Vaccine Delivery System Research Articles

Development of an oral nanovaccine for dogs against Echinococcus granulosus

Dogs are the main source of animal and human cystic echinococcosis caused by the Cestode parasite Echinococcus granulosus. Dog vaccination seems to be a good strategy to control this parasitic disease. Here we present the development of a polymeric nanoparticle-based oral vaccine for dogs against Echinococcus granulosus delivered in enteric-coated capsules. To achieve our target, we encapsulated two recombinant antigens into biodegradable polymeric nanoparticles in the presence of Monophosphoryl lipid A as an adjuvant to ensure efficient delivery and activation of a protective mucosal immune response. The formulated delivery system showed a nanoparticle size less than 200 nm with more than 80 % antigen encapsulation efficiency and conserved integrity and immunogenicity. The nanoparticle surface was coated with chitosan to enhance adhesion to the gut mucosa and a subsequent antigen delivery. Chitosan-coated nanoparticles showed a higher cell internalization in murine macrophages and dendritic cells as well as a higher penetration into Caco-2 cells in vitro. Antigen-loaded nanoparticles were freeze-dried and enteric-coated capsules were filled with the obtained powder. The obtained results show a promising nanoparticles delivery system for oral vaccination.

Drivers of early childhood vaccination success in Nepal, Senegal, and Zambia: a multiple case study analysis using the Consolidated Framework for Implementation Research

IntroductionThe fundamental components of a vaccine delivery system are well-documented, but robust evidence is needed on how the related processes and implementation strategies — including the facilitators and barriers — contribute to improvements in childhood vaccination coverage. The purpose of this study was to identify critical facilitators and barriers to the implementation of common interventions across three countries that have dramatically increased coverage of early childhood vaccination over the past 20 years, and to qualify common or divergent themes in their success.MethodsWe conducted 278 key informant interviews and focus group discussions with public health leaders at the regional, district, and local levels and community members in Nepal, Senegal, and Zambia to identify intervention activities and the facilitators and barriers to implementation. We used thematic analysis grounded in the Consolidated Framework for Implementation Research (CFIR) constructs of inner and outer settings to identify immunization program key facilitators and barriers.ResultsWe found that the common facilitators to program implementation across the countries were the CFIR inner setting constructs of (1) networks and communications, (2) goals and feedback, (3) relative priority, and (4) readiness for implementation and outer setting constructs of (5) cosmopolitanism and (6) external policies and mandates. The common barriers were incentives and rewards, available resources, access to knowledge and information, and patients’ needs and resources. Critical to the success of these national immunization programs were prioritization and codification of health as a human right, clear chain of command and shared ownership of immunization, communication of program goals and feedback, offering of incentives at multiple levels, training of staff central to vaccination education, the provision of resources to support the program, key partnerships and guidance on implementation and adoption of vaccination policies.ConclusionAdequate organizational commitment, resources, communication, training, and partnerships were the most critical facilitators for these countries to improve childhood vaccination.

Lentinan-functionalized graphene oxide hydrogel as a sustained antigen delivery system for vaccines

Hydrogel has been proven to have the ability to deliver antigens continuously to achieve slow vaccine delivery, which makes it a promising candidate for an adjuvant delivery platform. Meanwhile, graphene oxide (GO) has garnered significant attention due to its good biosafety, excellent surface area and easy modification. However, GO exists as weak colloidal particles and poses challenges in self-assembling into a hydrogel structure. Here, we propose an innovative strategy involving self-assembling lentinan-functionalized graphene oxide hydrogel ((LNT-GO Gel) by simply mixing lentinan (LNT)-functionalized GO with polyethylene imide (PEI), which can simultaneously encapsulate antigens, achieve long-lasting release of antigens and generate excellent adjuvant activity. The results indicated that the LNT-GO Gel can control the release of OVA at the injection site and confer targeted delivering capacity to lymph nodes. And the date demonstrates that LNT-GO Gel displays favorable safety and biodegradability in vivo. Moreover, LNT-GO Gel can enhance the activation and maturation of dendritic cells (DCs) in lymph node, induce stronger OVA-specific antibody response, and promote spleen T lymphocyte differentiation, which underscores that LNT-GO Gel has ability to generate stronger antigen-specific humoral and cellular immune responses. Collectively, these results demonstrate the adjuvant potential of the lentinan-functionalized graphene oxide hydrogel (LNT-GO Gel) for subunit vaccine.

