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Low-dose oral immunization with lyophilized tissue of herbicide-resistant lettuce expressing hepatitis B surface antigen for prototype plant-derived vaccine tablet formulation.

ABSTRACT: Efficient immunization against hepatitis B virus (HBV) and other pathogens with plant-based oral vaccines requires appropriate plant expressors and the optimization of vaccine compositions and administration protocols. Previous immunization studies were mainly based on a combination of the injection of a small surface antigen of HBV (S-HBsAg) and the feeding with raw tissue containing the antigen, supplemented with an adjuvant, and coming from plants conferring resistance to kanamycin. The objective of this study was to develop a prototype oral vaccine formula suitable for human immunization. Herbicide-resistant lettuce was engineered, stably expressing through progeny generation micrograms of S-HBsAg per g of fresh weight and formed into virus-like particles (VLPs). Lyophilized tissue containing a relatively low, 100-ng VLP-assembled antigen dose, administered only orally to mice with a long, 60-day interval between prime and boost immunizations and without exogenous adjuvant, elicited mucosal and systemic humoral anti-HBs responses at the nominally protective level. Lyophilized tissue was converted into tablets, which preserved S-HBsAg content for at least one year of room temperature storage. The results of the study provide indications on immunization methodology using a durable, efficacious, and convenient plant-derived prototype oral vaccine against hepatitis B.

SUBMITTER: Pniewski T

PROVIDER: S-EPMC3088802 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Transcutaneous immunization system using a hydrotropic formulation induces a potent antigen-specific antibody response.

Project description:BackgroundTranscutaneous immunization (TCI) is a novel vaccination strategy, which is expected to have therapeutic applications. However, to develop effective TCI systems, a simple, non-invasive and safe transdermal formulation is required. This study developed a novel TCI system utilizing the co-administration of a liposoluble absorption enhancer, propylene glycol monocaprylate (PGMC) and hydrosoluble protein antigen without pretreatment of any typical adjuvants and disruption of the skin. Novel transdermal formulations were also prepared with sodium salicylate (NaSal) as a hydrotropic agent to improve the solubility of poorly water-soluble substances.Methodology/principal findingsThe TCI system, which used a transdermal formulation containing hen lysozyme (HEL) and PGMC, solubilized with NaSal, resulted in a substantial HEL-specific antibody response in an HEL dose-dependent manner even in the absence of potent adjuvants, such as cholera toxin (CT). We also investigated whether NaSal activates antigen-presenting cells in vitro to clarify the mechanisms of antibody production by the hydrotropic formulation. NaSal enhanced the expression of MHC class II molecules and increased the production of IL-12 and TNF-? in dendritic cells, which were stimulated by lipopolysaccharide in vitro, indicating that NaSal had an effective adjuvant-like property. Moreover, the use of NaSal in the TCI system did not induce an HEL-specific, IgE-dependent anaphylactic reaction.Conclusion/significanceOur TCI system using a hydrotropic formulation effectively and safely induced the intended immune response, and this system thus represents a new advantageous method that will result in improved TCI strategies.

| S-EPMC3480500 | biostudies-literature

Mesalazine granule formulation improves clinical data in Crohn's disease compared with tablet formulation.

Project description:The efficacy of sustained-release preparations of mesalazine as a remission maintenance treatment for Crohn's disease remains to be established. We aimed to examine the changes in compliance rate and clinical data 2 years after switching from mesalazine tablet to granule formulation at our facility among patients with Crohn's disease in remission. We investigated the rate of continuous treatment of mesalazine granules and examined the changes in Crohn's Disease Activity Index (CDAI) and serum C-reactive protein (CRP), albumin, and hemoglobin (Hb) levels 2 years after the switch. Compliance rate (continuous treatment vs. additional treatment) and continuous treatment rate [good (rate of ≥ 70%) vs. poor (rate < 70%)] were investigated. Of 46 patients, 12 (27.3%) received additional treatment and 32 (72.7%) did not require additional treatment in 2 years. No significant change in CDAI after switching to granule modification was noted in 32 patients in the continuous treatment group. Nevertheless, clinical remission was maintained for 2 years, and serum CRP levels decreased significantly (P = 0.023) and Hb levels increased significantly (P = 0.002). No change in the compliance rate was found. Our results suggest that mesalazine granule formulation may have a remission maintenance effect that is superior to that of mesalazine tablets.

| S-EPMC7721736 | biostudies-literature

Randomized, Double-Blind Study of the Pharmacokinetics and Safety of Palivizumab Liquid Formulation Compared with Lyophilized Formulation.

