Search Results (18)

Adjuvants are a diverse group of substances that can be added to vaccines to enhance antigen-specific immune responses and improve vaccine efficacy. The first adjuvants, discovered almost a century ago, were soluble crystals of aluminium salts. Over the following decades, oil emulsions, vesicles, oligodeoxynucleotides, viral capsids, and other complex organic structures have been shown to have adjuvant potential. However, the detailed mechanisms of how adjuvants enhance immune responses remain poorly understood and may be a barrier that reduces the rational selection of vaccine components. Previous studies on mechanisms of action of adjuvants have focused on how they activate innate immune responses, including the regulation of cell recruitment and activation, cytokine/chemokine production, and the regulation of some “immune” genes. This approach provides a narrow perspective on the complex events involved in how adjuvants modulate antigen-specific immune responses. A comprehensive and efficient way to investigate the molecular mechanism of action for adjuvants is to utilize systems biology approaches such as transcriptomics in so-called “systems vaccinology” analysis. While other molecular biology methods can verify if one or few genes are differentially regulated in response to vaccination, systems vaccinology provides a more comprehensive picture by simultaneously identifying the hundreds or thousands of genes that interact with complex networks in response to a vaccine. Transcriptomics tools such as RNA sequencing (RNA-Seq) allow us to simultaneously quantify the expression of practically all expressed genes, making it possible to make inferences that are only possible when considering the system as a whole. Here, we review some of the challenges in adjuvant studies, such as predicting adjuvant activity and toxicity when administered alone or in combination with antigens, or classifying adjuvants in groups with similar properties, while underscoring the significance of transcriptomics in systems vaccinology approaches to propel vaccine development forward. Full article

Introduction: The autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is a rare condition caused by an immune response associated with over-reactivity of the immune system, triggered by adjuvants. The most common adjuvants are aluminium salts but can also be bioimplants or infectious agents. It may lead to the development of various autoimmunologic diseases. Case Report: In the following article, we present the case of a 26-year-old woman who developed SLE likely induced by ASIA syndrome after the aesthetic medicine procedures. The patient was admitted because of arthralgia and fever. She also presented with a butterfly-shaped erythema on her face and erythematous and infiltrative skin lesions on the posterior surface of the thighs and buttocks. We performed numerous diagnostic tests, including laboratory tests, immunological tests, imaging diagnostics such as chest X-ray and USG of the abdomen and joints, and the biopsy of the skin lesion on the left thigh. The results of the diagnostic process led us to diagnose SLE. The patient fulfilled the ACR/EULAR 2019 classification criteria of the SLE. Laboratory results also led to the diagnosis of autoimmune haemolytic anaemia. Due to exposure to numerous adjuvants like tattoo ink, hyaluronic acid, and piercing and the development of the delayed inflammatory reaction (DIR) to hyaluronic acid (HAF), the patient also fulfilled the criteria of ASIA. In the treatment process we applied antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), steroids, hydroxychloroquine, and cyclosporine. The treatment resulted in an improvement in the general condition, resolution of swelling and joint pain, and improvement in skin lesions. Conclusions: ASIA syndrome after bioimplantation is still underdiagnosed, probably due to ignorance or diagnostic difficulties, as symptoms are uncharacteristic and there is no immunological marker for this syndrome. In addition, as in the presented case, it can develop several years after the procedure, and it is difficult for both patient and physician to become aware of the connection. Early diagnosis requires a multidisciplinary approach and may require immunosuppressive treatment in specific cases. Full article