Vaccine microarray patch self-administration: An innovative approach to improve pandemic and routine vaccination rates

The high-density microprojection array patch (HD-MAP) is a novel vaccine delivery system with potential for self-administered vaccination. HD-MAPs provide an alternative to needle and syringe (N&S) vaccination. Additional advantages could include reduced cold-chain requirements, reduced vaccine dose, reduced vaccine wastage, an alternative for needle phobic patients and elimination of needlestick injuries. The drivers and potential benefits of vaccination by self-administering HD-MAPs are high patient acceptance and preference, higher vaccination rates, speed of roll-out, cost-savings, and reduced sharps and environmental waste. The HD-MAP presents a unique approach in pandemic preparedness and routine vaccination of adults. It could alleviate strain on the healthcare workforce and allows vaccine administration by minimally-trained workers, guardian or subjects themselves. Self-vaccination using HD-MAPs could occur in vaccination hubs with supervision, at home after purchasing at the pharmacy, or direct distribution to in-home settings. As a result, it has the potential to increase vaccine coverage and expand the reach of vaccines, while also reducing labor costs associated with vaccination. Key challenges remain around shifting the paradigm from medical professionals administrating vaccines using N&S to a future of self-administration using HD-MAPs. Greater awareness of HD-MAP technology and improving our understanding of the implementation processes required for adopting this technology, are critical factors underpinning HD-MAP uptake by the public.

Liponanoparticles as a novel delivery system for mRNA vaccines against VHSV

Liponanoparticles as a novel delivery system for mRNA vaccines against VHSV

Mapping the timeliness of routine childhood vaccination in The Gambia: A spatial modelling study

IntroductionTimeliness of routine vaccination shapes childhood infection risk and thus is an important public health metric. Estimates of indicators of the timeliness of vaccination are usually produced at the national or regional level, which may conceal epidemiologically relevant local heterogeneities and makeitdifficultto identify pockets of vulnerabilities that could benefit from targeted interventions. Here, we demonstrate the utility of geospatial modelling techniques in generating high-resolution maps of the prevalence of delayed childhood vaccination in The Gambia. To guide local immunisation policy and prioritize key interventions, we also identified the districts with a combination of high estimated prevalence and a significant population of affected infants. MethodsWe used the birth dose of the hepatitis-B vaccine (HepB0), third-dose of the pentavalent vaccine (PENTA3), and the first dose of measles-containing vaccine (MCV1) as examples to map delayed vaccination nationally at a resolution of 1 × 1-km2 pixel. We utilized cluster-level childhood vaccination data from The Gambia 2019–20 Demographic and Health Survey. We adopted a fully Bayesian geostatistical model incorporating publicly available geospatial covariates to aid predictive accuracy. The model was implemented using the integrated nested Laplace approximation—stochastic partial differential equation (INLA-SPDE) approach. ResultsWe found significant subnational heterogeneity in delayed HepB0, PENTA3 and MCV1 vaccinations. Specificdistricts in the central and eastern regions of The Gambia consistentlyexhibited the highest prevalence of delayed vaccination, while the coastal districts showed alower prevalence forallthree vaccines. We also found that districts in the eastern, central, as well as in coastal parts of The Gambia had a combination of high estimated prevalence of delayed HepB0, PENTA3 and MCV1 and a significant population of affected infants. ConclusionsOur approach provides decision-makers with a valuable tool to better understand local patterns of untimely childhood vaccination and identify districts where strengthening vaccine delivery systems could have the greatest impact.

Multiple Vaccines and Strategies for Pandemic Preparedness of Avian Influenza Virus.

Avian influenza viruses (AIV) are a continuous cause of concern due to their pandemic potential and devasting effects on poultry, birds, and human health. The low pathogenic avian influenza virus has the potential to evolve into a highly pathogenic avian influenza virus, resulting in its rapid spread and significant outbreaks in poultry. Over the years, a wide array of traditional and novel strategies has been implemented to prevent the transmission of AIV in poultry. Mass vaccination is still an economical and effective approach to establish immune protection against clinical virus infection. At present, some AIV vaccines have been licensed for large-scale production and use in the poultry industry; however, other new types of AIV vaccines are currently under research and development. In this review, we assess the recent progress surrounding the various types of AIV vaccines, which are based on the classical and next-generation platforms. Additionally, the delivery systems for nucleic acid vaccines are discussed, since these vaccines have attracted significant attention following their significant role in the fight against COVID-19. We also provide a general introduction to the dendritic targeting strategy, which can be used to enhance the immune efficiency of AIV vaccines. This review may be beneficial for the avian influenza research community, providing ideas for the design and development of new AIV vaccines.

