Safety and Efficacy of a Typhoid Conjugate Vaccine in Malawian Children.

BACKGROUND: Typhoid fever caused by multidrug-resistant H58 Salmonella Typhi is an increasing public health threat in sub-Saharan Africa. METHODS: We conducted a phase 3, double-blind trial in Blantyre, Malawi, to assess the efficacy of Vi polysaccharide typhoid conjugate vaccine (Vi-TCV). We randomly assigned children who were between 9 months and 12 years of age, in a 1:1 ratio, to receive a single dose of Vi-TCV or meningococcal capsular group A conjugate (MenA) vaccine. The primary outcome was typhoid fever confirmed by blood culture. We report vaccine efficacy and safety outcomes after 18 to 24 months of follow-up. RESULTS: The intention-to-treat analysis included 28,130 children, of whom 14,069 were assigned to receive Vi-TCV and 14,061 were assigned to receive the MenA vaccine. Blood culture-confirmed typhoid fever occurred in 12 children in the Vi-TCV group (46.9 cases per 100,000 person-years) and in 62 children in the MenA group (243.2 cases per 100,000 person-years). Overall, the efficacy of Vi-TCV was 80.7% (95% confidence interval [CI], 64.2 to 89.6) in the intention-to-treat analysis and 83.7% (95% CI, 68.1 to 91.6) in the per-protocol analysis. In total, 130 serious adverse events occurred in the first 6 months after vaccination (52 in the Vi-TCV group and 78 in the MenA group), including 6 deaths (all in the MenA group). No serious adverse events were considered by the investigators to be related to vaccination. CONCLUSIONS: Among Malawian children 9 months to 12 years of age, administration of Vi-TCV resulted in a lower incidence of blood culture-confirmed typhoid fever than the MenA vaccine. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT03299426.).

Transcriptome, Spliceosome and Editome Expression Patterns of the Porcine Endometrium in Response to a Single Subclinical Dose of Salmonella Enteritidis Lipopolysaccharide.

Endometrial infections at a young age can lead to fertility issues in adulthood. Bacterial endotoxins, such as lipopolysaccharide (LPS), can participate in long-term molecular changes even at low concentrations. Lipopolysaccharide plays a crucial role in the progression of septic shock, inflammation and auto-immune diseases. The aim of this study was to describe transcriptomic modulations in the porcine endometrium, induced in vivo by a single subclinical dose of LPS from Salmonella Enteritidis. which did not produce clinical symptoms of toxicity. The RNA-seq methodology was applied to reveal 456 differentially expressed regions, including 375 genes, four long noncoding RNAs, and 77 other unclassified transcripts. Two independent methods confirmed 118 alternatively spliced genes that participate i.a., in the formation of the MHC-I complex and the adaptive immune response. Single nucleotide variant-calling algorithms supported the identification of 3730 allele-specific expression variants and 57 canonical A-to-I RNA editing sites. The results demonstrated that the differential expression of genes involved in inflammation, immune response, angiogenesis and endometrial development may be maintained for up to 7 days after exposure to LPS. RNA editing sites and long noncoding RNAs (lncRNAs) play an important role in transcriptional regulatory machinery in the porcine endometrium in response to LPS administration.

Bacillus Calmette-Guerin, polysaccharide nucleic acid in the treatment of cutaneous and oral lichen planus.

The aim of this study was to evaluate the safety and efficacy of Bacillus Calmette-Guerin, polysaccharide nucleic acid (BCG-PSN) therapy in the treatment of oral and cutaneous LP. Twenty-four LP patients were included in this study and classified randomly into; Oral LP group (OLP), 11 patients and Cutaneous LP group (CLP), 13 patients. All patients received intradermal injections of BCG-PSN, twice weekly for three weeks. Patients with complete response were followed up for 3 months. The assessment in OLP was based on the reduction in the treated area, (Reticulation/Erythema/Ulceration) REU scoring system and numerical rating scale (NRS). CLP evaluated by the response to treatment as (complete, partial and no response) and visual analogue scale (VAS). There were highly significant differences in the diminution of lesion areas (p < .006), NRS scores (p < .001), REU score (p < .011), and VAS (p < .001) after treatment. The majority of patients achieved complete response after 3-week management. The BCG-PNS is safe and effective in the treatment of oral and cutaneous LP.

