Two hundred and seventy participants received study vaccination between May and December 2023. All mRNA-1010 vaccine compositions were well tolerated, with no safety concerns identified; all compositions induced HA-specific humoral and cellular immune responses against all influenza strains evaluated, with the optimized compositions exhibiting higher immune responses against influenza B strains compared with the original mRNA-1010 composition. These results, together with findings from other mRNA-1010 clinical studies, support continued evaluation of mRNA-1010 for enhanced protection against seasonal influenza.Clinical Trials Registration: Clinicaltrials.gov: NCT05868382.

ID: 42467780
Title: A distinct antigen presentation pathway drives potent T cell immunity in lipid nanoparticle-based mRNA vaccines.
Abstract: Lipid nanoparticle-encapsulated mRNA (mRNA-LNP) vaccines trigger the potent differentiation of antigen-specific cytotoxic CD8 T cells in addition to antibody production. Despite its high immunogenicity, the cellular mechanisms by which mRNA-LNP induces such unusual immune responses remain largely unclear. Here, we show that mRNA-LNP induces potent and long-lasting CD8 T cell expansion through an antigen presentation mechanism that differs from that of conventional adjuvants. In mice immunized with mRNA-LNP, the number of antigen-specific CD8 T cells was one order of magnitude higher than that induced by combining antigen proteins with immunostimulants such as lipopolysaccharide or polyinosinic:polycytidinic acid. Intramuscularly administered mRNA-LNPs were mainly taken up by migratory type 2 conventional dendritic cells in draining lymph nodes, resulting in notably strong and persistent antigen presentation through major histocompatibility complex class I. Furthermore, CD8 T cell induction by mRNA-LNP required migratory dendritic cells but not the traditional cross-presentation pathway that is otherwise essential for antiviral and antitumor immunity. Thus, the mRNA-LNP formulation exerts unconventional immune responses through a different antigen-presentation pathway from conventional component vaccines.

ID: 42474084
Title: Defining Composition-Cytokine Relationships Enables the Design of Lipid Nanoparticles with Programmed Immunogenicity.
Abstract: Lipid nanoparticles (LNPs) are central to next-generation vaccines, yet candidate selection remains largely empirical, limiting early identification of formulations associated with rare adverse events such as myocarditis. A better understanding of LNP composition-immunogenicity relationships is therefore critical for rational vaccine design. Here, we profiled a panel of clinically relevant LNP formulations across complementary in vitro and in vivo models to define mechanisms underlying innate immune activation and adaptive responses. We identified three distinct cytokine programs: (i) a monocyte chemoattractant protein-1 (MCP-1)-dominated inflammatory response associated with cytotoxic stress; (ii) inflammasome-dependent interleukin-1 beta (IL-1β) secretion requiring pro-inflammatory priming; and (iii) type I and II interferon-dependent responses in which LNPs synergize with interferon gamma (IFNγ) to amplify interferon gamma-induced protein 10 (IP-10) production. Using a design of experiments (DoE) framework with formulation feature analysis, we found that polyethylene glycol-conjugated (PEGylated) lipid content and ionizable lipid identity are key modulators of the IFNγ/IP-10 axis, previously implicated in vaccine-associated myocarditis. In vivo validation showed that innate cytokine responses are strongly influenced by lipid composition, whereas adaptive humoral and cellular responses correlate with transgene expression rather than cytokine magnitude. Collectively, these findings define relationships among LNP composition, cytokine induction, and vaccine efficacy, and provide a framework for rational design and screening of LNP-based vaccines that maximize immunogenicity while minimizing reactogenicity.

ID: 42486052
Title: Real-world effectiveness and safety of protein-based and mRNA COVID-19 vaccines (BEEHIVE trial).
Abstract: Real-world vaccine effectiveness (VE) and relative VE (rVE) data of protein-based and mRNA COVID-19 vaccines against symptomatic SARS-CoV-2 infections inform policy recommendations and reinforce public confidence. The study aim was to assess the safety and VE of the 2023-2024 protein-based and mRNA COVID-19 vaccines (XBB.1.5) in a real-world setting. The single-site, pragmatic BEEHIVE clinical trial was conducted among participants aged ≥18 years from the Salt Lake City, Utah, area, who had previously received ≥2 mRNA COVID-19 vaccines, from November 17, 2023, through September 9, 2024. Randomized participants received a protein-based or mRNA COVID-19 vaccine in a double-blind manner. An unblinded, nonrandomized comparator control group that did not receive a study vaccine was also enrolled. The primary aim measured VE between the randomized and comparator groups. The secondary aim was to measure rVE between the 2 vaccine platforms. In the modified intention-to-treat (mITT) analysis, VE and rVE were estimated using a proportional-hazards model for symptomatic infections confirmed by weekly self-administered rapid antigen tests (RATs) over 24 weeks, adjusted for covariates. Reactogenicity and treatment-emergent adverse events (TEAEs) were recorded. Randomized cohorts (N = 909; protein-based, n = 452; mRNA, n = 457) were largely well-balanced with some differences in baseline covariates versus the comparator group (n = 279), mostly age-related. The mITT population had 142 RAT-confirmed symptomatic SARS-CoV-2 cases with an adjusted VE of 43.6% (95% CI, 18.3-61.0); rVE (protein-based vs mRNA) was -26.7% (90% CI, -78.6% to 10.1%) and did not reach statistical significance. Safety and reactogenicity were comparable to previously reported findings, with no serious study vaccine-related TEAEs, myocarditis/pericarditis, hospitalization, or death. This is one of the earliest real-world trials evaluating the VE of the 2023-2024 COVID-19 vaccines (XBB.1.5). These results suggest that both protein-based and mRNA vaccines are well-tolerated and significantly reduce the risk of symptomatic SARS-CoV-2 infections.

