Search Results (2,426)

Therapeutic cancer vaccines represent a rational immunotherapeutic strategy aimed at inducing tumor-specific adaptive immune responses in patients with established malignancies. In contrast to prophylactic vaccines, these approaches must function within immunosuppressive tumor microenvironments characterized by antigenic heterogeneity, immune dysfunction, and dynamic tumor evolution. Effective vaccine design requires the integration of three essential components: the selection of appropriate tumor-associated or tumor-specific antigens, efficient delivery platforms that enable antigen presentation, and adjuvant systems that promote robust T-cell priming and expansion. Initial clinical investigations in B-cell malignancies and multiple myeloma demonstrated that idiotype-based vaccines can elicit tumor-specific immune responses. However, durable clinical benefit has been inconsistent, reflecting limitations in antigen selection, suboptimal immunogenicity, and tumor-mediated immune evasion. Over the past decade, advances in tumor genomics, next-generation sequencing, and immune monitoring have enabled the development of next-generation vaccine platforms, including dendritic cell-based approaches, personalized neoantigen vaccines, and mRNA-based technologies. Emerging evidence suggests that vaccine efficacy is highly dependent on disease context. Biologically favorable settings such as minimal residual disease (MRD) and post-transplant immune reconstitution provide reduced tumor burden and improved immune competence, thereby enhancing the likelihood of effective immune priming. In parallel, combination strategies incorporating immune checkpoint inhibitors, immunomodulatory agents, and cellular therapies are increasingly being explored to overcome tumor-induced immunosuppression. This review synthesizes current knowledge of therapeutic cancer vaccines in B-cell malignancies and multiple myeloma, with emphasis on immunologic mechanisms, antigen selection, vaccine platforms, and clinical evidence. We further propose a conceptual framework integrating tumor biology, immune context, and combination strategies to guide the rational development of next-generation vaccine therapies. Full article

Background/Objectives: Lipid nanoparticles (LNPs) are actively being studied as therapeutics and vaccines for various diseases. While LNPs can deliver nucleic acids, their efficiency is limited by the multi-step pathways involved in intracellular trafficking. Crucially, endosomal recycling-driven exocytosis acts as a major problem, rerouting LNPs away from the cytosol and thereby preventing efficient nucleic acid release. Upon entering the cell, LNPs are frequently expelled via endosomal recycling before delivering nucleic acids to cytosol. Previous studies reported that inhibition or deletion of Exo70, a component of the exocyst complex, leads to the accumulation of endosomes because of preventing endosomal recycling. In this study, we investigate the impact of Exo70 inhibition by endosidin-2 (ES-2), an Exo70 inhibitor, on LNP delivery efficiency. Methods: SM-102, cholesterol, DMG-PEG, and DSPC were dissolved in ethanol, while mRNA was dissolved in an aqueous phase to formulate LNPs. Co-treatment of ES-2 with LNPs was performed to evaluate its effect on mRNA delivery, and the resulting delivery efficiency was assessed both in vitro and in vivo. Results: Co-treatment of ES-2 with LNPs significantly enhanced mRNA delivery efficiency, resulting in up to a 4.06-fold increase in vitro and a 3.63-fold increase in vivo. Conclusions: Our findings demonstrate that suppression of Exo70 significantly enhances the mRNA delivery efficiency of LNPs, and this strategy could be applied for the development of mRNA therapeutics. Full article

