Safety and immunogenicity of heterologous prime-boost immunization with viral-vectored malaria vaccines adjuvanted with Matrix-M™

The use of viral vectors in heterologous prime-boost regimens to induce potent T cell responses in addition to humoral immunity is a promising vaccination strategy in the fight against malaria. We conducted an open-label, first-in-human, controlled Phase I study evaluating the safety and immunogenicity of Matrix-M adjuvanted vaccination with a chimpanzee adenovirus serotype 63 (ChAd63) prime followed by a modified vaccinia Ankara (MVA) boost eight weeks later, both encoding the malaria ME-TRAP antigenic sequence (a multiple epitope string fused to thrombospondin-related adhesion protein). Twenty-two healthy adults were vaccinated intramuscularly with either ChAd63-MVA ME-TRAP alone (n = 6) or adjuvanted with 25 μg (n = 8) or 50 μg (n = 8) Matrix-M. Vaccinations appeared to be safe and generally well tolerated, with the majority of local and systemic adverse events being mild in nature. The addition of Matrix-M to the vaccine did not increase local reactogenicity; however, systemic adverse events were reported more frequently by volunteers who received adjuvanted vaccine in comparison to the control group. T cell ELISpot responses peaked at 7-days post boost vaccination with MVA ME-TRAP in all three groups. TRAP-specific IgG responses were highest at 28-days post boost with MVA ME-TRAP in all three groups. There were no differences in cellular and humoral immunogenicity at any of the time points between the control group and the adjuvanted groups. We demonstrate that Matrix-M can be safely used in combination with ChAd63-MVA ME-TRAP heterologous prime-boost immunization without any reduction in cellular or humoral immunogenicity.Clinical Trials Registration NCT01669512.     

Safety,tolerability and efficacy of intradermal rabies immunization with DebioJect™

In a single-center study, 66 healthy volunteers aged between 18 and 50 years were randomized to be immunized against rabies with three different injection routes: intradermal with DebioJect™ (IDJ), standard intradermal with classical needle (IDS), also called Mantoux method, and intramuscular with classical needle (IM). “Vaccin rabique Pasteur®” and saline solution (NaCl 0.9%) were administered at D0, D7 and D28. Antigen doses for both intradermal routes were 1/5 of the dose for IM. Tolerability, safety and induced immunogenicity of IDJ were compared to IDS and IM routes. Pain was evaluated at needle insertion and at product injection for all vaccination visits. Solicited Adverse Event (SolAE) and local reactogenicity symptoms including pain, redness and pruritus were recorded daily following each vaccination visit. Adverse events (AE) were recorded over the whole duration of the study. Humoral immune response was measured by assessing the rabies virus neutralizing antibody (VNA) titers using Rapid Fluorescent Focus Inhibition Test (RFFIT). Results demonstrated that the DebioJect™ is a safe, reliable and efficient device. Significant decreases of pain at needle insertion and at vaccine injection were reported with IDJ compared to IDS and IM. All local reactogenicity symptoms (pain, redness and pruritus) after injection with either vaccine or saline solution, were similar for IDJ and IDS, except that IDJ injection induced more redness 30 min after saline solution.No systemic SolAE was deemed related to DebioJect™ and classical needles. No AE was deemed related to DebioJect™. No Serious Adverse Event (SAE) was reported during the study.At the end of the study all participants were considered immunized against rabies and no significant difference in humoral response was observed between the 3 studied routes.     

Use of Microtox™for assessing copper complexation with organic compounds

Microtox bioassay was used for assessing the complexation of copper with organic compounds including humic acids and corn root exudates. The bioassay, based on reduction of bacterial luminescence in the presence of toxicants, consists of determining the toxicity of organo-metallic complexes and thus assessing the bioavailability of copper to the test bacteria. Natural organic compounds reduced the extent of copper toxicity. Thus, Microtox can be used as a rapid tool for assessing the interactions of heavy metals with organic ligands.     