ID: 42504429
Title: Precisely Engineered Block Copolymers for Efficient PTEN mRNA Therapy of Non-Small Cell Lung Cancer.
Abstract: Restoring the tumor suppressor PTEN (phosphatase and tensin homolog) offers a promising therapeutic strategy for nonsmall cell lung cancer (NSCLC). In particular, mRNA-based therapy provides a compelling alternative to small molecules and DNA-based gene therapy, combining high specificity with an excellent safety profile. However, its clinical translation hinges on the development of safe and efficient delivery systems. In this study, we present a rationally designed diblock copolymer that mediates highly effective PTEN mRNA delivery both in vitro and in vivo. The copolymer consists of a stealth PEG block and a cationic binding block, with precisely engineered 3-acrylamidophenylboronic acid (AAPBA) and N-(3-dimethylaminopropyl) methacrylamide (DMAPMA) units. Following optimization of the PEG chain length, the structure PEG45-b-P(AAPBA21-co-DMAPMA18) achieved a critical balance of delivery properties, leading to enhanced cellular uptake, facilitated endosomal escape, and enabled mRNA release for protein translation. When further functionalized with folic acid (FA), the copolymer successfully restored PTEN expression and inhibited tumor growth (81.0% relative to the PBS control group) in vivo, with no significant toxicity observed under the tested conditions. We anticipate that this block copolymer-based PTEN mRNA delivery platform could provide a promising new approach for the treatment of NSCLC.

ID: 42505558
Title: From Pandemic Innovation to Platform Diversification: A Systematic Review of Clinical and Preclinical Development of Non-SARS-CoV-2 mRNA Vaccines.
Abstract: Background: Messenger RNA (mRNA) vaccines have emerged as a versatile platform beyond SARS-CoV-2, with expanding applications in infectious diseases and oncology. However, comprehensive evidence synthesis of non-SARS-CoV-2 mRNA vaccines remains limited. Methods: This systematic review followed PRISMA 2020 guidelines and was registered in PROSPERO (CRD420261323500). MEDLINE, Embase, Web of Science, Scopus, ClinicalTrials.gov, and WHO ICTRP were systematically searched for studies published between 1 January 2000 and 28 February 2026. Eligible studies included phase I-III clinical trials and in vivo preclinical studies evaluating non-SARS-CoV-2 mRNA vaccines. Two reviewers independently screened studies, extracted data, and assessed risk of bias using RoB 2, ROBINS-I, and SYRCLE tools. Findings were synthesized narratively because of substantial heterogeneity. Results: A total of 40 studies met the eligibility criteria and were included in the review, comprising 20 clinical studies and 20 preclinical studies. Advanced clinical programs targeted influenza and respiratory syncytial virus (RSV), with phase III trials displaying seroconversion rates above 70% with good safety profiles. Preliminary phase I studies for HIV, cytomegalovirus, rabies, and personalized cancer mRNA vaccines showed promising humoral and cellular immune responses. Preclinical studies showed strong antibody and T-cell responses against malaria, tuberculosis, Group B Streptococcus, and Zika virus. Most adverse events were mild to moderate, while serious vaccine-related adverse events were uncommon. Conclusions: Non-SARS-CoV-2 mRNA vaccines demonstrate substantial translational potential across infectious disease and oncology applications. Although the vaccine candidates have demonstrated promising immunogenicity and safety, most are in the early stages of development. This highlights the need for large trials, long-term safety follow-up and better global representation.

