Search Results (249)

Mucosal-associated invariant T (MAIT) cells exist in high numbers in the body and have a unique and highly conserved T cell receptor (TCR). They can be activated in a TCR-dependent manner by ligands presented on the monomorphic protein MHC class I-related protein 1 (MR1) which is found on many cell types, including professional antigen presenting cells (APCs) and epithelial cells. This has sparked interest in the potential to exploit the MR1-MAIT cell axis for the development of vaccines against infectious disease. Within this context an MR1 ligand, typically 5-(2-oxopropylideneamino)-d-ribitylaminouracil (5-OP-RU), is administered with or without a Toll-like receptor (TLR) ligand or cytokine in a pan vaccination approach that would prime the immune response to provide protection against a variety of bacterial and viral pathogens. This strategy has led to enhanced protection in murine models of Legionella longbeachae, Francisella tularensis, Klebsiella pneumoniae, Streptococcus pneumoniae and influenza infection. However, studies against Mycobacterium tuberculosis infection have proven less successful. The second vaccination approach involves pairing the MR1 ligand with more conventional antigens that could activate CD4⁺ and/or CD8⁺ T cells. This approach has been successful in murine models of cholera, influenza, and SARS-CoV-2, including in the context of subunit vaccines. However, there are several challenges when using MR1-MAIT cell-mediated vaccine adjuvants. These include the inherent instability of 5-OP-RU and the need for more advanced studies to better understand how the use of MR1 ligands would translate to applications in humans. This review will discuss these aspects and highlight the mechanistic studies that have been undertaken to understand how MAIT cells might elicit their effects within the context of MAIT cell-mediated vaccines for infectious disease. Full article

Annual influenza vaccination remains critical for mitigating severe illness and reducing healthcare strain, particularly among high-risk populations. Despite advancements in vaccine platforms, the comparative efficacy of novel vaccines—such as high-dose (HD-IIV), recombinant (rIV), cell-based (cIV), and adjuvanted (aIV) influenza vaccines—versus standard-dose non-adjuvanted (SD-IIV) vaccines remains a public health concern. Traditional Relative Vaccine Efficacy (rVE) metrics, though robust, may overestimate population-level benefits. This short communication explores alternative comparative efficacy measures: risk difference (ΔRD) and number needed to vaccinate (ΔNNV). Analysis of data derived from randomized controlled trials (RCTs), or robust pragmatic trials, shows that while rVE values for newer vaccines often indicate superior efficacy, ΔRD and ΔNNV highlight the limits in incremental protection at the population level, with ΔRD generally below 10 cases per 1000 vaccinated. These findings underline the sustained relevance of SD-IIV in immunization programs and emphasize the need for broader vaccine coverage to highlight the benefits of vaccination and enhance population health outcomes. Full article

Background/Objectives: While new vaccines are in development; one strategy to increase influenza vaccine coverage is to repurpose current influenza vaccines for intranasal delivery. Methods: To address this goal; mice were vaccinated intranasally with either a split inactivated virus vaccine (Fluzone) or a recombinant HA vaccine (Flublok) at one of two doses (1 μg high dose or 0.1 μg low dose). Both vaccines were adjuvanted with either a STING agonist; c-di-AMP (CDA); or a combination of a synthetic toll-like receptor (TLR) 4 and TLR7/8 agonist (TRAC478). Results: Mice vaccinated with either vaccine plus adjuvant had higher hemagglutination-inhibition titers than mice administered unadjuvanted vaccines. Mice vaccinated with either vaccine plus CDA had on average higher numbers of H3 and influenza B hemagglutinin (HA)-specific antibody-secreting cells (ASCs); whereas mice vaccinated with vaccine plus TRAC478 had on average higher number of H1 HA-specific ASCs. All vaccinated mice challenged with the H1N1 influenza virus were protected against both morbidity and mortality with no detectable virus in their lungs. Mice challenged with the H3N2 influenza virus all lost weight over the first 5 days of infection. Adding TRAC478 with either a high or low dose vaccine resulted in 80–100% survival following challenge. Almost all mice vaccinated with Flublok plus CDA died from H3N2 influenza virus challenged with ~2 logs higher viral lung titers than mice administered Flublok only or Flublok plus TRAC478. Conclusions: Overall; Fluzone and Flublok can effectively be used for intranasal vaccination. Full article