Protective Effect of Strawberry Extract against Inflammatory Stress Induced in Human Dermal Fibroblasts.

A protracted pro-inflammatory state is a major contributing factor in the development, progression and complication of the most common chronic pathologies. Fruit and vegetables represent the main sources of dietary antioxidants and their consumption can be considered an efficient tool to counteract inflammatory states. In this context an evaluation of the protective effects of strawberry extracts on inflammatory stress induced by E. coli LPS on human dermal fibroblast cells was performed in terms of viability assays, ROS and nitrite production and biomarkers of oxidative damage of the main biological macromolecules. The results demonstrated that strawberry extracts exerted an anti-inflammatory effect on LPS-treated cells, through an increase in cell viability, and the reduction of ROS and nitrite levels, and lipid, protein and DNA damage. This work showed for the first time the potential health benefits of strawberry extract against inflammatory and oxidative stress in LPS-treated human dermal fibroblast cells.

Sweetness and other sensory properties of model fruit drinks: Does viscosity have an impact?

BACKGROUND: The impact of thickening agents and viscosity levels on sensory perception was studied in model fruit drinks. Four formulations were prepared that varied in the sweetener blend (erythritol, maltitol and/or steviol glycosides). Locust bean gum and its blends with either xanthan or carrageenan were used to adjust viscosity levels (20, 40, and 70 mPa s). The ranges of viscosity and sweetness level were selected to represent a typical concentration range in commercially available beverages. RESULTS: An increase in viscosity resulted in significant increases in pulpiness, sliminess and perceived viscosity (P-values ≤ 0.001), which were not dependent on sweeteners or hydrocolloid type. Taste perception remained largely unchanged irrespective of the hydrocolloid used. CONCLUSION: The impact of viscosity on sweetness and taste perception was much smaller in the concentrations used than has been generally reported. The effect of the type of hydrocolloid on the perception of taste attributes was greater than that of viscosity.

A cluster-randomized effectiveness trial of Vi typhoid vaccine in India.

BACKGROUND: Typhoid fever remains an important cause of illness and death in the developing world. Uncertainties about the protective effect of Vi polysaccharide vaccine in children under the age of 5 years and about the vaccine's effect under programmatic conditions have inhibited its use in developing countries. METHODS: We conducted a phase 4 effectiveness trial in which slum-dwelling residents of Kolkata, India, who were 2 years of age or older were randomly assigned to receive a single dose of either Vi vaccine or inactivated hepatitis A vaccine, according to geographic clusters, with 40 clusters in each study group. The subjects were then followed for 2 years. RESULTS: A total of 37,673 subjects received a dose of a study vaccine. The mean rate of vaccine coverage was 61% for the Vi vaccine clusters and 60% for the hepatitis A vaccine clusters. Typhoid fever was diagnosed in 96 subjects in the hepatitis A vaccine group, as compared with 34 in the Vi vaccine group, with no subject having more than one episode. The level of protective effectiveness for the Vi vaccine was 61% (95% confidence interval [CI], 41 to 75; P<0.001 for the comparison with the hepatitis A vaccine group). Children who were vaccinated between the ages of 2 and 5 years had a level of protection of 80% (95% CI, 53 to 91). Among unvaccinated members of the Vi vaccine clusters, the level of protection was 44% (95% CI, 2 to 69). The overall level of protection among all residents of Vi vaccine clusters was 57% (95% CI, 37 to 71). No serious adverse events that were attributed to either vaccine were observed during the month after vaccination. CONCLUSIONS: The Vi vaccine was effective in young children and protected unvaccinated neighbors of Vi vaccinees. The potential for combined direct and indirect protection by Vi vaccine should be considered in future deliberations about introducing this vaccine in areas where typhoid fever is endemic. (ClinicalTrials.gov number, NCT00125008.)

Late onset necrotizing enterocolitis in infants following use of a xanthan gum-containing thickening agent.