Background/Objectives: Intranasal vaccination enhances protection against respiratory viruses by providing stimuli to the immune system at the primary site of infection, promoting a balanced and effective response. Influenza vectors with truncated NS1 are a promising vaccine approach that ensures a pronounced local CD8+ T-cellular immune response. Here, we describe the protective and immunomodulating properties of an influenza vector FluVec-N carrying the C-terminal fragment of the SARS-CoV-2 nucleoprotein within a truncated NS1 open reading frame. Methods: We generated several FluVec-N recombinant vectors by reverse genetics and confirmed the vector’s genetic stability, antigen expression in vitro, attenuation, and immunogenicity in a mouse model. We tested the protective potential of FluVec-N intranasal immunization in naïve mice and seropositive Th2-prone mice, primed with aluminium-adjuvanted inactivated SARS-CoV-2. Immune response in immunized and challenged mice was analyzed through serological methods and flow cytometry. Results: Double intranasal immunization of naïve mice with FluVec-N reduced weight loss and viral load in the lungs following infection with the SARS-CoV-2 beta variant. Mice primed with alum-adjuvanted inactivated coronavirus experienced substantial early weight loss and eosinophilia in the lungs during infection, demonstrating signs of enhanced disease. A single intranasal boost immunization with FluVec-N prevented the disease enhancement in primed mice by modulating the local immune response. Protection was associated with the formation of specific IgA and the early activation of virus-specific effector and resident CD8+ lymphocytes in mouse lungs. Conclusions: Our study supports the potential of immunization with influenza vector vaccines to prevent respiratory diseases and associated immunopathology. Full article

Vaccine antigens are partly adsorbed onto aluminium-based adjuvant particles, forming an unstable corona. At the inoculation site, the corona will be restructured, and the adsorbed antigens will be released through replacement with biomolecules from the interstitial fluid of the recipient. Aluminium-based adjuvants (ABAs) carrying a corona of serum proteins as a model of particles with a pre-formed antigen corona were shown to adsorb several categories of cytokines and growth factors, as assessed from a protein array covering 18 different analytes. Out of the 18 analytes, 12 were shown to be adsorbed by the aluminium-based adjuvant Alhydrogel^®, which had a pre-formed protein corona. The adsorption of TNF-α, IL-2, IL-4, IL-10, and IFN-γ was studied in detail. Among the studied cytokines, IL-2, IL-4, and IFN-γ, were adsorbed by Alhydrogel^®. Adsorbed IFN-γ was further studied to show that the adsorption of IFN-γ did not denature the cytokine, and the cytokine could be desorbed from adjuvant particles in a biologically active form and in relevant amounts. The adsorption of immune-stimulating molecules onto ABAs at the administration site of a vaccine is a neglected event in the mode of action of aluminium-based adjuvants. This process may modulate the immune response with a profound impact on initiating the innate immune response and consequently the adaptive immune response. Full article

Background: Type 1 diabetes (T1D) is an autoimmune disorder characterised by the destruction of insulin-producing beta cells in the pancreatic islets, resulting from a breakdown in immunological tolerance. Currently, T1D treatment primarily relies on insulin replacement or immunosuppressive therapies. However, these approaches often have significant drawbacks, including adverse effects, high costs, and limited long-term efficacy. Consequently, there is a pressing need for innovative immunotherapeutic strategies capable of inducing antigen-specific tolerance and protecting beta cells from autoimmune destruction. Among the various antigens, β-cell antigens like 65 kDa glutamic acid decarboxylase (GAD65) have been explored as vaccine candidates for T1D. Despite their potential, their effectiveness in humans remains modest, necessitating the use of appropriate adjuvants to enhance the vaccine’s protective effects. Methods: In this study, we evaluated the therapeutic potential of kynurenine (KYN), dexamethasone (DXMS), tacrolimus (FK506), and aluminium hydroxide (Alum) in combination with the GAD65 phage vaccine as adjuvants. Results: Our findings demonstrate that KYN, when used in conjunction with the GAD65 vaccine, significantly enhances the vaccine’s immunosuppressive effects. Compared to dexamethasone, FK506, and Alum adjuvants, KYN more effectively reduced the incidence and delayed the onset of T1D, preserved β-cell function, and promoted the induction of regulatory T cells and antigen-specific tolerance. These results suggest that KYN combined with vaccines could offer superior preventive and therapeutic benefits for T1D compared to existing treatments. Additionally, we investigated the dose-dependent effects of the GAD65 vaccine by including a low-dose group in our study. The results indicated that reducing the vaccine dose below 10¹⁰ plaque-forming units (pfu) did not confer any protective advantage or therapeutic benefit in combination with KYN. This finding underscores that 10¹⁰ pfu is the minimum effective dose for the GAD65 vaccine in achieving a protective response. In conclusion, KYN shows considerable promise as an adjuvant for the GAD65 vaccine in T1D therapy, potentially offering a more effective and durable treatment option than current immunosuppressive strategies. Full article