Background: Pertussis, diphtheria, tetanus, poliomyelitis, and Haemophilus influenzae type b (Hib) infections pose severe threats to children’s health globally. This study evaluated the safety and immunogenicity of a novel Sabin strain-based adsorbed pentavalent vaccine (DTacP-sIPV/Hib), which offers potential advantages in biosafety and cost-effectiveness compared to wild-type poliovirus-based vaccines. Methods: A repeated-dose toxicity study was conducted in 190 Sprague-Dawley rats, randomly divided into negative control, adjuvant control, low-dose, and high-dose groups. Animals received five intramuscular injections at 21-day intervals, followed by a 56-day recovery period. Parameters assessed included local reactions, body temperature, hematology, serum biochemistry, coagulation, histopathology, T-cell subsets, cytokine levels, and antigen-specific immunogenicity. Results: The primary adverse reaction was dose-dependent local muscle swelling, which was fully reversible within 3–21 days. Only transient body temperature fluctuations and adjuvant-related hematological/biochemical abnormalities were observed, all resolving after the recovery period. No vaccine-related damage occurred in hepatic/renal function or immune organs. Immunogenicity data showed 100% seroconversion for all bacterial components 21 days after the first dose. The high-dose group achieved 100% seropositivity for all poliovirus serotypes after the second dose, while the low-dose group reached the same after the third dose, with no significant difference in antibody levels between dose groups. Conclusions: The DTacP-sIPV/Hib vaccine exhibits a favorable safety profile and robust immunogenicity in rats, supporting its further clinical development. The use of Sabin strains reduces biosafety risks and manufacturing costs, making this vaccine a promising candidate for immunization programs, especially in resource-limited regions. Full article

Background: Older adults face increased risks of influenza infection and related complications due to declining immunity and reduced vaccine responsiveness. Despite widespread vaccination, only 30–40% mount immune response due to immunosenescence. However, no biomarkers exist to identify potential non-responders, limiting the ability to target vaccine strategies, like high-dose or adjuvanted formulations, to those unlikely to benefit from standard options. Methods: We analysed publicly available baseline bulk RNA sequencing data from peripheral blood mononuclear cells of individuals aged ≥65 years to determine baseline transcriptomic signatures predictive of influenza vaccine response. Using two independent cohorts (discovery and validation), we classified individuals as triple responders (TRs) or triple non-responders (TNRs) based on hemagglutination inhibition assay titers at Day 0 and Day 28 for three components: A/H1N1, A/H3N2, and B/Yamagata. Results: We identified 1152 differentially expressed genes between TRs and TNRs at baseline. TRs exhibited enrichment of genes involved in B cell activation and protein synthesis, while TNRs showed enrichment of genes associated with innate immune responses and platelet activation. A response score derived from gene expression achieved high predictive accuracy in the discovery cohort (area under the curve [AUC] = 0.98). However, performance declined in the validation cohort (AUC = 0.69), and did not outperform clinical predictors, such as baseline titers, sex and vaccine dose. Conclusions: While baseline transcriptomic profiles may reveal mechanistic insights into vaccine responsiveness in the elderly, they offer limited predictive utility. Future work should prioritise higher-resolution or combined cell-specific approaches, such as single-cell RNA-sequencing or flow cytometry. Full article

