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Immunological adjuvants are vaccine components that enhance long-lasting adaptive immune responses to weakly immunogenic antigens. Monophosphoryl lipid A (MPLA) is a potent and safe vaccine adjuvant that initiates an early innate immune response by binding to the Toll-like receptor 4 (TLR4). Importantly, the binding and recognition process is highly dependent on the monomeric state of MPLA. However, current vaccine delivery systems often prioritize improving the loading efficiency of MPLA, while neglecting the need to maintain its monomeric form for optimal immune activation. Here, we introduce a Pickering emulsion-guided MPLA monomeric delivery system (PMMS), which embed MPLA into the oil-water interface to achieve the monomeric loading of MPLA. During interactions with antigen-presenting cells, PMMS functions as a chaperone for MPLA, facilitating efficient recognition by TLR4 regardless of the presence of lipopolysaccharide-binding proteins. At the injection site, PMMS efficiently elicited local immune responses, subsequently promoting the migration of antigen-internalized dendritic cells to the lymph nodes. Within the draining lymph nodes, PMMS enhanced antigen presentation and maturation of dendritic cells. In C57BL/6 mice models, PMMS vaccination provoked potent antigen-specific CD8+ T cell-based immune responses. Additionally, PMMS demonstrated strong anti-tumor effects against E.G7-OVA lymphoma. These data indicate that PMMS provides a straightforward and efficient strategy for delivering monomeric MPLA to achieve robust cellular immune responses and effective cancer immunotherapy. Pickering emulsion-guided MPLA monomeric delivery system as a chaperone for MPLA, facilitating the efficient recognition of MPLA-TLR4. [Display omitted] • We construct a Pickering emulsion-guided MPLA monomeric delivery system (PMMS). • PMMS as a chaperone for MPLA, facilitating the efficient recognition of MPLA-TLR4. • PMMS can elicit robust cellular immune responses. • PMMS can achieve enhanced cancer immunotherapy. [ABSTRACT FROM AUTHOR]

The immunogenicity and toxicity of N -2-Hydroxypropyl trimethyl ammonium chloride chitosan/ N , O -carboxymethyl chitosan nanoparticles (N-2-HACC/CMCS NPs) as a universal vaccine adjuvant/delivery system remains unclear. The present study indicated that the positively charged N-2-HACC/CMCS NPs showed a regular spherical morphology, with a particle size of 219 ± 13.72 nm, zeta potential of 37.28 ± 4.58 mV, had hemocompatibility and biodegradation. Acute toxicity, repeated dose toxicity, abnormal toxicity, muscle stimulation, whole body allergic reaction evaluation in vitro , and cytotoxicity in vivo confirmed N-2-HACC/CMCS NPs is safe and non-toxic. N-2-HACC/OVA/CMCS NPs were prepared to evaluate the immunogenicity, which showed a particle size of 248.1 ± 15.53 nm, zeta potential of 17.24 ± 1.28 mV, encapsulation efficiency of 92.43 ± 0.96 %, and loading capacity of 42.97 ± 0.07 %. Oral or intramuscular route with the N-2-HACC/OVA/CMCS NPs in mice not only induced higher IgG, IgG1, IgG2a, and sIgA antibody titers, but also significantly produced higher levels of IL-6, IL-4, IFN-γ, and TNF-α, demonstrating that the N-2-HACC/OVA/CMCS NPs enhance humoral, cellular, and mucosal immune responses. Our results not only support the N-2-HACC/CMCS NPs to be a safe and potential universal nano adjuvant/delivery system in vaccine development, especially mucosal vaccines, but also rich the database knowledge of adjuvant/delivery systems, and provide new direction to introduce more licensed adjuvants. [ABSTRACT FROM AUTHOR]

