Search Results (256)

Background/Objectives: mRNA vaccines introduced during the COVID-19 pandemic were a significant step forward in the rapid development and deployment of vaccines in a global pandemic context. These vaccines showed good protective efficacy, but—due to limited breadth of the immune response—they required frequent boosters with manufactured spike sequences that often lagged behind the circulating strains. In order to enhance the breadth, durability, and magnitude of immune responses, we studied the effect of combining priming with an RNA vaccine technology with boosting with protein/adjuvant using a TLR4-agonist based adjuvant. Methods: Specifically, four proprietary adjuvants (EmT4^TM, LiT4Q^TM, MiT4^TM, and AlT4^TM) were investigated in combination with multiple modes of SARS-CoV-2 vaccination (protein, peptide, RNA) for their effectiveness in boosting antibody responses to SARS-CoV-2 spike protein in murine models. Results: Results showed significant improvement in immune response strength and breadth—especially against more distant SARS-CoV-2 variants such as Omicron—when adjuvants were used in combination with boosters following an RNA vaccine prime. Conclusions: The use of novel TLR4 adjuvants in combination with protein or RNA vaccinations presents a promising strategy for improving the efficacy of vaccines in the event of future pandemics, by leveraging rapid response using an RNA vaccine prime and following up with protein/adjuvant-based vaccines to enhance the breadth of immunity. Full article

Metformin, a long-established antidiabetic agent, is undergoing a renaissance as a prototype gerotherapeutic and immunometabolic oncology adjuvant. Mechanistic advances reveal that metformin modulates an integrated network of metabolic, immunological, microbiome-mediated, and epigenetic pathways that impact the hallmarks of aging and cancer biology. Clinical data now demonstrate its ability to reduce cancer incidence, enhance immunotherapy outcomes, delay multimorbidity, and reverse biological age markers. Landmark trials such as UKPDS, CAMERA, and the ongoing TAME study illustrate its broad clinical impact on metabolic health, cardiovascular risk, and age-related disease trajectories. In oncology, trials such as MA.32 and METTEN evaluate its influence on progression-free survival and tumor response, highlighting its evolving role in cancer therapy. This review critically synthesizes the molecular underpinnings of metformin’s polypharmacology, examines results from pivotal clinical trials, and compares its effectiveness with emerging gerotherapeutics and senolytics. We explore future directions, including optimized dosing, biomarker-driven personalization, rational combination therapies, and regulatory pathways, to expand indications for aging and oncology. Metformin stands poised to play a pivotal role in precision strategies that target the shared roots of aging and cancer, offering scalable global benefits across health systems. Full article

Outer-membrane vesicles (OMVs), naturally secreted by Gram-negative bacteria, have gained recognition as a versatile platform for the development of next-generation vaccines. OMVs are essential contributors to bacterial pathogenesis, horizontal gene transfer, cellular communication, the maintenance of bacterial fitness, and quorum sensing. Their intrinsic immunogenicity, adjuvant properties, and scalability establish OMVs as potent tools for combating infectious diseases and cancer. Recent advancements in genetic engineering and biotechnology have further expanded the utility of OMVs, enabling the incorporation of multiple epitopes and antigens from diverse pathogens. These developments address critical challenges such as antigenic variability and co-infections, offering broader immune coverage and cost-effective solutions. This review explores the unique structural and immunological properties of OMVs, emphasizing their capacity to elicit robust immune responses. It critically examines established and emerging engineering strategies, including the genetic engineering of surface-displayed antigens, surface conjugation, glycoengineering, nanoparticle-based OMV engineering, hybrid OMVs, and in situ OMV production, among others. Furthermore, recent advancements in preclinical research on OMV-based vaccines, including synthetic OMVs, OMV-based nanorobots, and nanodiscs, as well as emerging isolation and purification methods, are discussed. Lastly, future directions are proposed, highlighting the potential integration of synthetic biology techniques to accelerate research on OMV engineering. Full article