Background/Objectives: Serial passage in embryonated eggs is widely used to attenuate the infectious bronchitis virus (IBV) for vaccine production; however, the evolutionary processes underlying attenuation and immunogenicity remain incompletely understood. Here, we analyzed genome-wide viral evolution during serial passages to investigate how mutations emerge, persist, are lost, or become fixed over time and how these dynamics relate to changes in pathogenicity and immunogenicity. Methods: Deep sequencing was performed on 11 representative serial passages (P2–P79) of the UY/11/CA/18 strain, including two derivative lineages: P7 VIR (virulent) and P53 VAC (attenuated and immunogenic). Results: This study identified an early adaptive phase characterized by a limited set of mutations potentially associated with genome replication, viral RNA processing, and virion assembly, including a key change in non-structural protein 14 and variants in M and 3c (E). This phase was followed by a broader expansion of the variant spectrum across replicase genes and delayed accumulation of Spike protein variants. Most Spike changes emerged during later passages and exhibited transient dynamics, and only a subset reached a high frequency after the establishment of early replicase- and structural-associated changes. Consistent with these dynamics, P7 VIR diverged before the late accumulation of Spike variants and retained a pathogenic phenotype, whereas P53 VAC diverged after the emergence of early high-frequency variants but before the extensive late-stage Spike variation observed in P79, which was associated with reduced immunogenicity. Conclusions: These findings support a multi-step model of IBV attenuation in which progressive filtering of genome-wide variation shapes distinct evolutionary outcomes during serial passages. This evolutionary framework provides insight into the relationship between attenuation and immunogenicity and may help guide the rational design of live attenuated vaccines. Full article

Confirmed porcine sapovirus (PoSaV) infection in young pigs have been increasing in swine farms; however, studies evaluating strategies to control PoSaV under field conditions remain scarce. In a commercial farm, one group of pregnant sows and gilts (n = 13 sows and 2 gilts) were vaccinated intramuscularly twice with an RNA particle vaccine containing the PoSaV VP1 gene, while the other group served as non-vaccinated controls. We evaluated the viral neutralizing (VN) antibodies in colostrum and milk collected at 1, 2, and 3 weeks post-farrowing. Fecal PoSaV shedding in 2-week- and 3-week-old piglets from both groups was assessed by reverse transcription-quantitative PCR. Body weight was measured at birth and 3 weeks of age when piglets were weaned. The vaccination group had higher VN antibody titers than the non-vaccinated group in colostrum and milk samples, with significance for colostrum and milk samples at 1-week post-farrowing. The colostrum and milk samples from both groups contained high VN antibody titers (>10^3.5 VNT₅₀/mL) and remained high for at least three weeks, suggesting previous exposure to PoSaV. Corresponding to these high VN titers, all piglets were negative for PoSaV and had similar body weights at birth and 3 weeks of age. Future vaccination-challenge studies are warranted to confirm the efficacy of this vaccine. Full article

mRNA vaccines are a relevant approach in cancer immunotherapy, using messenger RNA to induce immune responses against tumor-associated antigens. In this review, BNT111 and BNT122 are compared as representative off-the-shelf and personalized models. BNT111 is a fixed mRNA vaccine that has demonstrated significant antitumor efficacy against shared melanoma antigens, particularly when combined with immune checkpoint inhibitors. It allows a standardized production via in vitro transcription (IVT) in a cell-free system. Conversely, BNT122 is a personalized vaccine designed to match an individual’s tumor mutations by targeting patient-specific neoantigens to elicit more robust immune responses. It has significant suitability in the adjuvant setting to target minimal residual disease. Despite favorable safety and immunogenicity, the effectiveness of these vaccines is influenced by various factors, including tumor heterogeneity, differences in antigen expression, off-target effects on mRNA-LNP distribution, molecular instability, and complex manufacturing constraints. Neither approach can be directly considered as the definitive optimal vaccine. A comprehensive analysis of their strengths and limitations is vital for a balanced and objective future research direction. Collectively, this emphasizes the need for further improvements in vaccine design and strategies, prioritizing high-quality, safe, and accessible treatments for every cancer-based patient and ensuring their successful integration into healthcare. Full article

In this review, the virulence factors involved in enterotoxigenic Escherichia coli (ETEC) colonization and pathogenesis are analyzed, with an emphasis on colonization factors, enterotoxins and antigenic diversity as central challenges in vaccine development. ETEC remains a major cause of diarrhea worldwide, particularly in vulnerable populations. Despite extensive research, no broadly protective licensed vaccines are available largely because of antigenic heterogeneity and the limited understanding of immune correlates of protection. We identified critical knowledge gaps in antigen prioritization and host–pathogen interactions and translational limitations that have hindered vaccine success. We critically evaluated emerging platforms (including mRNA vaccines, nanoparticles, multiepitope strategies, and reverse vaccinology) for their potential to overcome variability and increase immunogenicity. We examined the roles of ecological environmental reservoirs associated with human and animal systems, in addition to antimicrobial pressure, in shaping ETEC evolution and vaccine effectiveness within a One Health framework; moreover, we propose an integrated approach that links genomic surveillance-based vaccine ecology and next-generation vaccine technologies to support adaptive immunogen design. This review provides actionable recommendations for the development of broadly protective and translationally viable ETEC vaccines from the One Health perspective. Full article