ID: 42506657
Title: Possible Mechanisms of mRNA-LNP Degradation: A Comprehensive Review.
Abstract: Messenger RNA-lipid nanoparticle (mRNA-LNP)-based drug products represent a promising platform for prophylactic and therapeutic applications. However, their limited stability poses significant challenges for storage and global distribution. The instability of mRNA-LNP products makes them dependent on ultra-cold chain systems. This instability is driven by various physicochemical factors, including temperature, pH, light exposure, oxidation, aggregation, shear stress, and humidity. These factors destabilize the physical and chemical integrity of both mRNA and lipid nanoparticle (LNP) components, leading to reduced vaccine potency and potentially increasing the risk of adverse safety outcomes. Understanding these factors and their mechanisms is crucial for retaining mRNA-LNP efficacy. This review discusses the key physicochemical instability factors and molecular degradation mechanisms responsible for the structural and functional deterioration of mRNA-LNP formulations. Further, we summarize the stabilization strategies and analytical methods used to detect and quantify the degradation of mRNA-LNP products. Addressing these challenges is critical for advancing next-generation nucleic acid-based drug products and LNP-based delivery systems.

ID: 42516097
Title: Persistent SARS-CoV-2 Spike Protein in Vasculitic Skin Lesions after Infection or mRNA Vaccination: A Retrospective Case control Immunofluorescence Study.
Abstract: Vasculitic skin lesions have been reported in association with both SARS-CoV-2 infection and vaccination. Whether viral proteins persist in lesional vessels beyond the acute phase remains unclear. The aim of this study was to investigate the presence of SARS-CoV-2 spike protein in persistent or delayed-onset cutaneous vasculitis temporally associated with COVID-19 infection or vaccination. This retrospective case-control study includes 9 patients with persistent or delayed-onset vasculitic skin lesions following COVID-19 infection (n=4) or mRNA vaccination (n=5). Skin biopsies were analysed using immunofluorescence for SARS-CoV-2 spike protein. Prepandemic leukocytoclastic vasculitis (n=3) and healthy postinfection/postvaccination skin (n=3) served as controls. Spike protein was detected in vascular endothelial cells of all 9 patients with COVID-19- or vaccine-associated vasculitis. Staining was absent in all prepandemic vasculitis and healthy control samples. Histopathology showed typical features of leukocytoclastic vasculitis without evidence of viral cytopathic changes. We found that SARS-CoV-2 spike protein can persist in endothelial cells of vasculitic skin lesions weeks to months after COVID-19 infection or mRNA vaccination. These findings suggest that retained viral proteins may contribute to prolonged or delayed-onset vasculitic skin manifestations. Further studies are needed to clarify the mechanisms underlying spike persistence and its clinical significance.

ID: 42520140
Title: Effect of probiotics on humoral responses to COVID-19 vaccination in older adults: a randomized, placebo-controlled trial (PIRATES-COV study).
Abstract: Although COVID-19 vaccination has reduced morbidity and mortality, adults aged 65 y old and older are at high risk of complications from COVID-19. The evidence suggests that probiotics may enhance immune responses when co-administered with influenza vaccination. However, few studies have evaluated the potential benefit of probiotic supplementation in this context in this high-risk population. This study was a randomized controlled trial recruiting adults between 65 and 89 y of age living in Quebec, Canada, who received an mRNA booster (Pfizer-BioNTech or Moderna). Probiotic supplementation (Lacticaseibacillus rhamnosus Rosell®-11 and Lacticaseibacillus paracasei Rosell®-215, 1x 6 x 109CFU per capsule) versus placebo was administered from 15 d pre- to 15 d post-vaccination. Participants provided dried blood spot samples at baseline, at 3- and 6-month post-vaccination. The primary outcome was the proportion of participants without detectable anti-S1-receptor binding domain (anti-S1-RBD) antibodies at 6 months post-vaccination. Secondary outcomes included longitudinal anti-S1-RBD and anti-nucleocapsid (anti-N) antibody responses across the three timepoints. 592 adults were enrolled. At 6 months post-vaccination, anti-S1-RBD antibodies were comparable between groups, and the percentage of participants with undetectable antibody response in the placebo and probiotic groups (1.2% vs 1.6%) was comparable. Anti-N seropositivity was lower in the probiotic group at 6 months (OR 0.6, 95% CI 0.4-0.9; p = 0.02) and marginally lower at 3 months after adjustment. Self-reported COVID-19 infection incidence was 16.5% overall (19.1% placebo vs 13.9% probiotic; p = 0.134). Probiotic supplementation administered around COVID-19 vaccination did not change the proportion of seronegative participants for anti-S1-RBD antibodies at 6 months. However, in the probiotic group, anti-N antibody levels were lower, while self-reported COVID-19 infections also tended to be reduced, although this difference was not statistically significant. They may be consistent with earlier control of infection and reduced exposure to the nucleocapsid antigen, but this interpretation remains speculative. #NCT05195151.

