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Journal of Virology Dec 2020Aluminum (Al)-based salts are widely used adjuvants in ruminants and other species to strengthen the immune response elicited against vaccine antigen(s). However, they...
Aluminum (Al)-based salts are widely used adjuvants in ruminants and other species to strengthen the immune response elicited against vaccine antigen(s). However, they can lead to the formation of long-lasting granulomas composed of abundant activated macrophages. Small ruminant lentiviruses (SRLV) are widely distributed macrophage-tropic retroviruses that cause persistent infections in sheep and goats. Infected monocytes/macrophages and dendritic cells establish an inflammatory microenvironment that eventually leads to clinical manifestations. The aim of this work was to study the effect of Al-induced granulomas in the replication and pathogenesis of SRLV. Eleven adult, naturally SRLV-infected sheep showing clinical arthritis were distributed in vaccine ( = 6), adjuvant-only ( = 3), and control ( = 2) groups and inoculated with commercial Al-based vaccines, Al hydroxide adjuvant alone, or phosphate-buffered saline, respectively. studies demonstrated viral replication in Al-induced granulomas in 5 out of 10 sheep. Immunohistochemistry (IHC) evinced granular, intracytoplasmic SRLV presence in macrophages within granulomas. Viral sequences obtained from granulomas, blood monocytes, and other tissues were highly similar in most animals, suggesting virus circulation among body compartments. However, notable differences between isolated strains in granulomas and other tissues in specific animals were also noted. Interestingly, the B2 subtype was the most commonly found SRLV genotype, reaching a wider body distribution than previously described. Recombination events between genotypes B2 and A3 along the region were identified in two sheep. Our results indicate that Al-hydroxide-derived granulomas may represent an ideal compartment for SRLV replication, perhaps altering natural SRLV infection by providing a new, suitable target tissue. Granulomas are inflammation-derived structures elicited by foreign bodies or certain infections. Aluminum adjuvants included in vaccines induce granulomas in many species. In sheep, these are persistent and consist of activated macrophages. Small ruminant lentiviruses (SRLV), which are macrophage-tropic lentiviruses, cause a chronic wasting disease affecting animal welfare and production. Here, we studied the occurrence of SRLV in postvaccination granulomas retrieved from naturally infected ewes after vaccination or inoculation with aluminum only. SRLV infection was confirmed in granulomas by identification of viral proteins, genomic fragments, and enzymatic activity. The infecting SRLV strain, previously found exclusively in carpal joints, reached the central nervous system, suggesting that occurrence of SRLV in postvaccination granulomas may broaden tissue tropism. SRLV recombination was detected in inoculated animals, a rare event in sheep lentiviruses. Potentially, virus-host interactions within granulomas may modify viral pathogenesis and lead to more widespread infection.
Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Animals; Arthritis-Encephalitis Virus, Caprine; Genotype; Granuloma; Lentivirus Infections; Macrophages; Phylogeny; Recombination, Genetic; Sheep; Sheep Diseases; Viral Tropism; Virus Replication
PubMed: 33115880
DOI: 10.1128/JVI.01859-20 -
PloS One 2022The bovine virus diarrhea virus (BVDV) causes reproductive, enteric, and respiratory diseases. Vaccination is essential in increasing herd resistance to BVDV spread. The...
The bovine virus diarrhea virus (BVDV) causes reproductive, enteric, and respiratory diseases. Vaccination is essential in increasing herd resistance to BVDV spread. The selection of an adjuvant is an important factor in the success of the vaccination process. Monolaurin or glycerol monolaurate is a safe compound with an immunomodulatory effect. This study aimed to evaluate the efficacy of monolaurin as a novel adjuvant. This was examined through the preparation of an inactivated BVDV (NADL strain) vaccine adjuvanted with different concentrations of monolaurin and compared with the registered available locally prepared polyvalent vaccine (Pneumo-4) containing BVD (NADL strain), BoHV-1 (Abou Hammad strain), BPI3 (strain 45), and BRSV (strain 375L), and adjuvanted with aluminum hydroxide gel. The inactivated BVDV vaccine was prepared using three concentrations, 0.5%, 1%, and 2%, from monolaurin as adjuvants. A potency test was performed on five groups of animals. The first group, which did not receive vaccination, served as a control group while three other groups were vaccinated using the prepared vaccines. The fifth group received the Pneumo-4 vaccine. Vaccination response was monitored by measuring viral neutralizing antibodies using enzyme-linked immunosorbent assay (ELISA). It was found that the BVD inactivated vaccine with 1% and 2% monolaurin elicited higher neutralizing antibodies that have longer-lasting effects (nine months) with no reaction at the injection site in comparison to the commercial vaccine adjuvanted by aluminum hydroxide gel.
Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Animals; Antibodies, Neutralizing; Antibodies, Viral; Bovine Virus Diarrhea-Mucosal Disease; Cattle; Diarrhea; Diarrhea Virus 1, Bovine Viral; Diarrhea Viruses, Bovine Viral; Laurates; Monoglycerides; Vaccines, Inactivated; Viral Vaccines
PubMed: 35834444
DOI: 10.1371/journal.pone.0269031 -
Antimicrobial Agents and Chemotherapy Feb 1998This study was designed to determine the influence of aluminum hydroxide and famotidine on the bioavailability of tosufloxacin. Coadministration of aluminum hydroxide...
This study was designed to determine the influence of aluminum hydroxide and famotidine on the bioavailability of tosufloxacin. Coadministration of aluminum hydroxide reduced the bioavailability of tosufloxacin by 31.6% (P < 0.05). Famotidine did not alter tosufloxacin absorption. To avoid potential treatment failures, the concurrent use of tosufloxacin and aluminum hydroxide should be avoided altogether.
Topics: Adult; Aluminum Hydroxide; Antacids; Anti-Infective Agents; Anti-Ulcer Agents; Biological Availability; Drug Interactions; Famotidine; Fluoroquinolones; Humans; Male; Naphthyridines
PubMed: 9527806
DOI: 10.1128/AAC.42.2.453 -
Frontiers in Immunology 2022is the causative agent for the lethal disease anthrax, primarily affecting animals and humans in close contact with an infected host. The pathogenicity of is...
INTRODUCTION
is the causative agent for the lethal disease anthrax, primarily affecting animals and humans in close contact with an infected host. The pathogenicity of is attributed to the secreted exotoxins and their outer capsule. The host cell-binding exotoxin component "protective antigen" (PA) is reported to be a potent vaccine candidate. The aim of our study is to produce several PA constructs and analyze their vaccine potential.
METHODS
We have designed the various subunit, PA-based recombinant proteins, i.e., full-length Protective antigen (PA-FL), C-terminal 63 kDa fragment (PA63), Protective antigen domain 1-domain 4 chimeras (PA-D1-4) and protective antigen domain 4 (PA-D4) and analyzed their vaccine potential with different human-compatible adjuvants in the mouse model. We have optimized the process and successfully expressed our recombinant antigens as soluble proteins, except full-length PA. All the recombinant antigen formulations with three different adjuvants i.e., Addavax, Alhydrogel, and Montanide ISA 720, were immunized in different mouse groups. The vaccine efficacy of the formulations was analyzed by mouse serum antigen-specific antibody titer, toxin neutralization assay, and survival analysis of mouse groups challenged with a lethal dose of virulent spores.
RESULTS
We have demonstrated that the PA-FL addavax and PA63 addavax formulations were most effective in protecting spore-challenged mice and serum from the mice immunized with PAFL addavax, PA-FL alhydrogel, PA63 addavax, and PA63 alhydrogel formulations were equivalently efficient in neutralizing the anthrax lethal toxin. The higher levels of serum Th1, Th2, and Th17 cytokines in PA-FL addavax immunized mice correspond to the enhanced protection provided by the formulation in challenged mice.
DISCUSSION
We have demonstrated that the PA-FL addavax and PA63 addavax formulations exhibit equivalent efficiency as vaccine formulation both in a mouse model of anthrax and mammalian cell lines. However, PA63 is a smaller antigen than PA-FL and more importantly, PA63 is expressed as a soluble protein in coli, which imparts a translational advantage to PA63-based formulation. Thus, the outcome of our study has significant implications for the development of protective antigen-based vaccine formulations for human use against the lethal disease anthrax.
Topics: Animals; Mice; Humans; Bacillus anthracis; Anthrax; Aluminum Hydroxide; Escherichia coli; Anthrax Vaccines; Adjuvants, Immunologic; Exotoxins; Mammals
PubMed: 36713362
DOI: 10.3389/fimmu.2022.1075662 -
Frontiers in Immunology 2022Various chemical adjuvants are available to augment immune responses to non-replicative, subunit vaccines. Optimized adjuvant selection can ensure that vaccine-induced...
