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Intrapulmonary vaccination with delta-inulin adjuvant stimulates non-polarised chemotactic signalling and diverse cellular interaction.

ABSTRACT: There is an urgent need for novel vaccination strategies to combat respiratory pathogens. Mucosal vaccine delivery is an attractive option as it directly targets the site of infection; however, preclinical development has been hindered by a lack of suitable mucosal adjuvants and a limited understanding of their immune effects in the lung environment. Herein, we define the early immune events following the intrapulmonary delivery of a vaccine incorporating the adjuvant delta-inulin. Analysis of the early inflammatory response showed vaccine-induced innate cell recruitment to lungs and local lymph nodes (LN) was transient and non-polarised, correlating with an increase in pulmonary chemotactic factors. Use of fluorescently labelled adjuvant revealed widespread tissue dissemination of adjuvant particles, coupled with broad cellular uptake and transit to the lung-draining LN by a range of innate immune cells. Mass cytometric analysis revealed extensive phenotypic changes in innate and adaptive cell subsets induced by vaccination; this included identification of unconventional lymphocytes such as γδ-T cells and MAIT cells that increased following vaccination and displayed an activated phenotype. This study details a comprehensive view of the immune response to intrapulmonary adjuvant administration and provides pre-clinical evidence to support delta-inulin as a suitable adjuvant for pulmonary vaccines.

SUBMITTER: Ferrell KC

PROVIDER: S-EPMC7859722 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Advax Adjuvant : A Potent and Safe Immunopotentiator Composed of Delta Inulin

Project description:Highly potent adjuvants commonly have reactogenicity and safety issues. Unlike other immunologically active polysaccharides, inulin has no immune activity in its native soluble form, but when crystallized into the stable delta inulin isoform, it acquires potent immune actions. Most notably, delta inulin enhances both humoral and cellular immune responses against vaccine antigens, translating into enhanced protection against a broad range of viral, bacterial, parasitic, and toxin-mediated diseases. Delta inulin is distinct compared with typical vaccine adjuvants as it does not require adsorption to antigen and does not appear to work through induction of inflammatory danger signals. Delta inulin manufactured under current Good Manufacturing Practices (referred to as Advax) has been proved to be safe and effective in human trials of influenza vaccines, hepatitis B vaccines, and insect sting allergy vaccines. Advax thereby represents a novel nonreactogenic immune modulator with potential utility across a broad range of human prophylactic and therapeutic vaccines.

| S-EPMC7150192 | biostudies-literature

Polarised clathrin-mediated endocytosis of EGFR during chemotactic invasion.

Project description:Directed cell migration is critical for numerous physiological processes including development and wound healing. However chemotaxis is also exploited during cancer progression. Recent reports have suggested links between vesicle trafficking pathways and directed cell migration. Very little is known about the potential roles of endocytosis pathways during metastasis. Therefore we performed a series of studies employing a previously characterised model for chemotactic invasion of cancer cells to assess specific hypotheses potentially linking endocytosis to directed cell migration. Our results demonstrate that clathrin-mediated endocytosis is indispensable for epidermal growth factor (EGF) directed chemotactic invasion of MDA-MB-231 cells. Conversely, caveolar endocytosis is not required in this mode of migration. We further found that chemoattractant receptor (EGFR) trafficking occurs by clathrin-mediated endocytosis and is polarised towards the front of migrating cells. However, we found no role for clathrin-mediated endocytosis in focal adhesion disassembly in this migration model. Thus, this study has characterised the role of endocytosis during chemotactic invasion and has identified functions mechanistically linking clathrin-mediated endocytosis to directed cell motility.

| S-EPMC4309520 | biostudies-literature

Advax, a Delta Inulin Microparticle, Potentiates In-built Adjuvant Property of Co-administered Vaccines.

Project description:Advax, a delta inulin-derived microparticle, has been developed as an adjuvant for several vaccines. However, its immunological characteristics and potential mechanism of action are yet to be elucidated. Here, we show that Advax behaves as a type-2 adjuvant when combined with influenza split vaccine, a T helper (Th)2-type antigen, but behaves as a type-1 adjuvant when combined with influenza inactivated whole virion (WV), a Th1-type antigen. In addition, an adjuvant effect was not observed when Advax-adjuvanted WV vaccine was used to immunize toll-like receptor (TLR) 7 knockout mice which are unable to respond to RNA contained in WV antigen. Similarly, no adjuvant effect was seen when Advax was combined with endotoxin-free ovalbumin, a neutral Th0-type antigen. An adjuvant effect was also not seen in tumor necrosis factor (TNF)-? knockout mice, and the adjuvant effect required the presences of dendritic cells (DCs) and phagocytic macrophages. Therefore, unlike other adjuvants, Advax potentiates the intrinsic or in-built adjuvant property of co-administered antigens. Hence, Advax is a unique class of adjuvant which can potentiate the intrinsic adjuvant feature of the vaccine antigens through a yet to be determined mechanism.

| S-EPMC5233800 | biostudies-literature

Advax, a delta inulin microparticle, potentiates in-built adjuvant property of co-administered vaccines

Project description:Gene expression data from mouse organs after Advax injection Advax, an inulin-derived microparticle, has been developed as an adjuvant for several vaccines. Advax is a unique class of adjuvant which can potentiate the endogenous adjuvant effect of the vaccines through a not yet fully-identified, unique mechanisms of action.