Adverse event reports submitted to the US Food and Drug Administration suggested a possible association between necrotizing enterocolitis and ingestion of a commercial feed thickener by premature infants. Review in 2011 of 22 cases with exposure revealed a distinct illness pattern.

Effects of added PGX®, a novel functional fibre, on the glycaemic index of starchy foods.

The development of lower-glycaemic index (GI) foods requires simple, palatable and healthy strategies. The objective of the present study was to determine the most effective dose of a novel viscous fibre supplement (PGX®) to be added to starchy foods to reduce their GI. Healthy subjects (n 10) consumed glucose sugar (50 g in water × 3) and six starchy foods with a range of GI values (52-72) along with 0 (inert fibre), 2.5 or 5 g granular PGX® dissolved in 250 ml water. GI testing according to ISO Standard 26,642-2010 was used to determine the reduction in GI. PGX® significantly reduced the GI of all six foods (P < 0.001), with an average reduction of 19 % for the 2.5 g dose and 30 % for the 5 g dose, equivalent to a reducing the GI by 7 and 15 units, respectively. Consuming small quantities of the novel functional fibre PGX®, mixed with water at the start of a meal, is an effective strategy to reduce the GI of common foods.

[Causes of gelatinous material on ocular surface of a patient using timolol maleate long-acting eye drops].

PURPOSE: To ascertain the causes of the formation of gelatinous material observed on the ocular surface of a patient using a betamethasone sodium phosphate ophthalmic solution containing fradiomycin sulfate (Rinderon-A) together with a timolol maleate long-acting ophthalmic gel-forming solution (Timoptol-XE). METHODS: The gellan gum in the Timoptol-XE was suspect as it might have been gelatinized by the fradiomycin sulfate in the Rinderon-A. Mixtures of the chemical compounds such as fradiomycin sulfate with the Timoptol-XE was tested in vitro to find out whether any resulted in gelation. RESULTS: It was confirmed that Timoptol-XE was gelatinized by the aminoglycoside drugs in vitro. The density of the aminoglycoside drugs needed for the gelation was only about 0.2 mM on average. Gelation was also observed with benzalkonium chloride and vancomycin. CONCLUSION: The results suggest that the gellan gum in the Timoptol-XE gelatinized by the fradiomycin sulfate in the Rinderon-A and that aminoglycocide compounds act strongly on gellan gum as polycation.

Safety and immunogenicity of Vi-typhoid conjugate vaccine co-administration with routine 9-month vaccination in Burkina Faso: A randomized controlled phase 2 trial.

OBJECTIVES: In 2017, the World Health Organisation (WHO) pre-qualified a single-dose typhoid conjugate vaccine (TCV) and identified TCV co-administration studies as a research priority. Accordingly, we tested co-administration of Typbar TCV® (Bharat Biotech International) with measles-rubella (MR) and yellow fever (YF) vaccines. METHODS: We conducted a randomized, double-blind, and controlled, phase 2 trial in Ouagadougou, Burkina Faso. Healthy children aged 9-11 months were randomized 1:1 to receive TCV (Group 1) or control vaccine (inactivated polio vaccine (IPV), Group 2). Vaccines were administered intramuscularly with routine MR and YF vaccines. Safety was assessed by (1) local and systemic reactions on days 0, 3, and 7; (2) unsolicited adverse events within 28 days; and (3) serious adverse events (SAEs) within six months after immunization. RESULTS: We enrolled, randomized, and vaccinated 100 eligible children (49 Group 1 and 51 Group 2). Safety outcomes occurred with similar frequency in both groups: local/solicited reactions (Group 1: 1/49, Group 2: 3/50), systemic/solicited reactions (Group 1: 4/49, Group 2: 9/50), unsolicited adverse events (Group 1: 26/49, Group 2: 33/51), and SAEs (Group 1: 2/49, Group 2: 3/51). TCV conferred robust immunogenicity without interference with MR or YF vaccines. CONCLUSION: TCV can be safely co-administered with MR and YF vaccines to children at the 9-month vaccination visit.

Effect of Intake of Food Hydrocolloids of Bacterial Origin on the Glycemic Response in Humans: Systematic Review and Narrative Synthesis.