The Concurrent Validity of the ERGOS™ Work Simulator and the Ergo-Kit® with Respect to Maximum Lifting Capacity

The aim of this study was to investigate the concurrent validity—as regarding maximum lifting capacity—between the Functional Capacity Evaluation (FCE) methods, ERGOS Work Simulator and Ergo-Kit^®. Twenty-five healthy, male fire fighters participated. Dynamic lower and upper lifting capacities were determined using both FCE methods. Paired t tests showed the mean maximum lifting capacities to be significantly higher statistically when determined by the Ergo-Kit^® for lower, as well as, upper lifting. Spearman rank correlation coefficients varied between 0.49 and 0.66. It was concluded that the concurrent validity for lifting between both FCE methods was poor.     

Development and validation of a specific quality of life module in post-menopausal women with osteoporosis: The QUALIOST™

Established post-menopausal osteoporosis (PMO) has serious consequences on health related quality of life (HRQL), as long-term back and joint pain can severely limit normal activities. The quality of life questionnaire in osteoporosis (QUALIOST^™), a self-administered module consisting of 23 questions which complements the SF-36, was specifically designed to evaluate the repercussions of PMO on patient HRQL. The QUALIOST^™ was developed simultaneously in French and English after discussion with 45 patients. A validation study in France and the UK included 140 women with PMO, with at least one osteoporotic vertebral fracture. Patients completed the SF-36 and QUALIOST^™ twice, 7 days apart. Factorial analysis revealed a physical and emotional component. Three scores were calculated: physical repercussions (10 items), emotional repercussions (13 items) and the global score (23 items). Internal reliability and stability over time were excellent. Concurrent validity with the SF-36 physical and mental fields was satisfactory. A deterioration in clinical state, as measured by pain severity, hospital admission and walking stick use, increased the repercussions on HRQL for all three scores, demonstrating the clinical validity of the questionnaire. The QUALIOST^™, combined with the SF-36, is a valid rating scale for measuring HRQL in clinical trials for established PMO, providing both general and specific data on the effects of PMO on patient HRQL. This revised version was published online in June 2006 with corrections to the Cover Date.     

Contraceptive efficacy and safety of HerbOshield™ vaginal gel in rats

BackgroundSpermicides represent one of the methods of contraception. The synthetic agents available as spermicides produce severe side effects. Hence, there is a need to replace these agents with safe and effective agents such as plant-based contraceptive agents.Study DesignThe objective of the present study was to develop and evaluate a stable, safe, effective and easily acceptable contraceptive delivery system containing herbal drug. Efforts were made to evaluate the contraceptive potential of the hydroalcoholic extract from the seeds of Annona squamosa Linn. and the vaginal gel HerbOshield? containing the extract.ResultsSpermicidal effect was evaluated in vitro using healthy human spermatozoa and in vivo in rats. The in vitro results demonstrated that HerbOshield? vaginal gel is an effective spermicide. At a 100-mg/mL dose, complete immobilization of human spermatozoa was observed within 20 s. None of the treated animals conceived, indicating 100% contraceptive effect as compared to Gynol II, a nonoxynol-9-containing marketed formulation, which showed only 67% contraceptive effect in vivo. HerbOshield? vaginal gel was found to be safe in animals during a 14-day toxicity study.ConclusionsHerbOshield? vaginal gel was found to be safe and effective in rats and could be developed as a potential vaginal contraceptive for future use in humans.     

The PedsQL™ Family Impact Module: Preliminary reliability and validity

Background

The PedsQL? Measurement Model was designed to measure health-related quality of life (HRQOL) in children and adolescents. The PedsQL? 4.0 Generic Core Scales were developed to be integrated with the PedsQL? Disease-Specific Modules. The newly developed PedsQL? Family Impact Module was designed to measure the impact of pediatric chronic health conditions on parents and the family. The PedsQL? Family Impact Module measures parent self-reported physical, emotional, social, and cognitive functioning, communication, and worry. The Module also measures parent-reported family daily activities and family relationships.

Methods

The 36-item PedsQL? Family Impact Module was administered to 23 families of medically fragile children with complex chronic health conditions who either resided in a long-term care convalescent hospital or resided at home with their families.