Effective antigen delivery and immune stimulation in nasal mucosa determine the success of mucosal immunity. Here, an oil-in-ionic liquid (o/IL) nanoemulsion formulated with choline and niacin IL ([Cho][Nic]), squalene, and Tween 80 surfactant is explored as a vaccine delivery system for intranasal mucosal immunization. Compared to the o/w emulsion counterpart without the ILs, the o/IL manoemulsion showed a reduced and more uniform size of approximately 168 nm and significantly improved stability. Studies in mice model showed that when was used as an intranasal vaccine delivery system for influenza split-virus antigens, the antigens in the o/IL nanoemulsion induced strong mucosal immune responses with secretory IgA titers 25- and 5.8-fold higher than those of naked and commercial MF59-adjuvanted antigens, respectively. The o/IL nanoemulsion system also induced stronger systemic humoral responses. The excellent mucosal adjuvant effects of the o/IL nanoemulsion mainly benefited from the prolonged retention of antigens in the nasal cavity, enhanced antigen permeation into the submucosa, and the consequently promoted proliferation of CD11b cells and CD4+ T cells in nasal mucosa-associated lymphoid tissue. Moreover, when used as an injection adjuvant, the o/IL nanoemulsion also induced stronger humoral immune responses than MF59. Thus, the [Cho][Nic]-based o/IL nanoemulsion vaccine delivery system can serve as a promising adjuvant platform. [Display omitted] [ABSTRACT FROM AUTHOR]

An appropriate delivery system can improve the immune effects of antigens against various infections or tumors. Antigen-presenting cells (APCs) are specialized to capture and process antigens in vivo , which link the innate and adaptive immune responses. Functionalization of vaccine delivery systems with targeting moieties to APCs is a promising strategy for provoking potent immune responses. Additionally, the internalization and intracellular distribution of antigens are closely related to the initiation of downstream immune responses. With a deeper understanding of the intracellular microenvironment and the mechanisms of antigen presentation, vehicles designed to respond to endogenous and external stimuli can modulate antigen processing and presentation pathways, which are critical to the types of immune response. Here, an overview of extracellular targeting delivery of antigens to APCs and intracellular stimulus-responsiveness strategies is provided, which might be helpful for the rational design of vaccine delivery systems. [Display omitted] • Strategies for extracellular targeting to antigen-presenting cells are summarized in detail. • Antigen presentation pathways modulated by endogenous and external stimuli in antigen-presenting cells are discussed. • The types of immune response after antigen uptake and presentation are outlined. • Perspectives on the opportunities and major challenges of vaccine delivery systems are provided. [ABSTRACT FROM AUTHOR]

Clostridium perfringens is a major cause of food poisoning worldwide, with its enterotoxin (CPE) being the major virulence factor. The C-terminus of CPE (C-CPE) is non-toxic and is the part of the toxin that binds to epithelial cells via the claudins in tight junctions; however, C-CPE has low antigenicity. To address this issue, we have used protein engineering technology to augment the antigenicity of C-CPE and have developed a C-CPE-based vaccine against C. perfringens -mediated food poisoning. Moreover, C-CPE has properties that make it potentially useful for the development of vaccines against other bacterial toxins that cause food poisoning. For example, we hypothesized that the ability of C-CPE to bind to claudins could be harnessed to deliver vaccine antigens directly to mucosa-associated lymphoid tissues, and we successfully developed a nasally administered C-CPE-based vaccine delivery system that promotes antigen-specific mucosal and systemic immune responses. In addition, our group has revealed the roles that the nasal mucus plays in lowering the efficacy of C-CPE-based nasal vaccines. Here, we review recent advances in the development of C-CPE-based vaccines against the major bacterial toxins that cause food poisoning and discuss our C-CPE-based nasal vaccine delivery system. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • ε-PL-SA nanoparticles (PSNPs) were prepared and characterized as a vaccine carrier. • Three factors played important roles in particle size, zeta potential and EE of PSNPs. • PSNPs reduced burst release and presented a sustained-release behavior in vitro. • PSNPs showed no cytotoxicity and increased the efficiency of cellular uptake. Abstract Low immunogenicity prohibits the widespread use of subunit vaccine against infectious diseases and cancers. Hence, a new generation of adjuvants and delivery systems is indispensable for more potent antigen-specific immune responses. Predominantly, nanoparticles formulated from biodegradable polymers are being widely explored as carriers of novel vaccines owing to their outstanding natural properties. We fabricated a model antigen - bovine serum albumin (BSA) encapsulated ε-polylysine (ε-PL) - sodium alginate (SA) nanoparticles (PSNPs), which were self-assembled by ionotropic complexation method, a very simple and mild process, as a result of the electrostatic interaction between oppositely charged polyelectrolyte complexes (PEC). After the preparation, various in vitro parameters were characterized. Scanning electron microscope and dynamic light scattering were employed to study the morphology, size, zeta potential and optimize formulation. Forming mechanism of PSNPS was analyzed and verified by infrared absorption spectra and thermal analysis. Delivery behavior of PSNPs was assessed via release study, cytotoxicity measurement and cellular uptake. BSA-PSNPs with a mean particle diameter 133.2 ± 0.5 nm, narrow size distribution and negatively charged surface had been synthesized successfully by this method. The results of in vitro studies demonstrated that the nanosuspension was able to prevent burst release of loaded BSA and presented sustained-release behavior. It was no cytotoxicity by the bio-assessment using macrophage cells, and was observed significantly higher uptake compared with BSA free solution. Herein, ε-polylysine - sodium alginate nanoparticles had been found to be a potential candidate for vaccine delivery. [ABSTRACT FROM AUTHOR]