Cancer vaccines represent a promising strategy in cancer immunotherapy by inducing tumour-specific immune responses. However, their clinical efficacy remains limited due to challenges in antigen selection, including the distinction between self and non-self-antigens, as well as issues related to antigen delivery, immune activation, and tumour immune evasion. Advances in nanotechnology have introduced innovative approaches to improve vaccine stability, targeted delivery, and immunogenicity. Nanoparticle-based platforms, including lipid, polymeric, inorganic nanoparticles, and virus-like particles, enable efficient delivery of tumour antigens and immunostimulatory adjuvants to antigen-presenting cells, thereby enhancing adaptive immune responses. Despite these advances, several translational challenges persist, including immunosuppressive tumour microenvironments, inefficient lymph node targeting, safety concerns, and manufacturing limitations. This review summarizes key nanoparticle platforms used in cancer vaccine development and discusses major barriers to their clinical translation. We also emphasize platform-selection criteria, cargo-dependent carrier design, nanoparticle size constraints, engineering strategies used to improve cytosolic delivery and endosomal escape, and the current clinical pipeline of cancer nanovaccines. Additionally, emerging strategies such as personalized nanovaccines, mRNA vaccine platforms, and combination immunotherapies are highlighted as promising approaches to improve therapeutic efficacy. These advances are expected to accelerate the clinical translation of nanotechnology-enabled cancer vaccines and support the development of next-generation cancer immunotherapies. Full article

Melanoma adjuvant therapy has substantially improved recurrence-free and distant metastasis-free survival in patients with resected high-risk disease, and more recently, these advances have extended to earlier stages. However, important unmet needs remain, including the management of stage IIIA disease, the optimal treatment strategy after relapse on adjuvant therapy, and the identification of biomarkers capable of refining patient selection. This review summarizes recent advances and unresolved questions in the adjuvant and neoadjuvant treatment of melanoma. We discuss novel systemic strategies, including immune checkpoint inhibitor combinations and personalized neoantigen mRNA vaccines, together with the expanding role of neoadjuvant approaches. We also examine prognostic and predictive tools—such as clinicopathologic models, circulating tumor DNA, serum biomarkers, tumor microenvironment features, and gene expression profiling—that may help better define recurrence risk and therapeutic benefit. Current evidence suggests that although modern therapies have changed the natural history of resected melanoma, a substantial proportion of patients are still overtreated or undertreated when treatment decisions are based on stage alone. Future progress will depend on integrating biological risk stratification with clinical staging and optimizing treatment sequencing across adjuvant and neoadjuvant settings. Full article

Influenza A virus (IAV) remains a major global health threat despite available vaccines and antiviral agents, while current therapies are limited by drug resistance and safety concerns. Curcuminoids exhibit antiviral and anti-inflammatory activities but are constrained by poor water solubility and low bioavailability. To address these limitations, we investigated the antiviral and immunomodulatory properties of a water-solubilized curcuminoid nanoparticle formulation (C–S/M) in both in vitro and in vivo models of IAV infection. To evaluate the potential antiviral and anti-inflammatory effects of C–S/M, we performed a cytopathic effect (CPE) reduction assay in triplicate at 0.001 MOI and quantitative real-time PCR (qRT-PCR) targeting viral NS1 transcripts in MDCK cells. C–S/M suppressed viral NS1 vRNA levels in MDCK cells at lower curcuminoid-equivalent concentrations than native curcuminoids and attenuated IAV-induced TNF-α, IL-6, and IL-8 production. Furthermore, in vivo antiviral efficacy was evaluated in female C57BL/6 mice intranasally infected with IAV and treated orally with C–S/M. Survival, lung viral loads, pulmonary cytokine levels, and splenic immune cell phenotypes were analyzed. In IAV-infected mice, oral administration of C–S/M modestly improved survival and significantly reduced lung viral burden and pulmonary proinflammatory cytokine levels. In addition, in vivo C–S/M treatment was associated with recovery of virus-suppressed T-cell immune responses, including increased Th1 and activated CD8⁺ T cells, reduced regulatory T-cell expansion, and restoration of multifunctional CD4⁺ and CD8⁺ T cells. These findings suggest that C–S/M exerts antiviral and immunomodulatory effects in experimental IAV infection and may serve as a potential adjunctive candidate for further investigation against influenza-associated inflammation. Full article