ID: 42522246
Title: The Role of CD4 T Cell Repertoire and Immune Memory Mechanisms in Vaccination and Infection Immunity.
Abstract: CD4+ T cells orchestrate adaptive immunity against respiratory viruses through functionally distinct subsets, yet the qualitative differences between vaccine- and infection-induced responses remain incompletely understood. This review summarizes current evidence on how CD4+ T cell subsets shape the magnitude, breadth, and durability of immunity to SARS-CoV-2 and influenza virus. mRNA vaccines elicit a potent Th1/Tfh1-biased response that generates high-affinity neutralizing antibodies and cytotoxic CD4+ T cells (CD4-CTLs) with stem-cell memory properties. However, this strong type I bias may come at the cost of long-term maintenance of humoral memory. Natural infection additionally establishes tissue-resident memory CD4+ T cells (CD4 TRMs) at respiratory mucosal surfaces, providing a frontline defense that current intramuscular vaccines fail to recapitulate efficiently. Crucially, this T cell immunity proves far more resilient than neutralizing antibodies against Variants of Concern, as many memory T cell epitopes from the ancestral strain are conserved across successive variants, a robustness further reinforced by pre-existing cross-reactive CD4+ T cells primed through prior seasonal coronavirus exposure or influenza infection. These observations argue for a fundamental shift in vaccine design toward mucosal delivery and conserved-epitope antigens to achieve durable, broadly cross-reactive protection.

ID: 42528137
Title: Capless self-amplifying mRNA vaccine induces dose-sparing protective immunity against HPAI clade 2.3.4.4 H5 virus in mice.
Abstract: Self-amplifying mRNA (samRNA) vaccines can induce potent immune responses at lower doses than conventional non-replicating mRNA vaccines; however, large RNA size and manufacturing considerations associated with 5' capping remain important challenges. Here, we developed a capless samRNA (CLsamRNA) vaccine platform derived from a Coxsackievirus B5 replicon that uses IRES-mediated cap-independent translation. Systematic optimization of key genetic elements enhanced antigen expression from the CLsamRNA backbone. Using reporter RNAs, LNP-formulated CLsamRNA showed rapid early expression and RNA amplification, with expression kinetics distinct from VEEV-based saRNA and nucleoside-modified mRNA comparators. When encoding the hemagglutinin antigen of highly pathogenic avian influenza clade 2.3.4.4 H5 viruses, CLsamRNA induced potent immune responses after LNP formulation. In mouse models, CLsamRNA induced potent neutralizing antibody responses, cross-reactive activity against clade 2.3.4.4b H5N1 virus, Th1-skewed humoral immunity, and strong antigen-specific cellular immune responses. CLsamRNA also elicited platform-specific early inflammatory and lymph-node immune gene signatures associated with antigen presentation, costimulation, and cellular immune priming. Notably, a minimal 0.01 μg dose of CLsamRNA conferred complete protection against lethal H5N8 influenza virus challenge in BALB/c mice. These findings support CLsamRNA as a distinct cap-independent RNA vaccine platform with dose-sparing protective efficacy against HPAI H5 viruses.

ID: 42529204
Title: Toll-like receptors in infectious myocarditis: pathogen-specific recognition, spatiotemporal dynamic regulation and clinical translation.
Abstract: Infectious myocarditis is a life-threatening cardiovascular inflammatory disorder characterized by high heterogeneity in clinical onset, progression and prognosis. Large-sample clinical data have demonstrated that the in-hospital mortality of COVID-19-associated myocarditis reaches 19.4%, significantly higher than that of influenza-associated myocarditis (10.5%). Additionally, the incidence of adeno-associated virus (AAV) gene therapy-related myocarditis is 6.2%, while the mortality of sepsis-associated myocarditis is as high as 70%-90%. Toll-like receptors (TLRs), the core pattern recognition receptors of innate immunity, dominate the entire pathological cascade, ranging from pathogen recognition and acute inflammatory burst to myocardial injury and chronic fibrous remodeling. Nevertheless, most current studies merely focus on the linear correlation between individual TLR activation and myocardial inflammation, failing to systematically clarify pathogen-TLR matching specificity and the spatiotemporal dynamic regulatory mechanisms of TLR signaling throughout disease progression. This review comprehensively combs the latest epidemiological profiles of infectious myocarditis, characterizes the expression patterns and signaling regulatory features of the TLR family within the cardiac immune microenvironment, analyzes pathogen-specific recognition modes mediated by common pathogens, elaborates the spatiotemporal regulatory rules of TLR signaling across acute inflammation, immune deviation and chronic fibrosis stages, and summarizes pathogen-oriented intervention strategies as well as relevant translational bottlenecks. Cumulative clinical evidence confirms that pathogen-TLR matching determines inflammatory phenotypes and severity of infectious myocarditis, and that the spatiotemporal dynamics of TLR signaling directly govern disease progression. Notably, TLR-targeted therapies must adhere to the core principles of pathogen specificity and staged precise regulation. This review provides a systematic theoretical basis for precise immunodiagnosis and individualized immunotherapy of infectious myocarditis.