Results

Internal consistency reliability was demonstrated for the PedsQL? Family Impact Module Total Scale Score (α = 0.97), Parent HRQOL Summary Score (α = 0.96), Family Functioning Summary Score (α = 0.90), and Module Scales (average α = 0.90, range = 0.82 – 0.97). The PedsQL? Family Impact Module distinguished between families with children in a long-term care facility and families whose children resided at home.

Conclusions

The results demonstrate the preliminary reliability and validity of the PedsQL? Family Impact Module in families with children with complex chronic health conditions. The PedsQL? Family Impact Module will be further field tested to determine the measurement properties of this new instrument with other pediatric chronic health conditions.

     

Using Walk Score™ and Neighborhood Perceptions to Assess Walking Among Middle-Aged and Older Adults

We aimed to determine the relationship between neighborhood characteristics (walkability, cohesion/safety) and recommended activity levels among community-dwelling middle-aged and older adults. Subjective and objective data on 394 individuals aged ≥50 years were used to assess the likelihood of walking ≥150 min/week. Environmental factors associated with a greater likelihood of any walking ≥150 min/week included living in a neighborhood with high perception of cohesion/safety versus low, living in walkable areas versus car-dependent, and living in an area with a low-moderate median income versus the lowest. Middle-aged and older adults were more likely to walk ≥150 min/week in a walkable, perceived safe/cohesive neighborhood. Identifying neighborhood factors associated with promoting walking among this population can enable stakeholders (e.g., researchers, planners, and policy makers) to direct interventions focusing on the built environment.     

Reliability and validity of the PedsQL™ Multidimensional Fatigue Scale in Japan

Purpose  

To examine the reliability and validity of the Japanese-language version of the PedsQL™ Multidimensional Fatigue Scale and to investigate the agreement between child self-reported fatigue and parent proxy-reported fatigue.     

The effects of the organophosphorous insecticides Dursban™ and Lorsban™ on the ciliated epithelium of the frog palate In Vitro

The ciliotoxic potential of the organophosphorous insecticides Dursban and Lorsban, their active ingredient, chlorpyrifos, and their carrier ingredients (Blanks) were assessed. Since chlorpyrifos inhibits acetylcholinesterase, the acetylcholine-innervated ciliated epithelial cultures of frog palate were used as the model. All compounds caused a decrease in frequency of ciliary beat over time. EC₅₀ values followed the same order as the time to inhibition. The orders were Lorsban > Dursban > chlorpyrifos, and Lorsban > Dursban Lorsban Blank > Dursban Blank. Stimulation of ciliary beating occurred immediately after exposure to all compounds, followed by inhibition. Dursban, Lorsban, and both Blanks elicited stimulatory effects in the presence of atropine. Atropine only blocked the initial stimulatory response with chlorpyrifos. In addition to chlorpyrifos, some component(s) of the inert ingredients were initially stimulatory but ultimately inhibitory to ciliary beating in the frog palate model. All compounds caused mitochondrial damage, including swelling, disruption of cristae, and loss of matrix.     

A gold glyco-nanoparticle carrying a listeriolysin O peptide and formulated with Advax™ delta inulin adjuvant induces robust T-cell protection against listeria infection

In the search for an effective vaccine against the human pathogen, Listeria monocytogenes (Listeria), gold glyconanoparticles (GNP) loaded with a listeriolysin O peptide LLO_91–99 (GNP-LLO) were used to immunise mice, initially using a dendritic cell (DC) vaccine approach, but subsequently using a standard parenteral immunisation approach. To enhance vaccine immunogenicity a novel polysaccharide adjuvant based on delta inulin (Advax™) was also co-formulated with the GNP vaccine. Confirming previous results, DC loaded in vitro with GNP-LLO provided better protection against listeriosis than DC loaded in vitro using free LLO peptide. The immunogenicity of GNP-LLO loaded DC vaccines was further increased by addition of Advax™ adjuvant. However, as DC vaccines are expensive and impracticable for prophylactic use, we next asked whether the same GNP-LLO antigen could be used to directly target DC in vivo. Immunisation of mice with GNP-LLO plus Advax™ adjuvant induced LLO-specific T-cell immunity and protection against Listeria challenge. Protection correlated with an increased frequency of splenic CD4⁺ and CD8⁺ T cells, NK cells and CD8α⁺ DC, and Th1 cytokine production (IL-12, IFN-γ, TNF-α, and MCP-1), post-challenge. Enhanced T-cell epitope recruitment post-challenge was seen in the groups that received Advax™ adjuvant. Immunisation with GNP-LLO_91–99 plus Advax™ adjuvant provided equally robust Listeria protection as the best DC vaccine strategy but without the complexity and cost, making this a highly promising strategy for development of a prophylactic vaccine against listeriosis.     