Various chemical adjuvants are available to augment immune responses to non-replicative, subunit vaccines. Optimized adjuvant selection can ensure that vaccine-induced immune responses protect against the diversity of pathogen-associated infection routes, mechanisms of infectious spread, and pathways of immune evasion. In this study, we compare the immune response of mice to a subunit vaccine of Middle Eastern respiratory syndrome coronavirus (MERS-CoV) spike protein, stabilized in its prefusion conformation by a proprietary molecular clamp (MERS SClamp) alone or formulated with one of six adjuvants: either () aluminium hydroxide, () SWE, a squalene-in-water emulsion, () SQ, a squalene-in-water emulsion containing QS21 saponin, () SMQ, a squalene-in-water emulsion containing QS21 and a synthetic toll-like receptor 4 (TLR4) agonist 3D-6-acyl Phosphorylated HexaAcyl Disaccharide (3D6AP); () LQ, neutral liposomes containing cholesterol, 1.2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and QS21, () or LMQ, neutral liposomes containing cholesterol, DOPC, QS21, and 3D6AP. All adjuvanted formulations induced elevated antibody titers which where greatest for QS21-containing formulations. These had elevated neutralization capacity and induced higher frequencies of IFN and IL-2-producing CD4 and CD8 T cells. Additionally, LMQ-containing formulations skewed the antibody response towards IgG2b/c isotypes, allowing for antibody-dependent cellular cytotoxicity. This study highlights the utility of side-by-side adjuvant comparisons in vaccine development.
Topics: Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Aluminum Hydroxide; Animals; CD8-Positive T-Lymphocytes; Disaccharides; Emulsions; Immunoglobulin G; Interleukin-2; Liposomes; Mice; Phosphorylcholine; Saponins; Spike Glycoprotein, Coronavirus; Squalene; Toll-Like Receptor 4; Vaccines, Subunit; Water
PubMed: 36119058
DOI: 10.3389/fimmu.2022.976968 -
Journal of Dairy Science Sep 2022It is necessary for the dairy industry to reduce calf morbidity and mortality, and the reliance on antibiotics to treat sick calves, to address the growing concern...
It is necessary for the dairy industry to reduce calf morbidity and mortality, and the reliance on antibiotics to treat sick calves, to address the growing concern regarding antibiotic resistant bacteria. The primary objective of this study was to evaluate the effect that feeding dairy calves medium-chain fatty acids (MCFA) has on growth performance and health, and the secondary objective was to evaluate the effect of MCFA on energy status around weaning and the adaptive immune response following a vaccine challenge. Thirty-three Holstein bull calves (5 ± 1.6 d of age) were randomly assigned to 1 of 2 treatments. Control (CON) calves were fed milk replacer with no C8:0 or C10:0 oil added and MCFA calves were fed milk replacer with 0.5% of a combination of C8:0 or C10:0 oil added. Body weight and average daily gain were measured weekly. Feed efficiency (gain/feed) and the change in body condition score, hip width, hip height, heart girth, and paunch girth were calculated for the duration of the study. Fecal scores were recorded daily and all medical treatments were documented for the duration of the trial. On d 42, 49, and 56 of the study, a serum sample was collected from each calf and used to measure nonesterified fatty acids, β-hydroxybutyric acid, insulin, and glucose concentrations to evaluate energy status around weaning. A subset of 11 calves per treatment were enrolled in a vaccine challenge. At 21 ± 1.9 d of age (mean ± standard deviation) calves were vaccinated intramuscularly with 1 mL of endotoxin-free ovalbumin (OVA) mixed with aluminum hydroxide adjuvant. At 42 d of age (±1.9 d), blood samples were collected and used to analyze OVA-specific IgG and IgG, and calves were vaccinated a second time. At 56 d of age (±1.9 d), blood samples were collected to analyze IgG and IgG as well as IFN-γ and IL-4 secreted from peripheral blood mononuclear cells (PBMC) treated with OVA or phytohemagglutinin. Data were analyzed as a completely randomized design with repeated measures when applicable. A tendency for greater daily fecal score was observed for MCFA calves compared with CON. At d 42 of the study, nonesterified fatty acid concentrations were greater in CON calves compared with MCFA. At 42 and 56 d of age, anti-OVA IgG concentrations for CON and MCFA calves were greater than prevaccination samples. This study suggests that feeding MCFA to calves affects the energy status of calves around weaning and vaccinating dairy calves with ovalbumin combined with an aluminum hydroxide adjuvant is an effective way to evaluate the adaptive immune responses.