ID: 42531981
Title: Immunogenicity, reactogenicity, and safety of an mRNA-based seasonal influenza and SARS-CoV-2 multicomponent vaccine, mRNA-1083, in adults aged ≥50 years in Japan.
Abstract: A multicomponent vaccine targeting seasonal influenza and coronavirus disease 2019 (COVID-19) may reduce disease burden by providing simultaneous protection in a single injection. We report findings from Part 1 (Japan) of a phase 3, Asia-Pacific, randomized, observer-blind study evaluating immunogenicity, reactogenicity, and safety of mRNA-based multicomponent vaccine mRNA-1083, combining influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens. Participants aged ≥50 years were randomized (1:1) to receive mRNA-1083 + placebo or Japan-licensed influenza hemagglutinin (HA) vaccine + mRNA-1273. Overall, 2022 participants were randomized, and 2013 received study intervention. At Day 29, mRNA-1083 elicited noninferior immune responses versus active comparators for all evaluated influenza strains and SARS-CoV-2. Among high-risk participants (aged ≥65 years and 60 to <65 years with ≥1 comorbidity), noninferiority of mRNA-1083 was demonstrated for comparator-matched influenza strains and SARS-CoV-2. In the overall study population, mRNA-1083 demonstrated superiority for the comparator-matched influenza strains and for SARS-CoV-2. At Day 181, immune responses remained above baseline and were comparable to or numerically higher than those elicited by active comparators. Most solicited adverse reactions were grade 1 or 2. There were no cases of myocarditis or pericarditis, and no reported serious adverse events or deaths related to study intervention. Overall, mRNA-1083 demonstrated an acceptable safety profile, eliciting noninferior and superior immune responses against influenza and SARS-CoV-2 in the high-risk and overall study population, respectively. Immune responses were maintained through 6 months post-vaccination. These findings support mRNA-1083 as a single-dose approach to seasonal vaccination against influenza and SARS-CoV-2 in adults ≥50 years. ClinicalTrials.govidentifier: NCT06694389 (https://clinicaltrials.gov/study/NCT06694389).

ID: 42540005
Title: CXCL10 rs8878 identifies a genotype-associated immune phenotype linked to T-lymphocyte preservation and survival in sepsis.
Abstract: Sepsis is characterized by a dysregulated host response to infection, leading to concurrent hyperinflammation and immunosuppression, including profound alterations in T lymphocyte homeostasis. The chemokine CXCL10, an interferon-γ-inducible mediator of T cell trafficking, has been implicated in immune activation and tissue injury. However, it remains unclear whether genetic variation in CXCL10 contributes to T cell dysregulation and clinical outcomes in sepsis. In a prospective cohort of septic patients (n=278), we analyzed CXCL10 rs8878 genotypes, circulating immune cell counts, cytokine concentrations, and CXCL10 protein and mRNA expression in whole blood. Associations between genotype, immune parameters, plasma proteomics and 30-day survival were assessed using group comparisons and Kaplan-Meier analyses. Correlation analyses were performed to evaluate relationships between CXCL10 concentrations, cytokines, and clinical parameters. Variants in the CXCL10 gene were associated with T cell dysregulation. Carriers of the rs8878 AA genotype exhibited higher circulating T cell counts and improved survival compared with G-allele carriers. Higher total and CD8+ T cell counts were significantly associated with improved survival. Among non-survivors, AA-genotype carriers showed increased CXCL10 mRNA expression, indicating genotype-dependent regulation of CXCL10 expression under conditions of fatal disease progression. CXCL10 concentrations on day 1 were positively correlated with multiple inflammatory cytokines, including IL-6, IL-8, IL-10, IL-18, MCP-1, IFN-γ, and interferon-α2, and inversely correlated with total T cell counts, supporting a link between CXCL10, systemic inflammation, and T cell depletion. No significant associations were observed between CXCL10 genotype and plasma proteomics and routine clinical parameters. The CXCL10 rs8878 genotype is associated with T cell dynamics and 30-day survival in sepsis, suggesting a genotype-dependent modulation of the adaptive immune response. While the AA genotype is linked to preserved T cell counts and improved outcomes, increased CXCL10 expression in non-survivors points to a context-dependent role in inflammation-driven immune dysregulation. These findings identify CXCL10 as a potential biomarker for risk stratification and a candidate target for immunomodulatory therapies in sepsis.