Background: Vaccines have revolutionized disease prevention, yet their effectiveness is challenged by variable immunogenicity, individual response differences, and emerging variants. Biomimetic strategies, inspired by natural immune processes, offer new avenues to enhance vaccine performance. Objectives: This narrative review examines how bioinspired approaches—grounded in evolutionary medicine, immunology, and host–microbiota interactions—can improve vaccine immunogenicity and long-term protection. We further examine the evolutionary foundations of immune responses, highlighting how an evolutionary perspective can inform the development of durable, broadly protective, and personalized vaccines. Furthermore, mechanistic insights at the molecular and cellular level are explored, including Toll-like receptor (TLR) engagement, dendritic cell activation pathways, and MHC-I/MHC-II-mediated antigen presentation. These mechanisms are often mimicked in biomimetic systems to enhance uptake, processing, and adaptive immune activation. Results: The review highlights how immunosenescence, maternal immunity, genetic variation, and gut microbiota composition influence vaccine responses. Biomimetic platforms—such as nanoparticle carriers and novel adjuvants—enhance antigen presentation, boost adaptive immunity, and may overcome limitations in traditional vaccine approaches. Additionally, co-administration strategies, delivery systems, and microbiota-derived immunomodulators show promise in improving vaccine responsiveness. Conclusions: Integrating biomimetic and evolutionary principles into vaccine design represents a promising path toward safer, longer-lasting, and more effective immunizations Full article

Background/Objectives: There is a need for effective seasonal influenza virus vaccines that provide broad and long-lasting protection against influenza virus infections. Methods: In this study, next-generation influenza hemagglutinin (HA) and neuraminidase (NA) vaccine candidates designed using the computationally optimized broadly reactive antigen (COBRA) methodology were formulated with the TLR9 agonist, CpG 1018. These adjuvanted COBRA HA/NA vaccines were administered intramuscularly or intranasally to mice with pre-existing anti-influenza immunity or immunologically naïve mice. Results: Mice with pre-existing immune responses to historical influenza virus strains vaccinated intranasal (IN) with COBRA HA/NA vaccines adjuvanted with CpG 1018 had enhanced IgG titers in their bronchoalveolar lavages (BALF) compared to unadjuvanted vaccines. These mice also had increased serum IgG titers that were like antibody titers observed in mice that were vaccinated intramuscularly. Mice that were vaccinated intranasally with this adjuvanted vaccine also had antibodies with significantly higher hemagglutination inhibition activity against a broad range of H1N1 and H3N2 influenza viruses and more HA and NA specific antibody-secreting cells compared to unadjuvanted vaccine. Following the H1N1 influenza virus challenge, pre-immune mice that were vaccinated with the COBRA HA/NA vaccine with CpG 1018 were protected from morbidity and mortality and had no detectable viral lung titers. Conclusions: Overall, CpG 1018 adjuvanted COBRA HA/NA elicited enhanced protective antibodies compared to the unadjuvanted vaccine against several drifted H1N1 and H3N2 influenza viruses in pre-immune mice that were either intramuscularly or intranasally vaccinated with a balanced Th1/Th2 immune response. Full article

Porcine reproductive and respiratory syndrome virus (PRRSV) is a major viral threat to swine, causing significant economic loss in the global pig farming industry. This virus includes two major genotypes, PRRSV1 and PRRSV2, both characterized by high mutation rates and genetic variability, complicating the development of a universally effective vaccine and disease control. To address this challenge, this study utilizes immunoinformatics tools to identify conserved epitopes and design a multi-epitope vaccine candidate against PRRSV based on reverse vaccinology. The complete sequences of PRRSV-encoded proteins were retrieved worldwide, and the conserved fragments were identified through the alignment of polypeptide sequences. Subsequent screening was conducted to screen epitopes for their potential to be safe and to activate B cells, HTLs (helper T cells), and CTLs (cytotoxic T cells). By conjugating the selected epitopes with distinct adjuvant proteins, three vaccine candidates were designed and termed PRRSV-vaccine (PRRSV-V-1, PRRSV-V-2, and PRRSV-V-3, respectively). Furthermore, systematic evaluations of their physicochemical properties, structural stability, binding with pattern recognition receptors, and induction of the host immune system were performed. PRRSV-V-2 had the most promising physicochemical and structural characteristics, strong binding with toll-like receptors (TLR3 and TLR8), and the most vigorous reactions to host immune responses. As the most promising candidate, the recombinant PRRSV plasmid was in silico designed for expression in Escherichia coli. Our study proposed a novel approach to PRRSV vaccine development against PRRSV, offering a promising strategy for controlling the infection across diverse PRRSV strains in swine. Despite providing significant insights into vaccine design through computational methods, the results of this study remain predictive. So, it is open for the experimental validations of the scientific community to ensure its actual immunological properties, especially the safety and efficacy. Full article