Exosome-based vaccines represent a transformative platform in modern vaccinology, combining nanoscale delivery, biocompatibility, and potent immunogenicity. Among these, the StealthX platform developed by Capricor, Inc. has demonstrated exceptional versatility, enabling antigen presentation at nanogram level doses without the need for adjuvants. Preclinical studies using StealthX have shown strong humoral and cellular immune responses against SARS-CoV-2 variants, including Delta and Omicron, as well as broader applications against influenza and RSV antigens. The platform’s ability to accommodate multiple antigens within a single formulation addresses the challenges of viral variation and facilitates multivalent “mix-and-match” immunization strategies. This review offers an in-depth evaluation of the StealthX vaccine platform, covering the biological mechanisms underlying exosome function, the engineering approaches used to load antigens, and preclinical results demonstrated across three pivotal studies. By synthesizing current evidence, this review underscores the platform’s applicability for emerging infectious diseases and explores the strategic value of multivalent exosome-based vaccines in global immunization efforts as an emerging next-generation vaccine technology. Full article

Background: Adjuvants enhance the immune response to antigens incorporated in vaccine formulations. Given that the majority of infectious agents enter the body through mucosal surfaces, efficacious vaccines must generate protective immunity at these sites, which serve as the first line of defense. There is a need for mucosal adjuvants; hence, we explored the potential of repurposing existing drugs with established safety profiles in humans. Polymyxins are a class of clinically used antibiotics. They are cationic peptides and mast cell activators, which are a novel class of vaccination adjuvants. The goal was to assess the adjuvant properties of Polymyxin B microparticles in combination with vaccine candidates previously developed in our laboratory, such as microparticulate gonorrhea, influenza, measles, Zika, and canine coronavirus vaccines, and to compare their performance with FDA-licensed adjuvants, such as MF59 and Alum. Methods: Polymyxin microparticles were formulated using a double emulsion method, and the toxicity profile and autophagosome generation of Polymyxin B microparticles were assessed. The immunogenic potential of Polymyxin B in these vaccines was studied using multiple parameters such as nitric oxide release using Griess assay and immune profiling using flow cytometry for markers such as MHC I, MHC II, CD40, and CD80. Results: Polymyxin B microparticles were found to be non-cytotoxic to dendritic cells up to 500 μg/mL. Polymyxin B promoted autophagosome formation and nitric oxide release, and showed the upregulation of MHC I, MHC II, CD80, and CD40 pathways. Conclusions: The adjuvant activity of Polymyxin B across various vaccine platforms is significantly comparable to FDA-approved adjuvants, which is a critical requirement for generating T cell responses such as helper T cell and cytotoxic CD8+ T cell responses. Full article

Influenza viruses remain a major global public health concern, causing significant morbidity and mortality annually despite widespread vaccination efforts. The limitations of current seasonal vaccines, including strain-specific efficacy and manufacturing delays, have accelerated the development of next-generation candidates aiming for universal protection. This review comprehensively summarizes the recent progress in universal influenza vaccine research. We first outline the key conserved antigenic targets, such as the hemagglutinin (HA) stem, neuraminidase (NA), and matrix proteins (M2e, NP, and M1), which are crucial for eliciting broad cross-reactive immunity. We then delve into advanced antigen design strategies, including immunofocusing, multi-antigen combinations, computationally optimized broadly reactive antigens (COBRA), and nanoparticle-based platforms. Furthermore, we evaluate evolving vaccine delivery systems, from traditional inactivated and live-attenuated vaccines to modern mRNA and viral vector platforms, alongside the critical role of novel adjuvants in enhancing immune responses. The convergence of these disciplines—structural biology, computational design, and nanotechnology—is driving the field toward a transformative goal. We conclude that the successful development of a universal influenza vaccine will likely depend on the strategic integration of these innovative approaches to overcome existing immunological and logistical challenges, ultimately providing durable and broad-spectrum protection against diverse influenza virus strains. Full article