ID: 42541307
Title: N-terminal fusion length: The key to reliable and context-preserving regulatory sequence characterization.
Abstract: Regulatory sequences are commonly characterized using fluorescent reporters, yet how N-terminal coding context shapes these measurements has not been systematically quantified. Here, we evaluated the impact of N-terminal fusion length (45-180 bp) from four genes (lacZ, icd, zwf, bfp) on GFP reporter expression driven by 15 different promoter-RBS combinations in E. coli with normalized fluorescence, enzymatic activity assays and transcription analysis for a representative subset of constructs. Our results demonstrate that N-terminal fusion critically determines the reliability of regulatory-sequence characterization in target-gene-specific coding contexts, with strong gene- and length-dependent effects. Fusions as short as 45 bp failed to rescue context-sensitive cases. However, among the tested fusion lengths, fusions of 90 bp or longer achieved strong correlations (mean R2 > 0.75) between reporter fluorescence and target protein activity. Among the factors examined, N-terminal mRNA secondary structure showed a closer association with these fusion-length-dependent effects than transcription or translation initiation changes. This practical, context-preserving fusion strategy provides cost-effective guidance for scalable and accurate regulatory sequence profiling.

ID: 42541646
Title: Past achievements and future perspectives of personalized vaccines and the role of dendritic cells.
Abstract: Personalized vaccines provide the advantage of patient-specific antigen selection to optimize immune responses, a strategy extensively explored in oncology through neoantigen-targeted peptide, mRNA, and dendritic cell platforms. Peptide vaccines provide simplicity and stability though often elicit limited cytotoxic T-cell responses. What is more, mRNA vaccines lead to rapid, multiplexed neoantigen delivery, endogenous antigen processing and eventually improved immunogenic coverage. Dendritic cell-based vaccines have the potency to prime potent T-cells although this technology requires labor-intensive manufacturing and extensive production timelines. Integration with immune checkpoint inhibitors, adoptive cell therapies, and oncolytic viruses further enhances efficacy, suggesting that rational combinations may be more effective than single modalities. Recent advances in sequencing, computational epitope prediction, and bioinformatics pipelines have facilitated neoantigen prioritization and DC vaccine design, enabling more rapid and precise personalization. Hybrid vaccination strategies, such as ex-vivo mRNA-electroporated dendritic cells and in-vivo DC-targeted platforms, bridge the gap between manufacturing feasibility and potent immune activation. Emerging technologies, including AI-driven neoepitope prediction, receptor-targeted antigen delivery, biomaterial-based modulation, and distributed mRNA manufacturing, seem to be promising approaches to accelerate personalized vaccine development in future. From another point of view, lessons learned from the COVID-19 pandemic accelerated the development, large-scale deployment, and validation of mRNA vaccine platforms for infectious diseases. Host HLA diversity, prior immune history, and viral evolution create heterogeneity in immune responses, highlighting opportunities for semi-personalized or adaptive strategies. In this review, we provide a landscape of personalized vaccines, with a focus on DC-based platforms, and explore translational lessons for viral pathogens. A conceptual framework linking cancer immunotherapy and infectious disease preparedness is proposed, emphasizing hybrid personalization approaches, rapid manufacturing, and AI-enabled epitope selection. This perspective highlights how convergence of immunology, computational biology, and advanced vaccine technologies could expand the scope of personalized vaccination, from oncology to future epidemic and pandemic scenarios as well as the current challenges.

ID: 42546636
Title: Advances in clinical immunogenicity evaluation of influenza vaccines.
Abstract: Influenza vaccination is an effective intervention for preventing severe influenza, and assessing its immunogenicity is a critical step in determining vaccine protective efficacy. With the widespread use of influenza vaccines-including split-virion, subunit, recombinant protein, and live attenuated formulations-methods for evaluating immunogenicity have grown increasingly diverse and complex. This article systematically examines the advantages and limitations of various immunogenicity assessment approaches for influenza vaccines. It draws upon multidimensional evaluation frameworks covering humoral, cellular, and mucosal immunity, incorporating analytical techniques such as hemagglutination inhibition assays, microneutralization assays, enzyme-linked immunosorbent assays, mucosal secretory IgA detection, enzyme-linked immunospot assays, and flow cytometry. Furthermore, clinical challenge trials evaluations play an essential role in elucidating the relationship between immunogenicity and protective efficacy. This paper aims to establish a systematic and comprehensive reference framework for the development and immunogenicity evaluation of influenza vaccines, thereby advancing vaccine design and the prediction of protective outcomes toward greater precision.