Background/Objective: Recently, we published three studies describing the development and optimization of a new, safe, and efficacious vaccine to protect sheep from ovine enzootic abortion, which is caused by the zoonotic pathogen Chlamydia abortus. The vaccine, which can be delivered through a single inoculation, is based on a detergent-extracted outer membrane protein (chlamydial outer membrane complex or COMC) preparation of the pathogen. This study aimed to optimize the vaccine further by comparing the effects of different adjuvants on protective efficacy. Methods: We evaluated the effectiveness of three different vaccines (2.5 µg COMC) formulated with one of three adjuvants (Montanide ISA 70VG, Montanide ISA 61VG, and QuilA) to reduce the rate of abortion, placental load and pathology, and post-partum vaginal shedding of organisms in comparison to our benchmark 20 µg COMC/Montanide ISA 70 VG vaccine and a challenge control group of animals. The humoral and cellular immunological responses to vaccination and to challenge were also assessed. Results: The two low-dose Montanide formulated vaccines resulted in low abortion rates of 3.2 and 8.1% for ISA 70 VG and ISA 61 VG, respectively, which were comparable to the benchmark vaccine group (2.7%) and considerably lower than the QuilA (23.7%) and challenge control (36.8%) groups. Similarly, the Montanide-adjuvanted groups had much lower bacterial loads (range: 136–431 genome copies) on vaginal swabs post-parturition than the QuilA (8.9 × 10⁴ copies) and challenge control (2.4 × 10⁵ copies) groups. Conclusions: The results showed that both Montanide adjuvants are more effective for maximizing COMC vaccine efficacy than the QuilA adjuvant and result in much lower bacterial shedding of the pathogen post-parturition, which is important for minimizing potential transmission to naïve animals. Full article

The emergence of complex and rapidly evolving pathogens necessitates innovative vaccine platforms that move beyond traditional methods. This review explores the transformative potential of next-generation vaccine technologies, focusing on the combined use of synthetic biology, nanotechnology, and systems immunology. Synthetic biology provides modular tools for designing antigenic components with improved immunogenicity, as seen in mRNA, DNA, and peptide-based platforms featuring codon optimization and self-amplifying constructs. At the same time, nanotechnology enables precise antigen delivery and controlled immune activation through engineered nanoparticles such as lipid-based carriers, virus-like particles, and polymeric systems to improve stability, targeting, and dose efficiency. Systems immunology aids these advancements by analyzing immune responses through multi-omics data and computational modeling, which assists in antigen selection, immune profiling, and adjuvant optimization. This approach enhances both humoral and cellular immunity, solving challenges like antigen presentation, response durability, and vaccine personalization. Case studies on SARS-CoV-2, Epstein–Barr virus, and Mycobacterium tuberculosis highlight the practical application of these platforms. Despite promising progress, challenges include scalability, safety evaluation, and ethical concerns with data-driven vaccine designs. Ongoing interdisciplinary collaboration is crucial to fully develop these technologies for strong, adaptable, globally accessible vaccines. This review emphasizes next-generation vaccines as foundational for future immunoprophylaxis, especially against emerging infectious diseases and cancer immunotherapy. Full article

Background: Cancer immunotherapy has advanced, yet therapeutic resistance and low response rates remain problematic. This study explores histone deacetylase inhibitors (HDACis) as adjuvants for cancer vaccines to enhance anti-tumor immunity and overcome these challenges. Methods: A comprehensive review of relevant literature was conducted. Studies on the immunomodulatory mechanisms of HDACis, their effects on Individualized neoantigen therapy (INT), and clinical applications were analyzed. Results: HDACis enhance anti-tumor immunity through multiple mechanisms. They activate endogenous retroelements, expanding the “antigen repository”. HDACis also upregulate MHC class I and II molecules, enhance the antigen processing machinery, improve MHC—I complex stability, and remodel the tumor immune microenvironment. Early clinical trials of HDACis combined with peptide vaccines show promising safety and immunological responses. However, challenges exist, such as HDACi-mediated PD-L1 regulation, optimal sequencing strategies, and biomarker development. Conclusions: The combination of HDACis and cancer vaccines has significant potential in cancer immunotherapy. Despite challenges, it offers a new approach to overcome tumor heterogeneity and immune evasion, especially for patients with limited treatment options. Further research on toxicity management, triple-drug combinations, biomarker identification, and delivery systems is needed to fully realize its clinical benefits. Full article