Project description:ObjectiveTo assess the pharmacokinetics and safety of liquid palivizumab compared with lyophilized palivizumab.MethodsThis phase 2, randomized, double-blind crossover study included premature infants aged ≤6 months born ≤35 weeks gestational age. Patients were randomized in a 1:1 ratio to receive a single 15 mg/kg intramuscular dose of liquid (sequence A group) or lyophilized (sequence B group) palivizumab on Day 0. Patients crossed over to receive the alternate formulation on Day 30. Serum palivizumab and antidrug antibody (ADA) levels were measured on Day 0 (predose), Day 30 (before the dose of alternate formulation), and Day 60 (30 days after the dose of alternate formulation). Patients were followed for safety through Day 60 (30 days after the dose of alternate formulation).ResultsA total of 153 infants were randomized into the study (sequence A 75; sequence B 78). Sequence A and sequence B trough serum palivizumab levels were similar on Day 30 (51.7 and 49.1 µg/mL, respectively) and Day 60 (84.8 and 87.2 µg/mL, respectively). The ratio of the geometric means using both Day 30 and Day 60 serum concentrations was 1.040 (90% CI 0.998-1.083), which was within the prespecified bioequivalence range of 0.8-1.25. Adverse events (AEs) were similar between the palivizumab liquid and lyophilized groups and within each treatment sequence. Serious AEs (SAEs) were experienced by 3% of infants in both liquid palivizumab and lyophilized palivizumab groups. None of the SAEs were determined to be related to study drug. Among the 124 infants (81% of total) evaluated for ADA, 2 (1.6%) tested positive for ADA at Day 60 (1 in each of sequence A and B).ConclusionLiquid and lyophilized formulations of palivizumab were bioequivalent with similar safety profiles in infants.

| S-EPMC4269619 | biostudies-literature

Development of a Lyophilized Formulation of Pegaspargase and Comparability Versus Liquid Pegaspargase.

Project description:IntroductionPegaspargase, a pegylated asparaginase, is a core component in the treatment of acute lymphoblastic leukemia. Pegaspargase in liquid form has a limited shelf life of 8 months due to depegylation, leading to changes in purity and potency over time. Lyophilization is an approach that can improve the stability of biological drug conjugates.MethodsHere we describe the development of a lyophilized formulation of pegaspargase and present results of a series of tests demonstrating that the lyophilized form has comparable physicochemical properties to the liquid form.ResultsStability tests of critical quality attributes, including purity, potency, aggregates and total free polyethylene glycol, demonstrate that lyophilized pegaspargase remains stable for at least 3 years, with optimum stability achieved with storage under refrigerated conditions (2-8 °C).ConclusionsLyophilization improved the stability of pegaspargase without altering other physicochemical properties, permitting a prolonged shelf life of at least 2 years when stored at 2-8 °C. This may enable greater storage flexibility and allow for better management of pegaspargase.FundingStudy Sponsor: Baxalta (now part of Takeda). Publication Sponsor: Servier Affaires Médicales.

| S-EPMC6822849 | biostudies-literature

High Acceptability of an Orally Dispersible Tablet Formulation by Children.

Project description:There is a high unmet medical need for child-appropriate oral dosage forms. The acceptability of a novel placebo orally dispersible tablet formulation (pODT) was therefore evaluated. Monolithic tablets contain an inorganic calcium carbonate/calcium phosphate carrier material as the main excipient. They were assessed in a cross-sectional acceptability study. The 40 child participants were between 2 to 5 years and 6 to 10 years old. One pODT with 5 mm diameter was administered to each participating child by placement on the tongue or into the buccal cavity. Parents were asked to complete a questionnaire together with the study personnel. The spontaneous reactions of the children were recorded. The ease of administration and children's acceptance of the tablet was rated by research staff on a 4-point acceptability scale and by parents on a 5-point Likert scale. The older subjects answered how they had liked the pODT by pointing to the appropriate face of a Facial Hedonic Scale. pODT had very high acceptability as 93% of parents, and all questioned children reported the formulation to be acceptable or very acceptable. Staff reported administering pODT in these children without problems. None of the children showed distress on receipt of pODT. We conclude that the proposed child-friendly dosage form provides a convenient option for oral drug administration and is expected to enhance drug-adherence in pediatric patients.

| S-EPMC7999602 | biostudies-literature

Immunization with the gene expressing woodchuck hepatitis virus nucleocapsid protein fused to cytotoxic-T-lymphocyte-associated antigen 4 leads to enhanced specific immune responses in mice and woodchucks.

Project description:A number of options are available to modify and improve DNA vaccines. An interesting approach to improve DNA vaccines is to fuse bioactive domains, like cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4), to an antigen. Such fusion antigens are expressed in vivo and directed to immune cells by the specific bioactive domain and therefore possess great potential to induce and modulate antigen-specific immune responses. In the present study, we tested this new approach for immunomodulation against hepadnavirus infection in the woodchuck model. Plasmids expressing the nucleocapsid protein (WHcAg) and e antigen (WHeAg) of woodchuck hepatitis virus (WHV) alone or in fusion to the extracellular domain of woodchuck CTLA-4 and CD28 were constructed. Immunizations of mice with plasmids expressing WHcAg or WHeAg led to a specific immunoglobulin G2a (IgG2a)-dominant antibody response. In contrast, fusions of WHcAg to CTLA-4 and CD28 induced a specific antibody response with comparable levels of IgG1 and IgG2a. Furthermore, the specific IgG1 response to WHcAg/WHeAg developed immediately after a single immunization with the CTLA-4-WHcAg fusion. Woodchucks were immunized with plasmids expressing WHeAg or the CTLA-4-WHcAg fusion and subsequently challenged with WHV. CTLA-4-WHcAg showed an improved efficacy in induction of protective immune responses to WHV. In particular, the anti-WHsAg antibody response developed earlier after challenge in woodchucks that received immunizations with CTLA-4-WHcAg, consistent with the hypothesis that anti-WHs response is dependent on a Th cell response to WHcAg. In conclusion, the use of fusion genes represents a generally applicable strategy to improve DNA vaccination.

| S-EPMC1091665 | biostudies-literature

Development of Prototype Filovirus Recombinant Antigen Immunoassays.