2017-01-31 | GSE89249 | GEO

Human Phase 1 trial of low-dose inactivated seasonal influenza vaccine formulated with Advax™ delta inulin adjuvant.

Project description:Influenza vaccines are usually non-adjuvanted but addition of adjuvant may improve immunogenicity and permit dose-sparing, critical for vaccine supply in the event of an influenza pandemic. The aim of this first-in-man study was to determine the effect of delta inulin adjuvant on the safety and immunogenicity of a reduced dose seasonal influenza vaccine. Healthy male and female adults aged 18-65years were recruited to participate in a randomized controlled study to compare the safety, tolerability and immunogenicity of a reduced-dose 2007 Southern Hemisphere trivalent inactivated influenza vaccine formulated with Advax™ delta inulin adjuvant (LTIV+Adj) when compared to a full-dose of the standard TIV vaccine which does not contain an adjuvant. LTIV+Adj provided equivalent immunogenicity to standard TIV vaccine as assessed by hemagglutination inhibition (HI) assays against each vaccine strain as well as against a number of heterosubtypic strains. HI responses were sustained at 3months post-immunisation in both groups. Antibody landscapes against a large panel of H3N2 influenza viruses showed distinct age effects whereby subjects over 40years old had a bimodal baseline HI distribution pattern, with the highest HI titers against the very oldest H3N2 isolates and with a second HI peak against influenza isolates from the last 5-10years. By contrast, subjects >40years had a unimodal baseline HI distribution with peak recognition of H3N2 isolates from approximately 20years ago. The reduced dose TIV vaccine containing Advax adjuvant was well tolerated and no safety issues were identified. Hence, delta inulin may be a useful adjuvant for use in seasonal or pandemic influenza vaccines. Australia New Zealand Clinical Trial Registry: ACTRN12607000599471.

| S-EPMC4949042 | biostudies-literature

Embryo vaccination of chickens using a novel adjuvant formulation stimulates protective immunity against Eimeria maxima infection.

Project description:Our previous study demonstrated that chickens immunized subcutaneously with an Eimeria recombinant profilin protein vaccine emulsified in a Quil A/cholesterol/DDA/Carbopol (QCDC) adjuvant developed partial protection against experimental avian coccidiosis compared with animals immunized with profilin alone. Because in ovo vaccination is presently used in commercial applications worldwide throughout the poultry industry, the current study was undertaken to investigate chicken embryo vaccination with profilin plus QCDC adjuvant. Eighteen day-old embryos were immunized with isotonic saline (control), profilin alone, QCDC alone, or profilin plus QCDC, and orally challenged with live Eimeria maxima at 7 days post-hatch. Body weight gain, fecal oocyst output, and intestinal cytokine transcript levels were assessed as measures of protective immunity. While immunization with profilin alone or QCDC alone did not alter body weight gain of infected chickens compared with the saline control group, vaccination with profilin plus QCDC increased body weight gain such that it was equal to the uninfected controls. Immunization with profilin plus QCDC also reduced fecal oocyst shedding compared with unimmunized controls, although in this case QCDC failed to provide an adjuvant effect since no difference was observed between the profilin-only and profilin/QCDC groups. Finally, increased levels of transcripts encoding IL-1?, IL-15, and IFN-? were seen in the intestinal tissues of animals given profilin plus QCDC compared with the profilin-only or QCDC-only groups. In summary, this study demonstrates an adjuvant effect of QCDC on body weight gain and intestinal cytokine responses following in ovo vaccination of chickens with an Eimeria profilin vaccine.

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Delta Inulin Adjuvant Enhances Plasmablast Generation, Expression of Activation-Induced Cytidine Deaminase and B-Cell Affinity Maturation in Human Subjects Receiving Seasonal Influenza Vaccine.

Project description:UnlabelledThere is a major need for new adjuvants to improve the efficacy of seasonal and pandemic influenza vaccines. Advax is a novel polysaccharide adjuvant based on delta inulin that has been shown to enhance the immunogenicity of influenza vaccine in animal models and human clinical trials. To better understand the mechanism for this enhancement, we sought to assess its effect on the plasmablast response in human subjects. This pilot study utilised cryopreserved 7 day post-vaccination (7dpv) peripheral blood mononuclear cell samples obtained from a subset of 25 adult subjects from the FLU006-12 trial who had been immunized intramuscularly with a standard dose of 2012 trivalent inactivated influenza vaccine (TIV) alone (n=9 subjects) or combined with 5mg (n=8) or 10mg (n=8) of Advax adjuvant. Subjects receiving Advax adjuvant had increased 7dpv plasmablasts, which in turn exhibited a 2-3 fold higher rate of non-silent mutations in the B-cell receptor CDR3 region associated with higher expression of activation-induced cytidine deaminase (AID), the major enzyme controlling BCR affinity maturation. Together, these data suggest that Advax adjuvant enhances influenza immunity in immunized subjects via multiple mechanisms including increased plasmablast generation, AID expression and CDR3 mutagenesis resulting in enhanced BCR affinity maturation and increased production of high avidity antibody. How Advax adjuvant achieves these beneficial effects on plasmablasts remains the subject of ongoing investigation.Trial registrationAustralia New Zealand Clinical Trials Register ACTRN12612000709842 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=362709.

| S-EPMC4503308 | biostudies-literature

Laser adjuvant for vaccination.