Activity Relationship of Poly(ethylenimine)-Based Liposomes as Group A Streptococcus Vaccine Delivery Systems.

Untreated group A Streptococcus (GAS) can lead to a range of life-threatening diseases, including rheumatic heart disease. To date, no therapeutic or prophylactic vaccines are commercially available to treat or prevent GAS infection. Development of a peptide-based subunit vaccine offers a promising solution, negating the safety issues of live-attenuated or inactive vaccines. Subunit vaccines administer small peptide fragments (antigens), which are typically poorly immunogenic. Therefore, these peptide antigens require formulation with an immune stimulant and/or vaccine delivery platform to improve their immunogenicity. We investigated polyelectrolyte complexes (PECs) and polymer-coated liposomes as self-adjuvanting delivery vehicles for a GAS B cell peptide epitope conjugated to a universal T-helper epitope and a synthetic toll-like receptor 2-targeting moiety lipid core peptide-1 (LCP-1). A structure-activity relationship of cationic PEC vaccines containing different external PEI-coatings (poly(ethylenimine); 10 kDa PEI, 25 kDa PEI, and a synthetic mannose-functionalized 25 kDa PEI) formed vaccines PEC-1, PEC-2, and PEC-3, respectively. All three PEC vaccines induced J8-specific systemic immunoglobulin G (IgG) antibodies when administered intranasally to female BALB/c mice without the use of additional adjuvants. Interestingly, PEC-3 induced the highest antibody titers among all tested vaccines, with the ability to effectively opsonize two clinically isolated GAS strains. A comparative study of PEC-2 and PEC-3 with liposome-based delivery systems was performed subcutaneously. LCP-1 was incorporated into a liposome formulation (DPPC, DPPG and cholesterol), and the liposomes were externally coated with PEI (25 kDa; Lip-2) or mannosylated PEI (25 kDa; Lip-3). All liposome vaccines induced stronger humoral immune responses compared to their PEC counterparts. Notably, sera of mice immunized with Lip-2 and Lip-3 produced significantly higher opsonic activity against clinically isolated GAS strains compared to the positive control, P25-J8 emulsified with the commercial adjuvant, complete Freund's adjuvant (CFA). This study highlights the capability of a PEI-liposome system to act as a self-adjuvanting vehicle for the delivery of GAS peptide antigens and protection against GAS infection.

Self-Adjuvanting Calcium-Phosphate-Coated Microcrystal-Based Vaccines Induce Pyroptosis in Human and Livestock Immune Cells.

Successful vaccines require adjuvants able to activate the innate immune system, eliciting antigen-specific immune responses and B-cell-mediated antibody production. However, unwanted secondary effects and the lack of effectiveness of traditional adjuvants has prompted investigation into novel adjuvants in recent years. Protein-coated microcrystals modified with calcium phosphate (CaP-PCMCs) in which vaccine antigens are co-immobilised within amino acid crystals represent one of these promising self-adjuvanting vaccine delivery systems. CaP-PCMCs has been shown to enhance antigen-specific IgG responses in mouse models; however, the exact mechanism of action of these microcrystals is currently unclear. Here, we set out to investigate this mechanism by studying the interaction between CaP-PCMCs and mammalian immune cells in an in vitro system. Incubation of cells with CaP-PCMCs induced rapid pyroptosis of peripheral blood mononuclear cells and monocyte-derived dendritic cells from cattle, sheep and humans, which was accompanied by the release of interleukin-1β and the activation of Caspase-1. We show that this pyroptotic event was cell-CaP-PCMCs contact dependent, and neither soluble calcium nor microcrystals without CaP (soluble PCMCs) induced pyroptosis. Our results corroborate CaP-PCMCs as a promising delivery system for vaccine antigens, showing great potential for subunit vaccines where the enhancement or find tuning of adaptive immunity is required.