Shigellosis is one of the leading causes of diarrheal disease in low- and middle-income countries, particularly in young children, and is more often associated with antimicrobial resistance. Therefore, a preventive vaccine against shigellosis is an urgent medical need. We have proposed Generalised Modules for Membrane Antigens (GMMA) as an innovative delivery system for Shigella sonnei O-antigen, and an Alhydrogel formulation (1790GAHB) has been extensively tested in preclinical and clinical studies. Alhydrogel has been used as an adsorbent agent with the main purpose of reducing potential GMMA systemic reactogenicity. However, the immunogenicity and systemic reactogenicity of this GMMA-based vaccine formulated with or without Alhydrogel have never been compared. In this work, we investigated the potential adjuvant effect of aluminium salt-based adjuvants (Alhydrogel and AS37) on S. sonnei GMMA immunogenicity in mice and rabbits, and we found that S. sonnei GMMA alone resulted to be strongly immunogenic. The addition of neither Alhydrogel nor AS37 improved the magnitude or the functionality of vaccine-elicited antibodies. Interestingly, rabbits injected with either S. sonnei GMMA adsorbed on Alhydrogel or S. sonnei GMMA alone showed a limited and transient body temperature increase, returning to baseline values within 24 h after each vaccination. Overall, immunisation with unadsorbed GMMA did not raise any concern for animal health. We believe that these data support the clinical testing of GMMA formulated without Alhydrogel, which would allow for further simplification of GMMA-based vaccine manufacturing. Full article

Aluminium adjuvants are commonly used in vaccines to boost the effects of vaccination. Here, we assessed the benefits and harms of different aluminium adjuvants vs. other aluminium adjuvants or vs. the same aluminium adjuvant at other concentrations, administered a different number of doses, or at different particle sizes used in vaccines or vaccine excipients. We conducted a systematic review with meta-analysis and Trial Sequential Analysis to assess the certainty of evidence with Grading of Recommendations Assessment, Development and Evaluation (GRADE). We obtained data from major medical databases until 20 January 2023 and included 10 randomized clinical trials of healthy volunteers. The comparisons assessed higher vs. lower aluminium adjuvant concentrations; higher vs. lower number of doses of aluminium adjuvant; and aluminium phosphate adjuvant vs. aluminium hydroxide adjuvant. For all three comparisons, meta-analyses showed no evidence of a difference on all-cause mortality, serious adverse events, and adverse events considered non-serious. The certainty of evidence was low to very low. None of the included trials reported on quality of life or proportion of participants who developed the disease being vaccinated against. The benefits and harms of different types of aluminium adjuvants, different aluminium concentrations, different number of doses, or different particle sizes, therefore, remain uncertain. Full article