<Emphasis Type="Italic">In Vitro</Emphasis> Biotransformation of Amitriptyline and Imipramine with Rat Hepatic S9 Fraction: Evaluation of the Toxicity with Spirotox and Thamnotoxkit F™ Tests

Pharmaceutical products, as well as their related metabolites, end up in the aquatic environment after use. Little is known about the effects and the hazard of exposure to drugs for aquatic organisms. This study was designed to assess the ecotoxicity of amitriptyline (AMI), imipramine (IMI), and their metabolites. The tested drugs were very toxic to the protozoan Spirostomum ambiguum and the crustacean Thamnocephalus platyurus with the LC50 values around 1 mg l⁻¹. Moreover, simple additivity occurs between the drugs and their N-desmethyl metabolites. Tested compounds were incubated with S9 rat hepatocyte fraction at 37°C for 4 hours. Unchanged drugs and metabolites were determined using high-pressure liquid chromatography–photodiode array detector. AMI and IMI were biotransformed almost completely. Three AMI and IMI metabolites were detected: desmethyl-, didesmethyl-, and N-oxide. The toxicity of the deproteinated reaction mixtures (TU) was compared to the toxicity equivalency units (TEU) calculated based on the concentrations of the drugs and their LC50 values. It has been demonstrated that the toxicity of mixture of metabolites to Spirotox and Thamnotoxkit F™ is higher than the predicted value calculated from the concentrations of the drugs and their N-desmethylated derivatives in the sample. The results indicate that the harmfulness of the drug metabolites should be taken into consideration in the ecotoxicological studies.     

Principles of the EOS™ X-ray machine and its use in daily orthopedic practice

The EOS? X-ray machine, based on a Nobel prize-winning invention in Physics in the field of particle detection, is capable of simultaneously capturing biplanar X-ray images by slot scanning of the whole body in an upright, physiological load-bearing position, using ultra low radiation doses. The simultaneous capture of spatially calibrated anterioposterior and lateral images allows the performance of a three-dimensional (3D) surface reconstruction of the skeletal system by a special software. Parts of the skeletal system in X-ray images and 3D-reconstructed models appear in true 1:1 scale for size and volume, thus spinal and vertebral parameters, lower limb axis lengths and angles, as well as any relevant clinical parameters in orthopedic practice could be very precisely measured and calculated. Visualization of 3D reconstructed models in various views by the sterEOS 3D software enables the presentation of top view images, through which one can analyze the rotational conditions of lower limbs, joints and spine deformities in horizontal plane and this provides revolutionary novel possibilities in orthopedic surgery, especially in spine surgery.     

The PedsQL™ Infant Scales: feasibility,internal consistency reliability,and validity in healthy and ill infants

Objective  

The PedsQL™ (Pediatric Quality of Life Inventory™) is a modular instrument designed to measure health-related quality of life (HRQOL) and disease-specific symptoms in children and adolescents ages 2–18. The new PedsQL™ Infant Scales were designed as a generic HRQOL instrument specifically for healthy and ill infants ages 1–24 months. The objective of this study was to report on the initial feasibility, internal consistency reliability, and validity of the PedsQL™ Infant Scales in healthy, acutely ill, and chronically ill infants.     

Immunogenicity and safety of LBVH0101, a new Haemophilus influenzae type b tetanus toxoid conjugate vaccine, compared with Hiberix™ in Korean infants and children: a randomized trial

Background

The World Health Organization (WHO) recommends that all countries adopt Haemophilus influenzae type b (Hib) vaccine into routine child immunization programs to protect children from the significant burden of life-threatening pneumonia and meningitis.