Versatile dual responsive EGCG/Cys nano delivery system for atherosclerosis

Nanocarriers receive tremendous attention in nanomedicine and precision biomedicine, especially cardiovascular diseases. However, the ideal carriers for multiple agents are still got a long way to come. In this work, one REDOX dual responsive nanoparticle was designed and constructed by epigallocatechin gallate (EGCG) and cystamine (Cys). The particles presented uniform sphere, and its diameter was around 200 nm. The drug loading ability of the particles was evaluated using rhodamine 6G (Rh6G), rapamycin (Rapa) and bovine serum albumin as model drugs. The EGCG/Cys particles could intelligently release drugs based on the REDOX level of local environment. The morphology and cell viability results of endothelial cells (ECs) and macrophage cells verified the good biocompatibility of the particles. The biosecurity of the particles was further confirmed by injections in vivo. Moreover, the EGCG/Cys particles could effectively target the injured vascular. These results confirmed that the EGCG/Cys particles could be used as one universal carrier to build nano delivery system for drugs, biological agent and vaccines for targeted treatment of atherosclerosis. The work provides one novel promising universal nanocarrier with good bio-safety for multiple drugs and bio-agents for atherosclerosis treatment.

Current strategies in cationic liposomal vaccine development for anti-cancer therapy

Nanomedicine is currently at the forefront of technology. Nanovaccines are a relevant development derived from this field and comprise nanoparticles ranging from 50-250 nm to deliver antigens and other immunomodulatory agents. Their formulation can include liposomes, which are widely known as safe and allow their engineering to be cationic, conferring a superior immunostimulatory effect. This promising strategy for vaccine delivery has gained interest in cancer as it provides higher targeting efficiency, increased antigen stability, prolonged circulation time, and enhanced uptake by antigen-presenting cells, mainly dendritic cells. Therefore, this minireview discusses recent research on cationic liposome-based vaccine delivery systems for anti-cancer therapy. Pubmed, Science Direct, and Google Scholar were screened for original and review papers published in the last ten years. The antigen association with the cationic nanoparticles either by electrostatic interactions or complementary coiled coil peptide pair strategy were found as the most promising strategies. The work also highlights the potential of this therapeutic platform for enhancing the T-cell immune response against cancer through mRNA-containing formulations for different routes of administration, providing a detailed physicochemical characterization of the reported nanosystems.

The Bacterial Spore as a Mucosal Vaccine Delivery System.

The development of efficient mucosal vaccines is strongly dependent on the use of appropriate vectors. Various biological systems or synthetic nanoparticles have been proposed to display and deliver antigens to mucosal surfaces. The Bacillus spore, a metabolically quiescent and extremely resistant cell, has also been proposed as a mucosal vaccine delivery system and shown able to conjugate the advantages of live and synthetic systems. Several antigens have been displayed on the spore by either recombinant or non-recombinant approaches, and antigen-specific immune responses have been observed in animals immunized by the oral or nasal route. Here we review the use of the bacterial spore as a mucosal vaccine vehicle focusing on the advantages and drawbacks of using the spore and of the recombinant vs. non-recombinant approach to display antigens on the spore surface. An overview of the immune responses induced by antigen-displaying spores so far tested in animals is presented and discussed.

Magnetically Actuated Biodegradable Nanorobots for Active Immunotherapy.

An efficient and cost-effective therapeutic vaccine is highly desirable for the prevention and treatment of cancer, which helps to strengthen the immune system and activate the T cell immune response. However, initiating such an adaptive immune response efficiently remains challenging, especially the deficient antigen presentation by dendritic cells (DCs) in the immunosuppressive tumor microenvironment. Herein, an efficient and dynamic antigen delivery system based on the magnetically actuated OVA-CaCO3 -SPIO robots (OCS-robots) is rationally designed for active immunotherapy. Taking advantage of the unique dynamic features, the developed OCS-robots achieve controllable motion capability under the rotating magnetic field. Specifically, with the active motion, the acid-responsiveness of OCS-robots is beneficial for the tumor acidity attenuating and lysosome escape as well as the subsequent antigen cross-presentation of DCs. Furthermore, the dynamic OCS-robots boost the crosstalk between the DCs and antigens, which displays prominent tumor immunotherapy effect on melanoma through cytotoxic T lymphocytes (CTLs). Such a strategy of dynamic vaccine delivery system enables the active activation of immune system based on the magnetically actuated OCS-robots, which presents a plausible paradigm for incredibly efficient cancer immunotherapy by designing multifunctional and novel robot platforms in the future.