[Display omitted] With the pandemic of severe acute respiratory syndrome coronavirus 2, vaccine delivery systems emerged as a core technology for global public health. Given that antigen processing takes place inside the cell, the intracellular delivery and trafficking of a vaccine antigen will contribute to vaccine efficiency. Investigations focusing on the in vivo behavior and intracellular transport of vaccines have improved our understanding of the mechanisms relevant to vaccine delivery systems and facilitated the design of novel potent vaccine platforms. In this review, we cover the intracellular trafficking and in vivo fate of vaccines administered via various routes and delivery systems. To improve immune responses, researchers have used various strategies to modulate vaccine platforms and intracellular trafficking. In addition to progress in vaccine trafficking studies, the challenges and future perspectives for designing next-generation vaccines are discussed. [ABSTRACT FROM AUTHOR]

Foot-and-mouth disease (FMD) virus-like particles (VLPs) comprise a new and effective FMD vaccine, which often requires the addition of adjuvants to induce a vigorous immune response in order to protect livestock from the challenge of FMD virus (FMDV). Oil emulsion delivery systems have been developed and used widely in the field of veterinary vaccines because of their low cost, slow release, and efficient antigen protection. In this study, we designed and synthesized an optimized Achyranthes bidentata polysaccharide (ABP) delivery system (ABPOA) based on a pseudo-ternary phase diagram. We systematically evaluated the stability, biocompatibility, and immunological effects of the ABP delivery system. The results demonstrated that ABPOA is a stable adjuvant delivery system and capable of long-term storage at 37 °C for up to 6 months. ABP-VLPs can be effectively stored for long periods when ABPOA is used as the delivery system for VLPs. Importantly, guinea pig-specific antibodies were significantly increased within 28 days when ABPOA was used as a delivery system, thereby promoting the proliferation of splenic lymphocytes. In addition, immunization with one dose of ABP-VLPs resulted in complete protection from homologous FMDV challenge in guinea pigs. Therefore, the polysaccharide oil emulsion adjuvant comprising ABPOA effectively improved the immunogenicity of FMD-VLPs. These findings provide a theoretical basis for the preparation of oil emulsion adjuvants for veterinary vaccines. [Display omitted] • A high encapsulation rate delivery system for Chinese medicine. • ABPOA has good storage and thermodynamic stability performance. • ABPOA effectively preserves the biological activity of FMD-VLPs. • ABP-VLPs have good stability and immunological efficacy. [ABSTRACT FROM AUTHOR]

Abstract: For H5N1 influenza immunization, we developed a thermal-sensitive hydrogel as intranasal vaccine delivery system, which was formulated with N-[(2-hydroxy-3-trimethylammonium) propyl] chitosan chloride (HTCC) and α, β-glycerophosphate (α, β-GP). The flowing solution of HTCC/GP under room temperature could gelate rapidly at body temperature, which significantly prolonged the H5N1 split antigen residence time in nasal cavity. This system also enhanced the transepithelial transport via the paracellular routes due to the disorganization of ZO-1 protein in nasal epithelial tissue. In comparison to naked H5N1 split antigen and MF59 adjuvanted antigen, as designed hydrogel/H5N1 vaccine induced greater antigen-specific systemic immune responses and mucosal IgA immunity without adjuvants. Furthermore, a boosted cellular and humoral response was also obtained by examination of IFN-γ and IL-4 cytokines, respectively. In addition, hydrogel based formulation promoted the antigen-specific CD8+ T cell immune memory as determined by the proportion of central and effector memory CD8+ T cells in nasal associated lymphoid tissue (NALT). These results demonstrate that the HTCC hydrogel has potential as an adjuvant-free platform for H5N1 split antigen intranasal vaccination. [Copyright &y& Elsevier]