Background/Objectives: Recurrent influenza epidemics impose a severe global burden, with conventional vaccines constrained by production time lags and rapid viral mutation. This study aims to explore a novel influenza mRNA vaccine design that balances conserved and mutable antigen regions. By combining hemagglutinin (HA) and neuraminidase (NA) into a dual-target approach, the objective is to simultaneously block viral entry and inhibit progeny release, potentially establishing a proposed “front-blockade, rear-containment” dual protective barrier against multiple H1N1 strains. Methods: We engineered a dual-target tandem mRNA vaccine linking mutated HA with conserved NA, with strategic amino acid mutations introduced into key antigenic sites within the HA head domain. Vaccine efficacy was evaluated in a mouse model. Humoral immunity was assessed by measuring antigen-specific antibody titers, and cellular immunity was evaluated via ELISpot assay. Protective capacity was determined through lethal challenge experiments using diverse H1N1 viral strains. Results: The vaccine successfully expressed the HA-NA tandem antigen at 130 kDa, and the in vitro-expressed antigen exhibited normal neuraminidase activity. Preliminary evidence supported the dual-target concept in model mice: hemagglutination-inhibiting and micro-neutralizing antibodies targeting HA were detected, and serum neuraminidase-inhibiting activity was also observed. In addition to triggering potent cellular immune responses, the vaccine offered total protection against lethal doses of various H1N1 variants. Conclusions: This study suggests a promising dual-target strategy that harmonizes antigen conservation and mutation while potentially establishing a synergistic front-blockade and rear-containment defense. The approach offers a viable pathway for developing improved H1N1 influenza vaccines. Full article

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. Full article

Background: The development of an efficacious preventive human immunodeficiency virus (HIV) vaccine remains a central goal of global HIV elimination efforts, yet biological performance alone will not determine a future vaccine’s public health impact. Method: This review draws on behavioral science, communication research, vaccine implementation, and HIV prevention literature to identify cognitive, social, and structural challenges that are likely to shape public acceptance and uptake of a future HIV vaccine, as well as to outline evidence-based opportunities for addressing them. Results: Based on the available literature, mental models of both HIV and vaccination will be a critical determinant of how communities consider a future vaccine, particularly given that emerging mRNA and adjuvanted platforms may generate side effects that could be easily misinterpreted and that highly effective long-acting pre-exposure prophylaxis (PrEP) options already exist and will shape how individuals evaluate a vaccine’s relative value. HIV-related stigma further complicates this landscape by making vaccination a socially interpreted behavior, unlike some other vaccination efforts. Together, these factors suggest that hesitancy and misalignment between public understanding and scientific evidence are predictable and should be anticipated rather than addressed reactively. At the same time, decades of HIV prevention implementation research have established an evidence base for vaccine communication, and existing community engagement infrastructure offers a foundation upon which future rollout efforts can build. We highlight three evidence-based strategies as particularly promising levers for encouraging acceptance and adoption. Conclusions: We conclude with recommendations for HIV vaccine researchers and healthcare professionals to invest in formative research, build community partnerships in advance of vaccine availability, and pilot integrated delivery models within existing HIV prevention services. Full article