Background: We previously showed that peptides encompassing the unique b3a2 or b2a2 breakpoint amino-acid sequence of oncogenic p210 induced peptide-specific T-cell responses in chronic myeloid leukemia (CML) patients. Methods: From 2007 to 2011, two multicenter peptide vaccine phase II studies, GIMEMA CML0206 and SI0207, enrolling overall 109 CML patients (68 b3a2 and 41 b2a2) with persistence of molecular disease during imatinib treatment, were carried out. Peptide vaccination schedule included the following: “immunization phase” (six vaccinations every 2 weeks); “reinforcement” phase (three monthly boosts) and “maintenance” phase (two boosts at 3-month intervals). GM-CSF (granulocyte-macrophage-colony-stimulating factor, sarmograstim) served as the immunological adjuvant. Results: The short-term results (at completion of vaccine protocol—12 months) and long-term follow-up are reported. All patients completed the vaccination schedule with no toxicity. After vaccinations, the BCR::ABL1 peptide-specific CD4+ T-cell response was documented in 80% of patients. In the short term, 30% of patients achieved a reduction in BCR::ABL1, while the majority showed stable molecular disease with fluctuations. The median follow-up since diagnosis and last vaccination are 18 and 10 years, respectively, with an overall survival (OS) rate at 18 years of 89%. In addition, 97/109 (89%) patients are alive, while 12/109 (11%) died of CML-unrelated reasons. Overall, 18/109 (16.5%) patients are in treatment-free remission (TFR) for a median time of 48 months. Conclusions: The long-term results of p210 peptide vaccinations in CML patients with persisting disease during imatinib treatment showed its feasibility, safety, absence of off-targets events, high OS and not negligible rate of successful TFR. Active immunotherapeutic approaches in CML patients with low disease burden, eventually employing newer vaccine strategies such as mRNA vaccines, may be reconsidered. Full article

Background/Objectives: Following previous successful Phase I clinical trials conducted in men and women in a non-endemic area for schistosomiasis in Brazil, the Sm14 vaccine was evaluated in an endemic region in Senegal. We report successful clinical trials in adults (Phase IIa) and school children (Phase IIb), respectively, of a Schistosoma mansoni 14 kDa fatty acid-binding protein (Sm14) vaccine + a glucopyranosyl lipid A (GLA-SE) adjuvant. Methods: Participants were evaluated based on clinical assessments, laboratory tests (including hematologic and biochemical analyses of renal and hepatic functions), and immunological parameters (humoral and cellular responses) up to 12 months after the first vaccination dose in the Phase IIa trial and after 120 days in the Phase IIb trial. Results: The results showed strong immunogenic responses and good tolerance in both adults and children, with no major adverse effects. Importantly, significant increases in Sm14-specific total IgG (IgG1 and IgG3) were observed as early as 30 days after the first vaccination, with high titres remaining at least 120 days afterwards. Sm14-specific total IgG serum levels were also significantly enhanced in adults and in both infected and non-infected, vaccinated children and elicited robust cytokine responses with increased TNFα, IFN-γ, and IL-2 profiles. Conclusions: Overall, the Sm14+GLA-SE vaccine is safe and highly immunogenic, with a clearly protective potential against schistosomiasis, supporting progression to the next Phase III clinical trials. Full article