Abstract: Single shot vaccines of tetanus toxoid (TT) were manufactured using the NanoMix™ process – a low temperature solvent free encapsulation technology using supercritical fluids. The formulations were injected into mice, and compared to multiple injections of a commercially available alum adsorbed TT vaccine. After 5 months the antibody titres were found to be similar for both the alum adsorbed and microparticle formulations, demonstrating for the first time the potential of formulating antigens in PLA microparticles using the supercritical fluid (NanoMix™) technique to produce single shot vaccines. The results are likely to be due to the maintenance of toxoid bioactivity and some degree of sustained release of the encapsulated antigens, resulting in repeated stimulation of antigen presenting cells eliminating the need for multiple immunisations. This demonstrates the potential of this supercritical fluid processing technique to reduce the need for booster doses in a vaccine regimen. [Copyright &y& Elsevier]

Abstract: Bovine herpesvirus 1 (BHV-1), is a major pathogen of cattle which causes serious infections, including infectious bovine rhinotracheitis (IBR)/infectious pustular vulvovaginitis (IPV). At present, BHV-1 is still a serious threat to animal health and productivity in Turkey, hence to develop a more efficient and economical vaccine system against BHV-1 is certainly an important necessity. A mucosal vaccination strategy would provide both mucosal and systemic immune responses to protect disease progression and transmission. However, vaccination through mucosal membranes requires adjuvants/delivery systems in order to enhance the immunogenicity of the antigens. Chitosan, which is a biodegradable, biocompatible and bioadhesive natural polysaccharide, has been shown to be promising both as a delivery system and an adjuvant for mucosal vaccination. In this study, microparticles with appropriate size (<10μm), positive surface charge and high loading efficiency (∼95%) were prepared for mucosal delivery of BHV-1, using various types of chitosan with different molecular weight and solubility. Particles were shown to be taken up by the cells, mostly around the nucleus, whereas with aggregates which were bigger in size were adsorbed at the surface. Furthermore, gel formulations with a suitable viscosity which would provide easy application and remain on the mucosa for extended period of time were also developed with a high zeta potential indicating a stable system. Both the BHV-1 loaded microparticle and gel formulations were shown to maintain cell viability and antigen integrity. Chitosan-based formulations are suggested as promising adjuvant/delivery systems for mucosal immunization against BHV-1. [ABSTRACT FROM AUTHOR]

Abstract: Vaccine shortages are a major obstacle to influenza pandemic preparedness. Increasing vaccine efficiency provides a potentially effective way to overcome this problem. Specifically, using single-dose immunization to induce protective immunity is an attractive approach to emergency/massive vaccination. In this report, we propose a novel nanoemulsion comprised of the bioresorbable polymer, Span®85, and squalene forming a ready-to-use adjuvant, called PELC. After formulation with PELC, inactivated H5N1 virus was intramuscularly administered to mice via a single injection. The data demonstrate that inactivated virus containing 0.5μg hemagglutinin (HA) and formulated with PELC induced more potent antigen-specific antibodies, hemagglutination inhibition, and virus neutralization than non-adjuvanted inactivated virus containing 5μg HA. In addition, T-cell proliferative responses, as well as interferon-γ (IFN-γ) and interleukin-4 (IL-4) secretion were significantly enhanced after immunization with PELC-adjuvanted inactivated virus. These results indicate that PELC can be used for effective single-dose immunization and could thus play an important role in influenza pandemic preparedness. [Copyright &y& Elsevier]