Bringing a new drug to market is a complex, costly, and lengthy process, averaging $2.6 billion and about ten years of research and development. It involves multiple stages, from target discovery to post-approval monitoring, and relies heavily on innovation driven by collaboration among pharmaceutical sciences, biology, biochemistry, engineering, and artificial intelligence. Drug discovery can be divided into four main stages: target selection and validation; compound screening and optimization; preclinical studies; and clinical trials. First, researchers identify and validate a biological target associated with a disease using genomic, proteomic, and bioinformatic approaches. Next, potential compounds (“hits”) are identified through methods such as high-throughput and virtual screening, followed by iterative chemical optimization and functional testing. Promising candidates undergo preclinical in vivo studies to assess pharmacokinetics, pharmacodynamics, and toxicity. Clinical development proceeds in three phases: Phase I evaluates safety in healthy volunteers; Phase II assesses efficacy in patients; and Phase III confirms efficacy and safety in larger populations. After successful trials, regulatory agencies review the data for approval. While small molecules have long dominated due to their stability and oral bioavailability, biologics—such as monoclonal antibodies and mRNA-based therapies—have grown rapidly, highlighted by COVID-19 vaccine development and increasing FDA approvals. Full article

Background/Objectives: No licensed vaccine against cytomegalovirus (CMV) is currently available, despite the significant risk of mother-to-infant transmission leading to serious neurodevelopmental impairment and the substantial morbidity caused by CMV infection in immunocompromised persons. We report results from a phase 2 trial of the investigational CMV mRNA vaccine mRNA-1647 and a long-term extension study (NCT04232280; NCT04975893). Methods: This randomized, observer-blind, placebo-controlled phase 2 study, conducted at 9 US sites, enrolled participants in two parts. In the first part, healthy adults aged 18–40 years were stratified by baseline CMV status into CMV-seronegative and CMV-seropositive parallel cohorts and randomized 3:1 to receive mRNA-1647 (50, 100, or 150 μg) or placebo. In the second part, healthy female participants aged 18–40 years were randomized 3:1 to receive 100 μg mRNA-1647 or placebo. In both parts, vaccine or placebo was administered at Months 0, 2, and 6. Participants completing the Primary Trial through Month 18 were eligible to enroll in the extension study, wherein safety and immunogenicity were assessed every 6 months until all participants reached Month 48 (interim analysis) and a subset had Month 54 immunogenicity samples available. Primary objectives were to assess safety and neutralizing antibody responses. Results: Solicited adverse reactions were mostly grade 1 or 2 in severity, and no notable dose-related safety trends were identified. Neutralizing antibody and antigen-specific binding IgG responses were induced in CMV-seronegative participants and boosted in CMV-seropositive participants, with durability of responses through Month 48 and up to Month 54. Conclusions: The investigational vaccine mRNA-1647 was generally well tolerated and induced durable humoral immune responses across baseline CMV serostatus, with persistence supported through Month 48 and by available Month 54 data. Full article

Bacterial membrane vesicles (BMVs), encompassing outer membrane vesicles (OMVs) released from Gram-negative bacteria and extracellular vesicles (EVs) released from Gram-positive bacteria, have emerged as promising vaccine platforms owing to their intrinsic immunostimulatory properties and capacity to deliver a wide range of antigens. Although conventional vaccines effectively prevent infectious diseases, their long-term efficacy is often limited by antigenic variation and reliance on a restricted number of licensed adjuvants. BMVs, as self-adjuvanting systems, enable both antigen delivery and innate immune activation. BMVs are nanoscale lipid bilayer structures enriched with pathogen-associated molecular patterns (PAMPs), facilitating their recognition and uptake by antigen-presenting cells. This leads to the activation of pattern recognition receptors and the induction of pro-inflammatory cytokines, type I interferons, and adaptive immune responses, including antibody production and Th1- and Th17-biased cellular immunity. Recent studies highlight the versatility of BMVs as vaccine platforms across bacterial, fungal, and viral infection models. BMVs induce protective immunity by promoting both systemic and mucosal immune responses, thereby reducing bacterial burden and limiting pathogen colonization across diverse infection models. These properties have supported their application in viral vaccine development, including influenza and SARS-CoV-2, with the potential to enhance mucosal immunity. Despite these advantages, challenges remain in standardization, safety, and antigen-loading efficiency. Engineered BMVs incorporating protein or mRNA antigens may further enhance antigen presentation and CD8⁺ T cell responses. This review summarizes the biological features, immunological mechanisms, and future potential of BMVs in vaccine development. Full article