Diabetes mellitus is a chronic condition characterized by increased blood glucose levels from dysfunctional carbohydrate metabolism. Dietary intervention can help to prevent and manage the disease. Food hydrocolloids have been shown to have favorable properties in relation to glycaemic regulation. However, the use of food hydrocolloids of bacterial origin to modulate glucose responses is much less explored than other types of hydrocolloids. We, therefore, carried out the first review examining the impact of intake of food hydrocolloids of bacterial origin (as a direct supplement or incorporated into foods) on glycemic response in humans. Fourteen studies met the inclusion criteria. They used either xanthan gum, pullulan, or dextran as interventions. There was a wide variation in the amount of hydrocolloid supplementation provided and methods of preparation. Postprandial blood glucose responses were reduced in half of the studies, particularly at higher intake levels and longer chain hydrocolloids. When xanthan gum was added to the cooking process of muffins and rice, a significant reduction in postprandial blood glucose was observed. The use of these hydrocolloids is potentially effective though more research is needed in this area.

Role of meningococcal endotoxin in meningococcal purpura.

Enteric bacilli and meningococci (MGC) both contain potent endotoxins, but purpuric skin lesions indistinguishable from the experimental dermal Shwartzman reaction are much more common during meningococcal bacteremia than during bacteremia with enteric organisms. Highly purified lipopolysaccharides (LPS), virtually free of contamination by protein, RNA, and capsule, were extracted by a modification of the phenol-water technique from MGC (serogroups A, B, and C) and enteric bacilli (Escherichia coli 04 and 0:111, and Salmonella typhimurium). Polysaccharides in these LPS were similar by gas chromatography except for one galactose-deficient strain of MGC (135B). LPS from MGC and enterics were equally potent for the general Shwartzman reaction and mouse lethality, but LPS from MGC was 5-10 times more potent in inducing the dermal Shwartzman reaction. The greater skin potency of LPS from MGC explains the prominence of purpura in meningococcemia. Comparison of the properties of LPS may explain other differences in clinical syndromes caused by gram-negative bacteria.

A phase 1 randomized safety, reactogenicity, and immunogenicity study of Typhax: A novel protein capsular matrix vaccine candidate for the prevention of typhoid fever.

BACKGROUND: Typhoid fever remains a significant cause of morbidity and mortality in developing countries especially in children ≤5 years old. Although the widely available unconjugated Vi polysaccharide vaccines are efficacious, they confer limited, short-term protection and are not approved for young children or infants. Vi conjugate vaccines, however, are now licensed in several typhoid endemic countries for use in children >6 months of age. As an alternative to conjugate vaccines, Matrivax has applied its novel 'virtual conjugation' Protein Capsular Matrix Vaccine (PCMV) technology to manufacture Typhax, which is composed of Vi polysaccharide entrapped in a cross-linked CRM197 matrix. METHODOLOGY: A randomized, double-blinded, dose escalating Phase 1 study was performed to compare the safety and immunogenicity of three dose levels of aluminum phosphate adjuvanted Typhax (0.5, 2.5, or 10 µg of Vi antigen) to the FDA licensed vaccine, Typhim Vi, and placebo. Groups of 15 healthy adult subjects aged 18 to 55 years were randomized and received Typhax, Typhim Vi, or placebo at a ratio of 9:3:3. Typhax and placebo were administered in a two-dose regimen (Days 0 and 28) while Typhim Vi was administered as a single-dose on Day 0 with a placebo administered on Day 28. All doses were administered as a 0.5 mL intramuscular (IM) injection in a blinded fashion. The anti-Vi IgG antibody response was determined preimmunization (Day 0) and on Days 14, 28, 42, and 180 by ELISA. Seroconversion was defined as a titer 4-fold or greater above baseline. PRINCIPAL FINDINGS: All Typhax vaccine regimens were well tolerated and adverse events were low in number and primarily characterized as mild in intensity and similar in incidence across the treatment groups. Reactogenicity, primarily pain and tenderness at the injection site, was observed in both the Typhax and Typhim Vi treatment groups; a modest increase in incidence was observed with increasing Typhax doses. Following one dose of Typhax, seroconversion rates at day 28 were 12.5%, 77.8%, 66.7% at the 0.5, 2.5, and 10 µg dose levels, respectively, compared to 55.6% and 0% in the Typhim Vi and placebo groups, respectively. A second dose of Typhax on Day 28 did not elicit a significant increase in GMT or seroconversion at Day 42 or Day 180 at any dose level. CONCLUSIONS: Collectively, the results from this randomized phase 1 clinical trial indicate that Typhax is safe, well tolerated, and immunogenic. After a single dose, Typhax at the 2.5 and 10 µg dose levels elicited comparable anti-Vi IgG titers and seroconversion rates as a single dose of Typhim Vi (25 µg dose). A second dose of Typhax at Day 28 did not elicit a booster response. TRIAL REGISTRATION: ClinicalTrials.gov NCT03926455.