Background: Seasonal influenza vaccines must be reformulated annually due to the high genetic variability and antigenic drift of circulating influenza viruses. The annual update, guided by World Health Organization (WHO) recommendations, results in significant challenges, including compressed production time periods, elevated manufacturing costs, and global distribution pressures. Moreover, mismatches between vaccine strains and circulating viruses can severely reduce protective efficacy, underscoring the urgent need for broadly protective and long-lasting influenza vaccines. Methods: In this study, we developed an adjuvanted trivalent recombinant influenza virus-like particle vaccine (a-RIV) using the baculovirus–insect cell expression system and formulated it with an AS01-like adjuvant. The vaccine comprises full-length hemagglutinin (HA) proteins from WHO-recommended seasonal influenza strains: A/H1N1 (AH1), A/H3N2 (AH3), and B/Victoria (B/vic) lineages. The purified HA proteins were subsequently formulated with a liposomal adjuvant to enhance the immunogenicity. Results: In mouse immunization studies, the a-RIV vaccine elicited significantly stronger humoral and cellular immune responses than the licensed recombinant vaccine Flublok and the conventional inactivated influenza vaccine (IIV). High levels of functional anti-HA antibodies and antigen-specific T cell responses persisted for at least six months post-vaccination. Moreover, a-RIV induced broadly reactive antibodies capable of cross-binding to heterologous AH1 and AH3 influenza strains. Conclusions: Our data demonstrate that the a-RIV elicits enhanced, durable, and broadly cross-reactive immune responses against multiple influenza subtypes. These findings support the potential of adjuvanted recombinant HA-based vaccine as a promising candidate for the development of next-generation influenza vaccine. Full article

Influenza is a highly contagious disease and is transmitted by the upper respiratory tract. Vaccination is an effective strategy to prevent and control seasonal influenza. The current predominant split-inactivated influenza vaccine presents a high safety profile but has weak immunogenicity. The addition of adjuvants is one method to optimize the immunogenicity of the seasonal influenza vaccine. In this study, we compared the effect of aluminum (Alum), MF59-like adjuvant AddaVax, and ISA71 VG adjuvants for the seasonal split influenza vaccine in a mouse model based on the induction of influenza-virus-specific antibody levels, body weight changes, and survival rates after lethal challenge. Two very low and sub-optimal HA doses, 0.003 µg and 0.01 µg, representing the calculated amount of HA from the A/California/07/2009 (H1N1) strain only per mouse dose, were selected and used in this study. The 0.003 µg antigen (Ag) plus AddaVax showed the best adjuvant effect among these three adjuvants. The 0.01 µg Ag plus ISA 71 VG induced the highest total IgG, IgG1, and IgG2a. Both the 0.003 µg and 0.01 µg Ag plus AddaVax protected all the immunized mice from the lethal challenge, and Alum exhibited the protective potency intermediate between that of the AddaVax and ISA 71VG. The 0.01 µg Ag plus one of these three adjuvants could enhance the efficacy of the split influenza vaccine against lethal challenge. Therefore, AddaVax is the first candidate for the further development of the adjuvanted split seasonal influenza vaccine among these three adjuvants. These initial findings offer valuable guidance for selecting promising adjuvanted influenza vaccine formulations. Full article