Clostridium botulinum serotypes C and D cause botulism in livestock, a neuroparalytic disease that results in substantial economic losses. Vaccination with aluminium-based toxoid vaccines is widely used to control the spread of botulism. Aluminium-based adjuvants are preferred owing to their apparent stimulation of the immune responses to toxoid vaccines when compared to other adjuvants. The aim of our study was to evaluate aluminium hydroxide nanoparticles as a potential substitute for alhydrogel in the botulism bivalent vaccine. Botulism vaccines were formulated with either alhydrogel or nanoalum and comparative efficacy between the two formulations was conducted by evaluating the immune response in vaccinated guinea pigs. A significant increase in immunological parameters was observed, with the antibody titres higher in the serum of guinea pigs (20 IU/mL of anti-BoNT C/D) injected with nanoalum-containing vaccine than guinea pigs inoculated with the standard alhydrogel-containing vaccine (8.7 IU/mL and 10 IU/mL of anti-BoNT C and anti-BoNT D, respectively). Additionally, the nanoalum-containing vaccine demonstrated potency in a multivalent vaccine (20 IU/mL of anti-BoNT C/D), while the standard alhydrogel-containing vaccine showed a decline in anti-BoNT C (5 IU/mL) antibody titres. Full article

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. Full article

Although aluminium-based vaccines have been used for almost over a century, their mechanism of action remains unclear. It is established that antigen adsorption to the adjuvant facilitates delivery of the antigen to immune cells at the injection site. To further increase our understanding of aluminium-based vaccines, it is important to gain additional insights on the interactions between the aluminium and antigens, including antigen distribution over the adjuvant particles. Immuno-assays can further help in this regard. In this paper, we evaluated how established formulation strategies (i.e., sequential, competitive, and separate antigen addition) applied to four different antigens and aluminium oxyhydroxide, lead to formulation changes over time. Results showed that all formulation samples were stable, and that no significant changes were observed in terms of physical-chemical properties. Antigen distribution across the bulk aluminium population, however, did show a maturation effect, with some initial dependence on the formulation approach and the antigen adsorption strength. Sequential and competitive approaches displayed similar results in terms of the homogeneity of antigen distribution across aluminium particles, while separately adsorbed antigens were initially more highly poly-dispersed. Nevertheless, the formulation sample prepared via separate adsorption also reached homogeneity according to each antigen adsorption strength. This study indicated that antigen distribution across aluminium particles is a dynamic feature that evolves over time, which is initially influenced by the formulation approach and the specific adsorption strength, but ultimately leads to homogeneous formulations. Full article

Allergen-specific immunotherapy (AIT) is the only currently available curative treatment option for allergic diseases. AIT often includes depot-forming and immunostimulatory adjuvants, to prolong allergen presentation and to improve therapeutic efficacy. The use of aluminium salts in AIT, which are commonly used as depot-forming adjuvants, is controversially discussed, due to health concerns and Th2-promoting activity. Therefore, there is the need for novel delivery systems in AIT with similar therapeutic efficacy compared to classical AIT strategies. In this study, a triblock copolymer (hydrogel) was assessed as a delivery system for AIT in a murine model of allergic asthma. We show that the hydrogel combines the advantages of both depot function and biodegradability at the same time. We further demonstrate the suitability of hydrogel to release different bioactive compounds in vitro and in vivo. AIT delivered with hydrogel reduces key parameters of allergic inflammation, such as inflammatory cell infiltration, mucus hypersecretion, and allergen-specific IgE, in a comparable manner to standard AIT treatment. Additionally, hydrogel-based AIT is superior in inducing allergen-specific IgG antibodies with potentially protective functions. Taken together, hydrogel represents a promising delivery system for AIT that is able to combine therapeutic allergen administration with the prolonged release of immunomodulators at the same time. Full article

The meningococcal disease is a global health threat, but is preventable through vaccination. Adjuvants improve meningococcal vaccines and are able to trigger different aspects of the immune response. The present work evaluated the immune response of mice against Neisseria meningitidis outer membrane vesicles (OMV) complexed with the adjuvants aluminium hydroxide (AH), via subcutaneous route; and dimethyldioctadecylammonium bromide (DDA) or Saponin (Sap), via intranasal/subcutaneous routes. ELISA demonstrated that all adjuvants increased IgG titers after the booster dose, remaining elevated for 18 months. Additionally, adjuvants increased the avidity of the antibodies and the bactericidal titer: OMVs alone were bactericidal until 1:4 dilution but, when adjuvanted by Alum, DDA or Sap, it increased to 1/32. DDA and Sap increased all IgG isotypes, while AH improved IgG1 and IgG2a levels. Thus, Sap led to the recognition of more proteins in Immunoblot, followed by DDA and AH. Sap and AH induced higher IL-4 and IL-17 release, respectively. The use of adjuvants improved both cellular and humoral immune response, however, each adjuvant contributed to particular parameters. This demonstrates the importance of studying different adjuvant options and their suitability to stimulate different immune mechanisms, modulating the immune response. Full article