In vivo evaluation of the effectiveness of biocellulose facial masks as active delivery systems to skin.

BACKGROUND: In recent years, bacterial cellulose (BC), or biocellulose, a natural polymer synthesized by certain bacteria, has attracted great interest in dermatology and cosmetic applications. Several bioactive ingredients are currently loaded into BC masks. However, only a few studies have reported the effectiveness of such delivery systems. AIM: The aim of this study was to evaluate the effect on skin parameters of three biocellulose masks formulated to have different cosmetic effects (anti-aging, lifting, and cell renewal). In particular, skin moisturizing, skin color, skin viscoelastic properties, skin surface smoothness, wrinkle reduction, dermal homogeneity, and stratum corneum renewal were evaluated. MATERIALS AND METHODS: The study involved 69 healthy Caucasian female volunteers between 25 and 64 years, who were divided into three different studies. Biocellulose facial masks were applied using the split-face method three times a week for 4-8 weeks depending on the study. RESULTS: The results obtained from this work highlight that biocellulose masks are very well tolerated. A significant decrease in skin roughness and wrinkle breadth, and an improvement in dermal homogeneity and firmness, was observed after 2 months of treatment with "anti-aging" masks. A significant improvement in skin firmness and elasticity was observed after 1 month of treatment with "lifting" masks. Furthermore, a 1-month treatment with "cell renewal" masks promoted the production of new skin cells through a mild exfoliating action. CONCLUSIONS: This study highlights that biocellulose masks are effective delivery systems to successfully release into the skin several types of active compounds exerting many beneficial effects.

Supplementation of the diet with the functional fiber PolyGlycoplex is well tolerated by healthy subjects in a clinical trial.

BACKGROUND: The relationship of dietary fiber to overall health is of great importance, as beneficial effects have been demonstrated with the use of fiber from diverse sources, some traditional, other novel. PolyGlycopleX (PGX) is a unique proprietary product composed of three water-soluble polysaccharides, that when processed using novel technology give rise to a final product - a soluble, highly viscous functional fiber. METHODS: Because of its potential use in food and dietary supplements, a randomized, double-blind, placebo controlled clinical study was conducted to evaluate the tolerance to PGX ingestion for 21 days, to a maximum dose level of 10 g per day, in healthy male and female volunteers. The main objective of the study was to evaluate the overall gastrointestinal (GI) tolerance, while secondary objectives were to evaluate possible changes in hematological, biochemical, urinary and fecal parameters. RESULTS: Results show that PGX is well tolerated as part of a regular diet with only mild to moderate adverse effects, similar to those seen with a moderate intake of dietary fiber in general, and fruits and vegetables. Because PGX is a highly viscous, functional fiber, it also demonstrates several physiological responses including, but not limited to maintaining healthy total and LDL cholesterol and uric acid levels.

A diet including xanthan gum triggers a pro-inflammatory response in Wistar rats inoculated with Walker 256 cells.