Project description:The use of an immunologic adjuvant to augment the immune response is essential for modern vaccines which are relatively ineffective on their own. In the past decade, researchers have been consistently reporting that skin treatment with a physical parameter, namely laser light, augments the immune response to vaccine and functions as an immunologic adjuvant. This "laser adjuvant" has numerous advantages over the conventional chemical or biological agents; it is free from cold chain storage, hypodermic needles, biohazardous sharp waste, irreversible formulation with vaccine antigen, undesirable biodistribution in vital organs, or unknown long-term toxicity. Since vaccine formulations are given to healthy populations, these characteristics render the "laser adjuvant" significant advantages for clinical use and open a new developmental path for a safe and effective vaccine. In addition, laser technology has been used in the clinic for more than three decades and is therefore technically matured and has been proved to be safe. Currently, four classes of laser adjuvant have been reported; ultrashort pulsed, non-pulsed, non-ablative fractional, and ablative fractional lasers. Since each class of the laser adjuvant shows a distinct mechanism of action, a proper choice is necessary to craft an effective vaccine formulation toward a desired clinical benefit for a clinical vaccine to maximize protection. In addition, data also suggest that further improvement in the efficacy is possible when a laser adjuvant is combined with chemical or biological adjuvant(s). To realize these goals, further efforts to uncover the molecular mechanisms of action of the laser adjuvants is warranted. This review provides a summary and comments of the recent updates in the laser adjuvant technology.

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Intrapulmonary Vaccination Induces Long-lasting and Effective Pulmonary Immunity Against Staphylococcus aureus Pneumonia.

Project description:BackgroundStaphylococcus aureus causes community- and hospital-acquired pneumonia linked to a high mortality rate. The emergence and rapid transmission of multidrug-resistant S. aureus strains has become a serious health concern, highlighting the challenges associated with the development of a vaccine to combat S. aureus pneumonia.MethodsThis study evaluated the effects of intrapulmonary immunization on the immune response and protection against S. aureus lung infection in a respiratory mouse model using a subunit vaccine.ResultsCompared with the intranasal immunized mice, the intrapulmonarily immunized mice had lower levels of pulmonary bacterial colonization and lethality, accompanied by alleviated lung inflammation with reduced proinflammatory cytokines and increased levels of interleukin-10 and antimicrobial peptide following intrapulmonary challenge. Optimal protection was associated with increased pulmonary antibodies and resident memory T cells. Moreover, intrapulmonary immunization provided long-lasting pulmonary protection for at least 6 months, with persistent cellular and humoral immunity in the lungs.ConclusionsVaccine reaching the deep lung by intrapulmonary immunization plays a significant role in the induction of efficacious and long-lasting immunity against S. aureus in the lung parenchyma. Hence, intrapulmonary immunization can be a strategy for the development of a vaccine against S. aureus pneumonia.Immunization through the intrapulmonary route with a subunit of S. aureus vaccine elicited tissue resident memory T cells and antigen-specific antibodies in the lungs, and provided optimal and long-term protection against S. aureus pneumonia.

| S-EPMC8408773 | biostudies-literature

Transcriptomic profiling of mouse spleen mascrophages following adjuvant vaccination

Project description:Trained immunity is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to certain microbial components, altering their responses to future exposures. Intravesical instillation with Bacillus Calmette-Guérin (BCG) is the most effective adjuvant therapy in patients with high-risk non-muscle invasive bladder cancer (HR-NMIBC). HR-NMIBC is associated with a high risk of tumor recurrence and progression to muscle-invasive bladder cancer. The precise immunological mechanisms through which BCG mediates anti-tumor immunity are still unclear. The aim of our study was to investigate the (long-term) induction of trained immunity by repeated BCG instillations in NMIBC patients and elucidate the immunological and epigenetic mechanisms that are involved. Another aim was to assess the relationship between trained immunity response and clinical response of NMIBC patients, in terms of recurrence free survival and progression free survival. To determine whether BCG instillations induce trained immunity in peripheral blood mononuclear cells (PBMCs) we performed a prospective cohort study (‘Tribute’) and isolated PBMCs collected before BCG therapy and at 8 time points during BCG therapy. A total of 17 BCG-naïve HR-NMIBC patients were included. After isolation of PBMCs, monocytes were further purified using an isolation procotol with a percoll gradient. RNA was isolated from these purified monocytes were and used as input for RNA-seq analysis.

2023-08-24 | GSE216062 | GEO

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