The emergence of many new viruses in recent times has resulted in a significant scientific challenge for discovering drugs and vaccines that effectively treat and prevent viral diseases. Nanotechnology has opened doors to prevent the spread of several diseases, including those caused by viruses. Polymer-hybrid nanodevices are a class of nanotechnology platforms for biomedical applications that present synergistic properties among their components, with improved performance compared to conventional forms of therapy. Considering the growing interest in this emerging field and the promising technological advantages of polymer-hybrid nanodevices, this work presents the current status of these systems in the context of prevention and treatment of viral diseases. A brief description of the different types of polymer-hybrid nanodevices highlighting some peculiar characteristics such as their composition, biodistribution, delivery of antigens, and overall immune responses in systemic tissues are discussed. Finally, the work presents the future trends for new nanotechnological hybrid materials based on polymers and perspectives for clinical use. [Display omitted] • A direct physical interaction between the nanoparticles and the virus is a reality. • Nanoparticles can act as a viral entry inhibitor, blocking the early viral replication stage. • Hybrid-polymer nanosystems have a relevant potential for viral target therapy. • Hybrid-nanoparticles revealed potent activity against coronavirus. [ABSTRACT FROM AUTHOR]

Abstract: A vaccine delivery system based on mannosylated chitosan microspheres (MCMs) was studied in vitro and in vivo. Bordetella bronchiseptica antigens containing dermonecrotoxin (BBD) were loaded in MCMs or chitosan microspheres (CMs). Fluorescence confocal microscopy indicated that BBD-loaded MCMs (BBD–MCMs) bound with mannose receptors on murine macrophages (RAW264.7 cells). In vitro experiments using macrophages demonstrated that BBD–MCMs had more effective immune-stimulating activity than BBD-loaded CMs (BBD–CMs). Mice intranasally immunized with BBD–MCMs showed significantly higher BBD-specific IgA antibody responses in saliva and serum than mice immunized with BBD–CMs (p <0.05). After challenge with B. bronchiseptica via the nasal cavity, groups treated with BBD–MCMs or BBD–CMs showed similar patterns with a high survival rate even though there was no significant difference between those groups. These results suggested that mannose moieties in the MCMs enhanced immune-stimulating activities through mucosal delivery due to a specific interaction between mannose groups in the MCMs and mannose receptors on the macrophages. [Copyright &y& Elsevier]

Two continuous delivery injectable silicone implants were tested to determine if they were capable of delivering vaccines in a single shot. The Type A implant delivers antigen in vitro over a 1-month-period and the Type B over several months. Vaccination studies in sheep were designed to compare the responses induced by the Type A and B implants, Alzet™ mini-osmotic pumps and conventional antigen delivery. A model antigen, avidin, was used along with IL-1β or alum as adjuvants. Sheep were immunised with various formulations and the titre and isotype of the antigen specific antibodies monitored. The Type B implant induced antibody (Ab) titres of greater magnitude and duration than soluble vaccines or the Type A implant with adjuvant, but only if IL-1β was included in the formulation. Both implants induced antibodies of IgG1 and IgG2 isotype. A memory response to soluble antigen challenge was induced by the Type B+IL-1β implant, which was predominantly of an IgG1 isotype. [Copyright &y& Elsevier]

The appropriate delivery of vaccines is a significant factor for the proper immunization. The proper delivery of the cargo vaccine/antigen along with stimulation of high antigen mediated immune response are the prime factors of an efficient vaccine deliver system. Different delivery systems have been explored for vaccine delivery and immunization. However, significant limitations like inefficient immunogenicity and undesired inflammatory immunogenic reactions are also notable. Thus, the development of an efficient vaccine delivery system is challenging task. Polymer based systems have also been utilized for vaccine delivery. Research also have indicated that a polymeric hydrogel can become an efficient delivery system of foreign antigens and vaccines. These systems can harbor and deliver the cargo vaccine/antigen in desired target organ and also facilitate the antigen mediated immunogenicity. Keeping in view the above perspectives, an attempt has been made to review the significance of polymeric hydrogel based systems for vaccine delivery. [Display omitted] • The appropriate delivery of cargo vaccines is a significant issue for proper vaccination. • Different polymers were utilized to develop significant vaccine delivery systems. • Polymeric hydrogel is proficient for vaccine delivery and efficient immunization. • Increased immunogenicity facilitate synthetic and natural polymer based vaccine delivery systems. [ABSTRACT FROM AUTHOR]