Vaccinations are one of the most important preventive tools against infectious diseases. Over time, many different types of vaccines have been developed concerning the antigen component. Adjuvants are essential elements that increase the efficacy of vaccination practises through many different actions, especially acting as carriers, depots, and stimulators of immune responses. For many years, few adjuvants have been included in vaccines, with aluminium salts being the most commonly used adjuvant. However, recent research has focused its attention on many different new compounds with effective adjuvant properties and improved safety. Modern technologies such as nanotechnologies and molecular biology have forcefully entered the production processes of both antigen and adjuvant components, thereby improving vaccine efficacy. Microparticles, emulsions, and immune stimulators are currently in the spotlight for their huge potential in vaccine production. Although studies have reported some potential side effects of vaccine adjuvants such as the recently recognised ASIA syndrome, the huge worth of vaccines remains unquestionable. Indeed, the recent COVID-19 pandemic has highlighted the importance of vaccines, especially in regard to managing future potential pandemics. In this field, research into adjuvants could play a leading role in the production of increasingly effective vaccines. Full article

Aluminium (Al) compounds are used as adjuvants in human and veterinary prophylactic vaccines due to their improved tolerability compared to other adjuvants. These Al-based adjuvants form microparticles (MPs) of heterogeneous sizes ranging from ~0.5 to 10 µm and generally induce type 2 (Th2)-biased immune responses. However, recent literature indicates that moving from micron dimension particles toward the nanoscale can modify the adjuvanticity of Al towards type 1 (Th1) responses, which can potentially be exploited for the development of vaccines for which Th1 immunity is crucial. Specifically, in the context of cancer treatments, Al nanoparticles (Al-NPs) can induce a more balanced (Th1/Th2), robust, and durable immune response associated with an increased number of cytotoxic T cells compared to Al-MPs, which are more favourable for stimulating an oncolytic response. In this review, we compare the adjuvant properties of Al-NPs to those of Al-MPs in the context of infectious disease vaccines and cancer immunotherapy and provide perspectives for future research. Full article

Aluminium salts have been the adjuvant of choice in more than 100 licensed vaccines. Here, we have studied the synergistic effect of aluminium hydroxide nanoparticles (AH np) and non-ionic surfactant-based vesicles (NISV) in modulating the immune response against protective antigen domain 4 (D4) of Bacillus anthracis. NISV was prepared from Span 60 and cholesterol, while AH np was prepared from aluminium chloride and sodium hydroxide. AH np was co-administered with NISV encapsulating D4 (NISV-D4) to formulate AHnp/NISV-D4. The antigen-specific immune response of AHnp/NISV-D4 was compared with that of commercial alhydrogel (alhy) co-administered with NISV-D4 (alhydrogel/NISV-D4), NISV-D4, AHnp/D4, and alhydrogel/D4. Co-administration of NISV-D4 with AH np greatly improved the D4-specific antibody titer as compared to the control groups. Based on IgG isotyping and ex vivo cytokine analysis, AHnp/NISV-D4 generated a balanced Th1/Th2 response. Furthermore, AH np/NISV-D4 showed superior protection against anthrax spore challenge in comparison to other groups. Thus, we demonstrate the possibility of developing a novel combinatorial nanoformulation capable of augmenting both humoral and cellular response, paving the way for adjuvant research. Full article