ID: 42546637
Title: Switching the default: a formative evaluation of pre-booked appointments on COVID-19 vaccination uptake and effects on intended uptake.
Abstract: In autumn 2023, COVID-19 vaccination invitations in the Netherlands shifted from self-scheduling to pre-booked appointments for selected groups. While defaulting to pre-booked slots may increase uptake, potential rebound effects remain unclear. We examine preferences between appointment types, their effect on vaccination intentions, and whether effects are different for individuals hesitant about this vaccination round. A mixed-methods approach was used to assess vaccination intentions for three groups (<60 with influenza vaccination indication, 60-69 and 70+ years) eligible for pre-booked appointments. In a two-phase formative evaluation study, we examined attitudes around pre-booked appointments in 15 interviews (phase 1) and experimentally tested (phase 2) perceived burden of pre-booked appointments vs self-scheduled appointments and their effect on vaccination intentions in a representative online panel (n = 1.886) and those who experience hesitancy about this vaccination. Interviews (phase 1) showed that pre-booked appointments are seen as presumptuous or inconvenient by some, but also as a useful aid in support of vaccination uptake, sometimes by the same people. Participants in the experiment (phase 2) indicated to perceive self-scheduling as less burdensome (Coefficient = -0.23) but this perception did not translate to differences in vaccination intentions (Adjusted OR = 1.11) Similar results were observed in the hesitant subgroup (Coefficient = -0.25; Adjusted OR = 0.88). In our study pre-booked appointments do not change COVID-19 vaccination intentions. As pre-booked appointments evoked negative and positive sentiments and self-scheduling was found easier and more pleasant, we conservatively recommend its implementation for older adults who received their COVID-19 vaccination the previous year.

ID: 42546898
Title: Adjuvanted and high-dose influenza vaccines had comparable effectiveness against test-confirmed influenza outcomes including hospitalizations in overall and high-risk older adults in the 2022-2023 and 2023-2024 seasons.
Abstract: Evaluate relative vaccine effectiveness (rVE) of adjuvanted quadrivalent influenza vaccine (aQIV) versus high-dose QIV (HD-QIV) in preventing test-confirmed influenza during 2023-2024 in any setting and emergency department (ED)/hospitalization settings, as well as in preventing hospitalizations in overall and high-risk older adults in a pooled analysis from 2022-2024. This retrospective test-negative design study included US adults aged ≥65 years vaccinated with aQIV or HD-QIV who presented with acute respiratory or febrile illness and were tested for influenza per routine care. The rVE of aQIV versus HD-QIV was evaluated combining inverse probability of treatment weighting and logistic regression to adjust for potential confounders. The 2023-2024 season included 37,377 vaccinated and tested individuals (3,174 cases; 34,203 controls). rVE of aQIV versus HD-QIV was -0.9% (95% CI: -9.9, 7.3) in any setting and 0.5% (-12.1, 11.6) in ED/hospitalization settings. For pooled analyses of hospitalizations, rVE was -0.5% (-13.4, 10.9) overall and -1.3% (-14.4, 10.4) in the high-risk subgroup. aQIV and HD-QIV provided comparable protection for prevention of test-confirmed influenza among older adults in any and ED/hospitalization settings in the 2023-2024 season and for hospitalizations in overall and high-risk older adults in pooled 2022-2024 analyses.

ID: 42550058
Title: Indirect comparison of mRNA-1010 versus enhanced influenza vaccines in adults aged 65 years and older during the 2024-2025 US influenza season.
Abstract: Seasonal influenza continues to cause severe disease among older adults in the United States despite enhanced vaccine recommendations, driven by immunosenescence and vaccine mismatch with circulating influenza viruses. mRNA-based influenza vaccines (mRNA-1010), addressing some of these challenges, have been developed for this population. A previous trial found mRNA-1010 demonstrated superior immunogenicity compared to enhanced high-dose influenza vaccination. As no direct evidence exists comparing mRNA-1010 efficacy to currently available enhanced influenza vaccines (EVs), we aimed to indirectly compare the effectiveness of mRNA-1010 and licensed EVs against medically attended influenza infection among adults ≥65 years in the US. We conducted an anchored indirect treatment comparison (ITC) using the Bucher method to estimate the relative vaccine effectiveness (rVE) of mRNA-1010 vs EV, with standard-dose egg-based influenza vaccine as the anchor, using individual patient-level data from adults ≥65 years from a real-world Optum claims-based analysis and the pivotal mRNA-1010-P304 clinical trial. Target trial emulation and inverse probability weighting (IPW) were implemented to address potential bias due to cross-population differences. Sensitivity analyses were conducted using alternative outcome definition, alternative weighting approaches and US trial sites only. Assessments of post-IPW supported a comparable common anchor for the ITC. Among adults ≥65 years, the indirect rVE of mRNA-1010 vs. enhanced vaccines against medically attended influenza was 12.82% (95% CI: -36.91%, 44.49%). Sensitivity analyses also supported these findings. mRNA-1010, a new mRNA-based influenza vaccine, was shown to be comparable to currently licensed EVs among older adults ≥65 years against medically attended influenza outcomes. Consistency of findings across sensitivity analyses support the robustness of these results. Newer influenza vaccine modalities, including mRNA-based vaccines provide an additional comparable option to existing EVs to help further reduce severe influenza disease burden among older adults ≥65 years for whom enhanced vaccines are recommended.