Project description:BackgroundThroughout the 2014-2015 Ebola outbreak in West Africa, major gaps were exposed in the availability of validated rapid diagnostic platforms, protective vaccines, and effective therapeutic agents. These gaps potentiated the development of prototype rapid lateral flow immunodiagnostic (LFI) assays that are true point-of-contact platforms, for the detection of active Ebola infections in small blood samples.MethodsRecombinant Ebola and Marburg virus matrix VP40 and glycoprotein (GP) antigens were used to derive a panel of monoclonal and polyclonal antibodies. Antibodies were tested using a multivariate approach to identify antibody-antigen combinations suitable for enzyme-linked immunosorbent assay (ELISA) and LFI assay development.ResultsPolyclonal antibodies generated in goats were superior reagents for capture and detection of recombinant VP40 in test sample matrices. These antibodies were optimized for use in antigen-capture ELISA and LFI assay platforms. Prototype immunoglobulin M (IgM)/immunoglobulin G (IgG) ELISAs were similarly developed that specifically detect Ebola virus-specific antibodies in the serum of experimentally infected nonhuman primates and in blood samples obtained from patients with Ebola from Sierra Leone.ConclusionsThe prototype recombinant Ebola LFI assays developed in these studies have sensitivities that are useful for clinical diagnosis of acute ebolavirus infections. The antigen-capture and IgM/IgG ELISAs provide additional confirmatory assay platforms for detecting VP40 and other ebolavirus-specific immunoglobulins.

| S-EPMC4564556 | biostudies-literature

Lyophilized, antigen-bound liposomes with reduced MPLA and enhanced thermostability.

Project description:Thermostability and decreased component costs are desirable features for adjuvanted, recombinant vaccines. We previously showed that a model malaria transmission-blocking vaccine candidate antigen, Pfs25, can be rendered more immunogenic when mixed with liposomes containing cobalt porphyrin-phospholipid (CoPoP) and a synthetic monophosphoryl lipid A (MPLA) variant. CoPoP can induce stable particle formation of recombinant antigens based on interaction with their polyhistidine tag. In the present work, different synthetic MPLA variants and concentrations were assessed in CoPoP liposomes. Long-term biophysical stability and immunogenicity were not adversely impacted by a 60% reduction in MPLA content. When admixed with Pfs25, the adjuvant formulations effectively induced functional antibodies in immunized mice and rabbits. Lyophilized, antigen-bound liposomes were formed using sucrose and trehalose cryoprotectants, which improved vaccine reconstitution for a variety of model antigens. Compared to liquid storage, the lyophilized Pfs25 and CoPoP liposomes exhibited thermostability with respect to size, biochemical integrity, binding capacity, protein folding and immunogenicity. Following 6 weeks of storage at 60 °C, the most extended storage period assessed, the lyophilized formulation induced functional antibodies in mice with immunization.

| S-EPMC7854498 | biostudies-literature

Protein microarray epitope mapping of monoclonal antibody 5H2 raised by human immunization with the 4CMenB vaccine formulation containing the fusion antigen NHBA-NMB1030.

Project description:The aim of the study was to determine the epitope targeted by 5H2 human Fab directed against NHBA and the crossreactivity aginst a panel of nine different NHBA long and short peptide variants (p2, p3, p5, p10, p17, p20, p21, p24, p29). 5H2 were diluted at 1:2000 and incubated on a non-commercial Protein Microarray platform printed with NHBAp2 specific recombinant protein fragments and full length NHBA of different variants.

2018-08-30 | GSE112752 | GEO

Immunization against Hepatitis E.

Project description:Soon after the 1991 molecular cloning of hepatitis E virus (HEV), recombinant viral capsid antigens were expressed and tested in nonhuman primates for protection against liver disease and infection. Two genotype 1 subunit vaccine candidates entered clinical development: a 56 kDA vaccine expressed in insect cells and HEV 239 vaccine expressed in Escherichia coli Both were highly protective against hepatitis E and acceptably safe. The HEV 239 vaccine was approved in China in 2011, but it is not yet prequalified by the World Health Organization, a necessary step for introduction into those low- and middle-income countries where the disease burden is highest. Nevertheless, the stage is set for the final act in the hepatitis E vaccine story-policymaking, advocacy, and pilot introduction of vaccine in at-risk populations, in which it is expected to be cost-effective.

| S-EPMC6211382 | biostudies-literature

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