Background/Objectives: FLU-v is a peptide-based broad-spectrum influenza vaccine proven to induce humoral and cellular immune responses in humans. In this study, FLU-v-specific IgG1 and IgG3 subclass antibodies, induced by adjuvanted or non-adjuvanted FLU-v vaccination in healthy adults participating in a phase II clinical study, were quantitated. The ability of these antibodies to induce NK cell activation was investigated. Methods: An ELISA was developed to quantify FLU-v-specific IgG1 and IgG3 antibodies in serum. A flowcytometric assay based on an NK cell line was used to evaluate NK cell activation by expression of degranulation marker CD107a. Results: In the adjuvanted FLU-v group, IgG1 and IgG3 seroconversion on day 42 was 88.5% and 86.5% compared to 53.4% and 29.3% in the non-adjuvanted FLU-v group, which was significantly different from the respective placebo groups (0–6.3%). Adjuvanted FLU-v vaccination induced a raise in median IgG1 and IgG3 levels from 435 and 167 ng/mL pre vaccination to 4422 and 2020 ng/mL 42 days post vaccination, representing a fold increase of 16.3 for IgG1 and 11.6 for IgG3, which was sustained on day 180 post vaccination (10.4-fold and 5.0-fold, respectively). Non-adjuvanted vaccination induced a more modest increase in IgG1 and IgG3 from 655 and 206 ng/mL pre vaccination to 1808 and 264 ng/mL 42 days post vaccination. A correlation between levels of FLU-v-specific IgG, IgG1, or IgG3 and their ability to induce NK cell activation was demonstrated. Conclusions: A single dose of adjuvanted FLU-v induced high levels of long-lasting antigen-specific IgG1 and IgG3 antibodies with NK cell-mediated effector functions relevant to protection against influenza disease. Full article

The influenza virus is one of the major global health concerns, causing significant morbidity and mortality in both humans and animals, with substantial impacts on public health. Vaccination remains the primary strategy for managing influenza virus infections; however, the virus undergoes frequent genetic changes through antigenic drift and shift. These mutations lead to new seasonal strains that evade pre-existing immunity. These mutations can potentially result in virulent strains that could trigger future pandemics. Therefore, developing a vaccine capable of providing robust protection despite these genetic changes is essential. Vaccine adjuvants are essential for boosting and directing the immune system’s response, broadening the spectrum of protection, and reducing the amount of antigen required to achieve protection, which is particularly valuable in the face of rapidly evolving strains and during pandemics. Recent advances in adjuvant design and formulation strategies have demonstrated promising improvements in both the overall potency and durability of influenza vaccines, importantly, significant reductions in losses due to influenza infection. This review highlights the current status of different types of influenza virus vaccines, their benefits, and challenges. Further, the review focuses on the role of adjuvants, discussing their advantages, limitations, and methodological approaches, while also considering their potential contribution in developing a universal flu vaccine intended to provide extensive and lasting protection. Full article

Background/Objectives: Influenza poses a substantial global public health challenge, disproportionately affecting vulnerable populations. Vaccination is the most effective preventive measure, and recent strategies in Italy emphasize the principle of “appropriateness”—the alignment of specific vaccine formulations (e.g., adjuvanted or high-dose) with targeted risk groups to optimize protection. Nevertheless, challenges persist in ensuring the consistent administration of the most suitable vaccine, particularly among high-risk individuals who would benefit most. Methods: A retrospective descriptive study was conducted using data from the 2023–2024 and 2024–2025 influenza vaccination campaigns of the Local Health Authority of Catania. Vaccination data were analyzed by age group and vaccine type, based on national immunization guidelines. Population categories included individuals ≥ 65 years, adults 60–64 years, adults 18–59 years (with/without chronic conditions), children, and pregnant/postpartum women. Vaccine types analyzed were aQIV, QIV-HD, QIV-SD, QIVcc, and LAIV. Descriptive statistics were used, and Relative Risk (RR) with 95% Confidence Intervals (CI) was calculated using the 60–64 age group as a reference. Analyses were performed with Stata 18.0. Results: In 2023–2024, 78.8% of individuals ≥ 65 received recommended vaccines, compared to 100% in the 60–64 group (RR = 0.23; 95% CI: 0.225–0.231). Adults 18–59, children, and pregnant/postpartum women showed ≥99% adherence. In 2024–2025, appropriateness in the ≥65 group improved to 96.1% (RR = 0.12; 95% CI: 0.118–0.128). All other groups maintained high adherence (≥99%), except for 6.2% of children aged 6 months–2 years who inappropriately received LAIV. Conclusions: Despite dramatically improved vaccination appropriateness in the elderly, a persistent and critical safety issue--inappropriate administration LAIV use in 6.2% of young children—highlights the need for targeted interventions to ensure complete patient safety. Full article