Topics: Aluminum Hydroxide; Animal Feed; Animals; Body Weight; Cattle; Diet; Fatty Acids; Fatty Acids, Nonesterified; Immunity; Immunoglobulin G; Leukocytes, Mononuclear; Male; Ovalbumin; Weaning
PubMed: 35940917
DOI: 10.3168/jds.2021-21567 -
British Journal of Clinical Pharmacology Sep 19871 Twelve healthy volunteers received a single oral dose of tenoxicam 20 mg on six occasions separated by 3 weeks. 2 The six occasions were: fasted overnight;... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
1 Twelve healthy volunteers received a single oral dose of tenoxicam 20 mg on six occasions separated by 3 weeks. 2 The six occasions were: fasted overnight; postprandial; fasting and 15 ml aluminium hydroxide gel; postprandial and 15 ml aluminium hydroxide gel; fasting and 15 ml aluminium and magnesium hydroxide gel; postprandial and 15 ml aluminium and magnesium hydroxide gel. 3 Twenty plasma samples were collected over 15 days following dosing with tenoxicam. 4 The following kinetic parameters for plasma tenoxicam were compared: peak concentrations, time taken to reach peak concentrations, area under the plasma concentration-time curve (AUC) and half-life of elimination. 5 Food lengthened the time taken to reach peak tenoxicam concentrations (5.82 +/- 4.6 vs 1.84 +/- 1.0 h in the fasting state; P less than 0.02) and marginally reduced the peak concentrations achieved. AUC was not affected by any of the different regimens. 6 These effects of food on tenoxicam bioavailability are unlikely to be of clinical significance during chronic dosing with the drug.
Topics: Adult; Aluminum Hydroxide; Antacids; Anti-Inflammatory Agents, Non-Steroidal; Biological Availability; Female; Food; Humans; Intestinal Absorption; Magnesium Hydroxide; Male; Middle Aged; Piroxicam
PubMed: 3499163
DOI: 10.1111/j.1365-2125.1987.tb03176.x -
Journal of Drug Targeting 2018In an effort to improve the adjuvanticity of insoluble aluminium salts, we discovered that the adjuvant activity of aluminium salt nanoparticles is significantly... (Comparative Study)
Comparative Study
In an effort to improve the adjuvanticity of insoluble aluminium salts, we discovered that the adjuvant activity of aluminium salt nanoparticles is significantly stronger than aluminium salt microparticles, likely related to nanoparticle's stronger ability to directly activate NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome as the nanoparticles are more efficiently taken up by phagocytic cells. Endogenous signals such as uric acid from cell damage or death caused by the cytotoxicity of aluminium salts are thought to indirectly activate inflammasome, prompting us to hypothesise that the potent adjuvant activity of aluminium salt nanoparticles is also related to their ability to stimulate uric acid production. In the present study, we prepared aluminium (oxy)hydroxide nanoparticles (∼ 30-100 nm) and microparticles (X, 9.43 μm) and showed that intraperitoneal injection of mice with the nanoparticles, absorbed with ovalbumin, led to a significant increase in uric acid level in the peritoneal lavage, whereas the microparticles did not. The aluminium (oxy)hydroxide nanoparticles' ability to stimulate uric acid production was also confirmed in cell culture. We concluded that the stronger adjuvant activity of insoluble aluminium (oxy)hydroxide nanoparticles, relative to microparticles, may be attributed at least in part to their stronger ability to induce endogenous danger signals such as uric acid.
Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Animals; Female; Inflammasomes; Injections, Intraperitoneal; Mice; Mice, Inbred BALB C; NLR Family, Pyrin Domain-Containing 3 Protein; Nanoparticles; Ovalbumin; Particle Size; Uric Acid; Vaccines
PubMed: 29334279
DOI: 10.1080/1061186X.2018.1428808 -
Antimicrobial Agents and Chemotherapy May 1999The pharmacokinetics of gatifloxacin (400 mg orally) and the influence of the antacid aluminum magnesium hydroxide (20 ml of Maalox 70) on the bioavailability of... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The pharmacokinetics of gatifloxacin (400 mg orally) and the influence of the antacid aluminum magnesium hydroxide (20 ml of Maalox 70) on the bioavailability of gatifloxacin in 24 healthy volunteers were assessed. In an open, randomized, six-period crossover study, the volunteers received either gatifloxacin alone (treatments A and D); aluminum magnesium hydroxide concomitant with gatifloxacin (treatment C); or aluminum magnesium hydroxide 2 h before (treatment B), 2 h after (treatment E), or 4 h after gatifloxacin administration (treatment F). Gatifloxacin concentrations were measured by a validated bioassay and high-performance liquid chromatography. Pharmacokinetics of a single 400-mg dose of gatifloxacin alone were characterized as follows (mean +/- standard deviation): peak concentration (Cmax), 3.8 +/- 0. 5 (treatment A) and 3.4 +/- 0.9 (treatment D) microgram/ml; time to Cmax, 1.4 +/- 0.8 (treatment A) and 1.7 +/- 0.7 (treatment D) h; area under the curve from time zero to infinity (AUC0-infinity), 33. 5 +/- 5.9 (treatment A) and 31.4 +/- 3.4 (treatment D) microgram. h/ml; urine recovery, (83 +/- 6)% (treatment A) and (84 +/- 8)% (treatment D). Comparison of the results obtained by bioassay showed a good correlation. Aluminum magnesium hydroxide administration 2 h before (treatment B) or concomitant with (treatment C) gatifloxacin decreased the Cmax by 45% (2.1 +/- 1.2 microgram/ml) or even 68% (1.2 +/- 0.4 microgram/ml) highly significantly (P < 0.01). AUC0-infinity was significantly reduced from 33.5 +/- 5.9 to 19.4 +/- 6.9 microgram. h/ml (by 42%) or even to 11.9 +/- 3.3 microgram. h/ml (by 64%) (P < 0. 01). If aluminum magnesium hydroxide was given 2 h after gatifloxacin (treatment E), there was no significant reduction of concentration in serum but AUC0-infinity was significantly reduced from 31.4 +/- 3.4 to 25.9 +/- 5.3 microgram. h/ml (18%) (P < 0.01). Aluminum magnesium hydroxide given 4 h after gatifloxacin (treatment F) showed no influence on the gatifloxacin pharmacokinetics. Therefore, the optimal time between gatifloxacin application and the intake of an aluminum-containing antacid should be 4 h.
Topics: Administration, Oral; Aluminum Hydroxide; Antacids; Anti-Infective Agents; Chromatography, High Pressure Liquid; Cross-Over Studies; Drug Combinations; Drug Interactions; Fluoroquinolones; Gatifloxacin; Humans; Magnesium Hydroxide
PubMed: 10223915
DOI: 10.1128/AAC.43.5.1067 -
Journal of Immunology (Baltimore, Md. :... May 2018Allergen immunotherapy (AIT) is the only modality that can modify immune responses to allergen exposure, but therapeutic coverage is low. One strategy to improve AIT...
Microcrystalline Tyrosine and Aluminum as Adjuvants in Allergen-Specific Immunotherapy Protect from IgE-Mediated Reactivity in Mouse Models and Act Independently of Inflammasome and TLR Signaling.
Allergen immunotherapy (AIT) is the only modality that can modify immune responses to allergen exposure, but therapeutic coverage is low. One strategy to improve AIT safety and efficacy is the use of new or improved adjuvants. This study investigates immune responses produced by microcrystalline tyrosine (MCT)-based vaccines as compared with conventional aluminum hydroxide (alum). Wild-type, immune-signaling-deficient, and TCR-transgenic mice were treated with different Ags (e.g., OVA and cat dander Fel d 1), plus MCT or alum as depot adjuvants. Specific Ab responses in serum were measured by ELISA, whereas cytokine secretion was measured both in culture supernatants by ELISA or by flow cytometry of spleen cells. Upon initiation of AIT in allergic mice, body temperature and further clinical signs were used as indicators for anaphylaxis. Overall, MCT and alum induced comparable B and T cell responses, which were independent of TLR signaling. Alum induced stronger IgE and IL-4 secretion than MCT. MCT and alum induced caspase-dependent IL-1β secretion in human monocytes in vitro, but inflammasome activation had no functional effect on inflammatory and Ab responses measured in vivo. In sensitized mice, AIT with MCT-adjuvanted allergens caused fewer anaphylactic reactions compared with alum-adjuvanted allergens. As depot adjuvants, MCT and alum are comparably effective in strength and mechanism of Ag-specific IgG induction and induction of T cell responses. The biocompatible and biodegradable MCT seems therefore a suitable alternative adjuvant to alum-based vaccines and AIT.
Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Animals; Desensitization, Immunologic; Disease Models, Animal; Hypersensitivity; Immunoglobulin E; Inflammasomes; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Signal Transduction; Toll-Like Receptors; Tyrosine
PubMed: 29592962
DOI: 10.4049/jimmunol.1800035