ID: 42553356
Title: Estimation of populations at risk for severe influenza and vaccination coverage in Mexico, 2010-2021.
Abstract: Influenza remains an important cause of morbidity among populations with underlying medical conditions associated with increased risk of severe disease. This study aimed to estimate the size of populations eligible for influenza vaccination according to the Mexican Universal Vaccination Program and to evaluate vaccination coverage gaps among populations at risk in Mexico between 2010 and 2021. A retrospective analytical study was conducted using epidemiological and administrative healthcare databases from Mexican public healthcare institutions. Population estimates were constructed using prevalence-based epidemiological projections, healthcare system records, and attended patient data from populations at risk. Descriptive analyses and time-series modeling were performed to evaluate vaccination coverage patterns and healthcare demand over time. Across all analyzed populations at risk, the number of individuals receiving healthcare services was consistently lower than the number of notified cases and substantially lower than prevalence-based epidemiological estimates. Vaccination coverage varied considerably across populations at risk and remained incomplete throughout the study period. In 2021, although approximately 12.5 million influenza vaccine doses were administered among populations at risk, a substantial proportion of potentially eligible individuals remained unvaccinated. Forecasting analyses suggested a progressive increase in healthcare demand among populations at risk over time. Important gaps persist between the estimated population at risk, diagnosed individuals, healthcare utilization, and influenza vaccination coverage in Mexico. The analytical framework proposed in this study integrates epidemiological prevalence estimates, healthcare utilization patterns, and vaccination data to identify unmet vaccination needs and may support improved public health planning, prioritization strategies, and strengthening of influenza vaccination programs in Mexico and similar settings.

ID: 42555398
Title: Respiratory syncytial virus inhibits type I interferon signaling to maintain HLA-DM expression in CD1c+ dendritic cells.
Abstract: Respiratory syncytial virus (RSV) infection often elicits ineffective long-term immune responses due to inefficient immune priming, complicating disease management and vaccine development. Dendritic cells (DCs) are central regulators of antiviral immunity and antigen presentation; yet, the direct impact of RSV on these pathways remains poorly understood. In this study, we identify sustained HLA-DM expression as a unique hallmark of RSV infected CD1c+ DCs, a phenotype not observed following influenza infection or poly(I:C) stimulation. Using single cell RNA sequencing, pharmacological inhibition, and complementary controls, we demonstrate that TBK1 dependent Type I Interferon signaling is a key regulator of HLA-DM expression during DC maturation. Co-culture experiments further suggest that HLA-DM-high DCs influence CD4+ T cell differentiation, supporting a model in which sustained HLA-DM expression reshapes antigen presentation and downstream adaptive immunity. Together, these findings uncover a previously unknown link between innate antiviral signaling and antigen presentation machinery in human DCs.

ID: 42560331
Title: Expanding the role of pharmacists as vaccinators in New Zealand: a retrospective analysis of influenza vaccination trends following policy change.
Abstract: Pharmacy-based influenza vaccination became part of New Zealand's public vaccination programme in 2017, eliminating out-of-pocket costs to consumers. This study evaluated trends in pharmacy-based influenza vaccination among adults aged ≥65 in New Zealand following the 2017 funding policy change, with the aim of examining whether the availability of government-funded influenza vaccination increased pharmacy-based vaccination in this population. Data on influenza vaccinations administered between 2015 and 2021 to adults ≥65 were provided by the New Zealand Ministry of Health from the National Immunisation Register. Descriptive analyses were employed to assess the absolute number and percentage of vaccinations given by each provider type from 2015 through 2021 to document trends after the public funding policy change and in the early years of the COVID-19 pandemic. The total number of influenza vaccinations administered increased from 322 161 in 2015 to 525 769 in 2021. After public funding for influenza vaccination began in pharmacies, annual physician- and nurse-administered vaccinations ranged from 401 840 to 426 005 and 12 590 to 19 586, respectively, between 2018 and 2021, while pharmacist-administered vaccinations steadily increased from 16 042 to 96 343. The percentage of influenza vaccinations administered by pharmacists grew from nearly 0% in 2015 to 3.7% in 2018 and 18.3% in 2021. Research findings suggest that public funding for pharmacist-administered influenza vaccinations contributed to expanding overall influenza vaccine access in New Zealand among adults ≥65. In addition, the increase in pharmacist-delivered vaccinations did not negatively impact vaccinations administered by traditional providers, further demonstrating the value and growing role of pharmacies in advancing national immunization efforts.