Biodistribution assessment of cationic pullulan nanogel, a nasal vaccine delivery system, in mice and non-human primates

Cationic cholesteryl-group–bearing pullulan nanogel (cCHP-nanogel) is an effective drug-delivery system for nasal vaccines. However, cCHP-nanogel-based nasal vaccines might access the central nervous system due to its close proximity via the olfactory bulb in the nasal cavity. Using real-time quantitative tracking of the nanogel-based nasal botulinum neurotoxin and pneumococcal vaccines, we previously confirmed the lack of deposition of vaccine antigen in the cerebrum or olfactory bulbs of mice and non-human primates (NHPs), rhesus macaques. Here, we used positron emission tomography to investigate the biodistribution of the drug-delivery system itself, cCHP-nanogel after mice and NHPs were nasally administered with 18F-labeled cCHP nanogel. The results generated by the PET analysis of rhesus macaques were consistent with the direct counting of radioactivity due to 18F or 111In in dissected mouse tissues. Thus, no depositions of cCHP-nanogel were noted in the cerebrum, olfactory bulbs, or eyes of both species after nasal administration of the radiolabeled cCHP-nanogel compound. Our findings confirm the safe biodistribution of the cCHP-nanogel-based nasal vaccine delivery system in mice and NHPs.

Research Progress of Aluminum Phosphate Adjuvants and Their Action Mechanisms.

Although hundreds of different adjuvants have been tried, aluminum-containing adjuvants are by far the most widely used currently. It is worth mentioning that although aluminum-containing adjuvants have been commonly applied in vaccine production, their acting mechanism remains not completely clear. Thus far, researchers have proposed the following mechanisms: (1) depot effect, (2) phagocytosis, (3) activation of pro-inflammatory signaling pathway NLRP3, (4) host cell DNA release, and other mechanisms of action. Having an overview on recent studies to increase our comprehension on the mechanisms by which aluminum-containing adjuvants adsorb antigens and the effects of adsorption on antigen stability and immune response has become a mainstream research trend. Aluminum-containing adjuvants can enhance immune response through a variety of molecular pathways, but there are still significant challenges in designing effective immune-stimulating vaccine delivery systems with aluminum-containing adjuvants. At present, studies on the acting mechanism of aluminum-containing adjuvants mainly focus on aluminum hydroxide adjuvants. This review will take aluminum phosphate as a representative to discuss the immune stimulation mechanism of aluminum phosphate adjuvants and the differences between aluminum phosphate adjuvants and aluminum hydroxide adjuvants, as well as the research progress on the improvement of aluminum phosphate adjuvants (including the improvement of the adjuvant formula, nano-aluminum phosphate adjuvants and a first-grade composite adjuvant containing aluminum phosphate). Based on such related knowledge, determining optimal formulation to develop effective and safe aluminium-containing adjuvants for different vaccines will become more substantiated.

Inside-out assembly of viral antigens for the enhanced vaccination

Current attempts in vaccine delivery systems concentrate on replicating the natural dissemination of live pathogens, but neglect that pathogens evolve to evade the immune system rather than to provoke it. In the case of enveloped RNA viruses, it is the natural dissemination of nucleocapsid protein (NP, core antigen) and surface antigen that delays NP exposure to immune surveillance. Here, we report a multi-layered aluminum hydroxide-stabilized emulsion (MASE) to dictate the delivery sequence of the antigens. In this manner, the receptor-binding domain (RBD, surface antigen) of the spike protein was trapped inside the nanocavity, while NP was absorbed on the outside of the droplets, enabling the burst release of NP before RBD. Compared with the natural packaging strategy, the inside-out strategy induced potent type I interferon-mediated innate immune responses and triggered an immune-potentiated environment in advance, which subsequently boosted CD40+ DC activations and the engagement of the lymph nodes. In both H1N1 influenza and SARS-CoV-2 vaccines, rMASE significantly increased antigen-specific antibody secretion, memory T cell engagement, and Th1-biased immune response, which diminished viral loads after lethal challenge. By simply reversing the delivery sequence of the surface antigen and core antigen, the inside-out strategy may offer major implications for enhanced vaccinations against the enveloped RNA virus.