Methods

In this blind, comparative, randomized, phase-III Korean multicenter study, we assessed immunogenicity and safety following primary vaccination of a new H. influenzae type b tetanus toxoid conjugate vaccine, LBVH0101 (LG Life Sciences, Ltd., Seoul, Korea) compared with Hiberix™ (GSK, Rixensart, Belgium) in Korean children at 2, 4 and 6 months of age followed by a booster vaccination at 12–15 months. Serum anti-PRP IgG concentration and bactericidal activity were determined. Local/systemic symptoms were assessed after vaccination. Serious adverse events were recorded throughout the study.

Results

A total of 185 infants were included in immunogenicity evaluations. After the second and third doses of LBVH0101, 90.32% and 100% of infants achieved an antibody level ≥1 μg/mL, respectively, compared with 78.26% and 96.74% of those who received Hiberix™. After the second vaccination, the geometric mean concentration (GMC) of LBVH0101 recipients was 7.34 μg/mL and was higher than that of Hiberix™ recipients (3.55 μg/mL). After the third vaccination, the GMCs were 14.59 μg/mL and 12.15 μg/mL in the LBVH0101 and Hiberix™ recipients, respectively. The booster dose produced higher antibody concentrations: 30.25 μg/mL and 71.64 μg/mL for LBVH0101 and Hiberix™ recipients, respectively. Bactericidal capacity and antibody potency of anti-PRP IgG induced by LBVH0101 was 35.05 and 116.27 after the second and third vaccinations, respectively, compared with 53.76 and 79.64 for Hiberix™. Anti-PRP IgG seroprotection rate and GMC were similar post-primary immunization between the groups; both showed functional maturation and similar booster responses. LBVH0101 had comparable safety results as the control vaccine, Hiberix™, as most of the solicited adverse events and unsolicited adverse events upon LBVH0101 administration were mild in severity. No serious vaccination-related adverse reactions were observed.

Conclusions

LBVH0101 showed a good immunogenicity and safety profile in infants and children. The two-dose infant-priming schedule with a booster dose may suffice for Hib immunization in Korean infants (Clinical trial registration numbers: NCT01019772 and NCT01251133).     

Novel hemagglutinin nanoparticle influenza vaccine with Matrix-M™ adjuvant induces hemagglutination inhibition,neutralizing, and protective responses in ferrets against homologous and drifted A(H3N2) subtypes

Influenza viruses frequently acquire mutations undergoing antigenic drift necessitating annual evaluation of vaccine strains. Highly conserved epitopes have been identified in the hemagglutinin (HA) head and stem regions, however, current influenza vaccines induce only limited responses to these conserved sites. Here, we describe a novel seasonal recombinant HA nanoparticle influenza vaccine (NIV) formulated with a saponin-based adjuvant, Matrix-M™. NIV induced hemagglutination inhibition (HAI) and microneutralizing (MN) antibodies against a broad range of influenza A(H3N2) subtypes. In a comparison of NIV against standard-dose and high-dose inactivated influenza vaccines (IIV and IIV-HD, respectively) in ferrets NIV elicited HAI and MN responses exceeding those induced by IIV-HD against homologous A(H3N2) by 7 fold, A(H1N1) by 26 fold, and B strain viruses by 2 fold. NIV also induced MN responses against all historic A/H3N2 strains tested, spanning more than a decade of viral evolution from the 2000–2017 influenza seasons whereas IIV and IIV-HD induced HAI and MN responses were largely directed against the homologous A(H3N2), A(H1N1), and B virus strains. NIV induced superior protection compared to IIV and IIV-HD in ferrets challenged with a homologous or 10-year drifted influenza A(H3N2) strain. HAI positive and HAI negative neutralizing monoclonal antibodies derived from mice immunized with NIV were active against homologous and drifted influenza A(H3N2) strains. Taken together these observations suggest that NIV can induce responses to one or more highly conserved HA head and stem epitopes and result in highly neutralizing antibodies against both homologous and drift strains.