OBJECTIVE: The aim of this study was to evaluate the effect of adding xanthan gum to the diet of rats on the production of cytokines and pro-inflammatory factors and on tumor development in rats inoculated with Walker 256 tumor cells. METHODS: Fifty-six rats were divided into 4 groups: control diet (C), control diet with tumor (TC), xanthan gum diet (XG), xanthan gum diet with tumor (TXG). RESULTS: The ingestion of xanthan gum promotes changes in cytokine content: increasing IL-6 TNF-α and IL-10 in retroperitoneal adipose tissue compared to the control group; and increasing TNF-α in the mesenteric adipose tissue compared to the C and TXG groups. On the contrary, the addition of xanthan gum to the diet did not affect the development of Walker 256 tumors in rats. CONCLUSION: The continuous use of xanthan gum triggered a pro-inflammatory response, promoting an increase in pro-inflammatory cytokines in the adipose tissue, but it did not have an effect on the tumor development in the animals inoculated with Walker 256 tumor cells.

Vaccine Allergy? Skin Testing and Challenge at a Tertiary Pediatric Hospital in Melbourne, Australia.

BACKGROUND: The rate of true vaccine allergy is unknown. Children with potential IgE-mediated adverse events following immunization (AEFI) should undergo allergy investigation that may include skin testing or challenge. Previous protocols tend to be highly conservative and often suggest invasive testing for all, a practice not evidence based, technically difficult, and unpleasant in children. It has more recently been suggested that skin testing may be restricted to those with allergic-like events within the first hour and those with a history of anaphylaxis. OBJECTIVE: We aimed to describe the outcome of vaccine skin testing and challenge in children referred to a tertiary pediatric hospital with a potential IgE-mediated AEFI. The secondary aim was to identify any significant risk factors for vaccine allergy. METHODS: A retrospective review of all children (<18 years) who underwent vaccine skin testing (skin prick testing or intradermal testing [IDT]) or challenge over a 5-year period (May 1, 2011, to April 30, 2016) at the Royal Children's Hospital Melbourne is presented. RESULTS: There were 95 admissions in 73 children. Eight percent (6 of 73) of children had confirmed vaccine allergy (positive skin testing or challenge to the index vaccination). Two had positive IDT to a suspect vaccine but challenge negative to an alternative brand vaccine. Two had negative IDT but subsequent positive challenge and two had immediate urticaria on challenge without prior skin testing. All children in the positive group either had index reaction within 15 minutes of vaccination or had history consistent with anaphylaxis. CONCLUSIONS: The vast majority of children (92%) presenting with a potential IgE-mediated AEFI are able to tolerate challenge to a suspect vaccine without reaction. We present our investigation protocol recommending skin testing in all children with anaphylaxis and challenge with a suspect vaccine if negative testing or previous nonanaphylactic potential IgE-mediated AEFI.

The effects of aspirated thickened water on survival and pulmonary injury in a rabbit model.

OBJECTIVES/HYPOTHESIS: Liquid thickeners are one of the most frequently utilized treatment strategies for persons with oropharyngeal swallowing dysfunction. The effect of commercially available thickeners on lung injury is uncertain. The purpose of this study was to compare the effects of aspiration of water alone, xanthan gum (XG)-thickened water, and cornstarch (CS)-thickened water on survival and lung morphology in a rabbit model. STUDY DESIGN: Animal model. Prospective small animal clinical trial. METHODS: Adult New Zealand White rabbits (n = 24) were divided into three groups of eight rabbits. The groups underwent 3 consecutive days of 1.5 mL/kg intratracheal instillation of water (n = 8), XG-thickened water (n = 8), and CS-thickened water (n = 8). The animals were euthanized on day 4, and survival and pulmonary histopathology were compared between groups. RESULTS: In all, 12.5% of rabbits (n = 8) instilled with CS-thickened water survived until the endpoint of the study (day 4). All animals instilled with water (n = 8) or XG-thickened water (n = 8) survived. A mild increase in intra-alveolar hemorrhage was observed for the animals instilled with CS-thickened water compared to the other groups (P < .05). In the groups that survived to the endpoint of the study, instillation of water thickened with XG resulted in greater pulmonary inflammation, pulmonary interstitial congestion, and alveolar edema than water alone (P < .05). CONCLUSIONS: These data suggest that 3 consecutive days of 1.5 mg/kg of aspirated CS-thickened water are fatal, and that XG-thickened water is more injurious than aspirated water alone. Additional research is necessary to further delineate the dangers of aspirated thickened liquids. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:327-331, 2018.