Validation of an HPLC-CAD Method for Determination of Lipid Content in LNP-Encapsulated COVID-19 mRNA Vaccines.

Lipid nanoparticles (LNPs) are widely used as delivery systems for mRNA vaccines. The stability and bilayer fluidity of LNPs are determined by the properties and contents of the various lipids used in the formulation system, and the delivery efficiency of LNPs largely depends on the lipid composition. For the quality control of such vaccines, here we developed and validated an HPLC-CAD method to identify and determine the contents of four lipids in an LNP-encapsulated COVID-19 mRNA vaccine to support lipid analysis for the development of new drugs and vaccines.

Biomedical application of polymer based nanomaterials: Vaccines & drugs

Polymer nanoparticles have drawn attention worldwide due to their extensive use in many domains like physics, chemistry, and biology. Drug development greatly benefits from the use of nanotechnology. Vaccine antigens, therapeutic proteins, and other substances can be delivered to the site of action using polymeric nanoparticles. When administered via the mucosa, polymeric nanoparticles with low cytotoxicity can prevent the breakdown of antigens or medicines. Due to their ability to extend the duration of the vaccination antigen, nanoparticles are frequently used in vaccine delivery systems. The biocompatibility and biodegradability of biodegradable polymer nanoparticles in various delivery methods are their key features. Shortly, more drug delivery methods utilizing nanoparticles are anticipated to become accessible.

Provider and Practice Factors Associated With On-Time HPV Vaccination in Primary Care.

In 2018, only one third of girls and boys completed the 2-dose series of the human papillomavirus vaccine by their 13th birthday, the target for on-time vaccination. The study objective was to identify key patient, provider and practice-level factors associated with on-time vaccination in the primary care setting. We examined data from 20 primary care pediatric practices (89 providers) in St. Louis including: the percentage of eligible patients with on-time vaccination assessed from medical records; providers' knowledge, attitudes and behaviors regarding on-time vaccination assessed with a survey; and practice-level strategies used to optimize vaccine delivery assessed with a 19-item vaccine delivery system score (VDSS). Factors that increased on-time vaccination were identified using logistic regression, controlling for clustering within providers. Completion of on-time vaccination occurred in 1347/3125 (43.10%) of patients (95% confidence interval [CI], 41.36%-44.86%) and varied among practices (7.39%-64.24%) and among providers (2.63%-82.50%). Independent predictors for higher completion of on-time vaccination included more frequent use by providers of the announcement style for vaccine recommendation (odds ratio [OR] 1.18, 95% CI, 1.04, 1.35), higher provider self-efficacy to deliver the vaccine according to guideline recommendations if parents were hesitant (OR 1.21, 95% CI, 1.05, 1.40), and higher VDSS (OR 1.20, 95% CI, 1.10, 1.31). Provider and practice-level factors were identified that may represent modifiable targets for improvement in on-time vaccine uptake. Future research is needed to test interventions built on these findings.

Microneedles: An Emerging Vaccine Delivery Tool and a Prospective Solution to the Challenges of SARS-CoV-2 Mass Vaccination.

Vaccination is an effective measure to prevent infectious diseases. Protective immunity is induced when the immune system is exposed to a vaccine formulation with appropriate immunogenicity. However, traditional injection vaccination is always accompanied by fear and severe pain. As an emerging vaccine delivery tool, microneedles overcome the problems associated with routine needle vaccination, which can effectively deliver vaccines rich in antigen-presenting cells (APCs) to the epidermis and dermis painlessly, inducing a strong immune response. In addition, microneedles have the advantages of avoiding cold chain storage and have the flexibility of self-operation, which can solve the logistics and delivery obstacles of vaccines, covering the vaccination of the special population more easily and conveniently. Examples include people in rural areas with restricted vaccine storage facilities and medical professionals, elderly and disabled people with limited mobility, infants and young children afraid of pain. Currently, in the late stage of fighting against COVID-19, the main task is to increase the coverage of vaccines, especially for special populations. To address this challenge, microneedle-based vaccines have great potential to increase global vaccination rates and save many lives. This review describes the current progress of microneedles as a vaccine delivery system and its prospects in achieving mass vaccination against SARS-CoV-2.