Influenza vaccines are the primary strategy to prevent severe influenza disease; however, their efficacy is often suboptimal, particularly in older adults (OAs). LiteVax Adjuvant (LVA), a novel adjuvant containing carbohydrate fatty-acid monosulphate ester (CMS) as the active ingredient, has demonstrated a favourable safety profile and enhanced immunogenicity when combined with a low-dose seasonal influenza vaccine in adults aged 18 to 50 years in a first-in-human phase 1 study. The present study investigates the reactogenicity and immunogenicity of CMS-based adjuvanted seasonal influenza vaccine in OAs, with a comparison to responses in younger adults (YAs). In this phase 1b, double-blind, active-controlled clinical trial, 36 YAs (18–50 years) and 48 OAs (≥60 years) were randomized (1:1:1) to receive either 0.5 mg or 1 mg LVA combined with VaxigripTetra, or VaxigripTetra alone. Solicited adverse events (AEs) were recorded using an electronic diary for 7 days following vaccination. Hemagglutination inhibition (HI) titers against four influenza strains were measured at baseline (pre-vaccination) and at 7-, 28-, and 180-days post-vaccination. All 24 YAs and 31 out of 32 OAs receiving CMS-based adjuvanted vaccines reported pain post-vaccination, compared to 8/12 YAs and 4/16 OAs receiving VaxigripTetra. Systemic AEs were more frequently reported among YAs receiving CMS-based adjuvanted vaccines (22/24) compared to those receiving VaxigripTetra (8/12). In OAs, the number of systemic AEs was similar regardless of CMS-based adjuvant administration. Most AEs were mild to moderate and resolved within 3 days. Both CMS-based adjuvanted formulations elicited increased HI titers at Day 7, peaking at Day 28, with a decline thereafter that remained above baseline at Day 180. In YAs, HI titers were comparable between the CMS-based adjuvanted and non-adjuvanted vaccines across all strains and timepoints. In contrast, CMS-based adjuvanted vaccination in OAs induced higher HI titers at Days 28 and 180 for all influenza strains tested. LVA shows an acceptable safety profile in both age cohorts and enhances humoral immune responses in older adults. The 1 mg dose of LVA was more immunogenic, highlighting its potential utility in this target population. Future research will focus on elucidating the mechanisms underlying the immunostimulatory effect of the CMS-based adjuvant. Full article

The presently used vaccines do not offer solid immunity/protection against the currently circulating strains of the H5N1 viruses. We aim to design a pan-H5N1 vaccine that protects birds against the presently circulating clade 2.3.4.4b in chickens. We used AI tools, including epitope mapping, molecular docking, and immune simulation, to design a multiepitope DNA vaccine including the top-ranked B and T cell epitopes within four major proteins (HA, NA, NP, and M2) of H5N1 clade 2.3.4.4b. We selected the top-ranked 12 epitopes and linked them together using linkers. The designed vaccine is linked to IL-18 as an adjuvant. The molecular docking results showed a high binding affinity of those predicted epitopes from the MHC I and MHC II classes of molecules with chicken alleles. The immune simulation results showed that the designed vaccine has the potential to stimulate the host immune response, including antibody and cell-mediated immunity in chickens and other birds. We believe this vaccine is going to be a universal vaccine that offers good protection against HPAI-H5N1 clade 2.3.4.4b. We are reporting the successful molecular cloning of a recombinant multiepitope-based vaccine spanning some key epitopes within some key proteins of the currently circulating H5N1 clade 2.3.4.4b. These designed vaccines could be a great positive impact on the protection of birds and various species of animals, as well as humans, against the HP-H5N1 influenza virus. Further studies are required to validate this vaccine candidate in chickens. Full article