Hepatitis B virus (HBV) infection is a major public health risk. Despite the introduction of successful vaccines, which are normally single adjuvanted, there are still some drawbacks, including non-responsiveness in certain groups, short durability of immunity, inadequate protection, and the need for additional doses to be addressed. This study aimed to develop an optimized combination of Cytosine-phosphate-Guanine Oligonucleotides (CPG-ODN2395, CPG-ODN-18281-2 23 mer) and calcium phosphate, and to assess its immunogenicity and toxicity when co-administrated with the commercial HBV vaccine (BEVAC, containing aluminum hydroxide) and an in-house aluminum hydroxide-adjuvanted HBs purified antigen in Balb/c mice. Tail blood was collected from vaccinated Balb/c mice on days 14 and 28 post-immunization to determine the antibody secretion level using an enzyme-linked immunosorbent assay (ELISA). The Tumor Necrosis Factor (TNF-a) and interleukin-6 (IL-6) cytokine expression levels were assessed through real-time PCR, and the safety profile was checked through biochemical and hematological analysis. Our results showed that the combination of CPG-ODN2395, CPG-ODN 18281-2 23 mer, and CAP significantly enhanced the IgG antibody secretion level (p < 0.0001), which also showed a significant increase in IL-6 expression (p < 0.0001). The safety evaluations revealed no adverse impact on liver and kidney function, with normal ALT, AST, urea, and creatinine levels (p < 0.55). Hematological assessments revealed stable parameters across all groups. This study concludes that combining CpG ODNs and calcium phosphate adjuvants with hepatitis B vaccinations has the potential to enhance a stronger immunological response to hepatitis B infection than single adjuvants. These results highlight the promise of this innovative adjuvant system, necessitating more research in clinical environments to increase vaccine effectiveness and sustained protection against HBV. Full article

Background: Klebsiella pneumoniae infections pose a great burden worldwide, causing high morbidity and mortality, which are worsened by the increase in multidrug-resistant strains. New therapeutic/prophylactic strategies are urgently needed to overcome antibiotic resistance and reduce the health and economic impacts of diseases caused by this pathogen. Fimbriae are important virulence factors involved in biofilm formation and adhesion to host cells. Their exposed location, conservation among clinical isolates and adjuvant properties make them interesting candidates for inclusion in protein-based vaccines. Therefore, the present work investigated the immunological potential of type 1 and 3 fimbriae subunits in a murine model of K. pneumoniae lung infection. Methods: MrkA and FimA were produced as recombinant proteins in E. coli, purified and used to immunize mice subcutaneously. The immune responses were characterized and protection against pneumonia was evaluated after intranasal challenge. Results: Subcutaneous immunization with recombinant FimA and MrkA induced high IgG1 production; the antibodies efficiently recognized the native proteins at the bacterial surface, promoted C3 deposition and reduced biofilm formation by K. pneumoniae in vitro. Mice vaccinated with the co-administered proteins reduced the bacterial loads in the lungs after intranasal challenge, less inflammation and reduced tissue damage. Conclusion: The results suggest that both type 1 and type 3 fimbriae contribute to protection against K. pneumoniae lung infection, inducing antibodies that bind to the bacteria and favoring Complement deposition and clearance by the host, while inhibiting biofilm formation. Full article

Cancer vaccines offer an exciting option for active immunotherapy, providing a potentially safe and effective treatment that also prevents or minimizes toxic side effects in vaccinated patients. Clinical results from previous phase III clinical trials have suggested that the efficacy of cancer vaccines largely depends on their potential to trigger robust immunological responses. A preexisting immune response to cancer-specific peptides is crucial for achieving a meaningful clinical outcome during vaccinations. However, various factors may hinder the effectiveness of therapeutic vaccines. By overcoming these challenges, cancer vaccines have the potential to become a cornerstone in immunotherapy. This review aims to share our insights on the major challenges that are encountered when optimizing the potential of cancer vaccines, particularly focusing on important aspects regulating their clinical efficacy, such as vaccine composition, the adjuvant to be used and the HLA-restricting element for the tumor peptides targeted by a particular vaccine. Additionally, we discuss several obstacles which hindered the successful clinical development of therapeutic cancer vaccines, such as the standard of care, the clinical design, and the choice of the antigen(s) to be included in vaccine formulation. The identification of patients that are most likely to respond to vaccinations by developing immunological responses and the desirable clinical efficacy are also crucial, and, therefore, predictive biomarkers are strictly required. Finally, we present our views on future prospects that may lead to an enhancement of the anticancer effects of vaccines, ensuring their pivotal role in cancer immunotherapy. Full article