Optimal Dosing and Dynamic Distribution of Vaccines in an Influenza Pandemic

Limited production capacity and delays inherent in vaccine development are major hurdles to the widespread use of vaccines to mitigate the effects of a new influenza pandemic. Antigen-sparing vaccines have the most potential to increase population coverage but may be less efficacious. The authors explored this trade-off by applying simple models of influenza transmission and dose response to recent clinical trial data. In this paper, these data are used to illustrate an approach to comparing vaccines on the basis of antigen supply and inferred efficacy. The effects of delays in matched vaccine availability and seroconversion on epidemic size during pandemic phase 6 were also studied. The authors infer from trial data that population benefits stem from the use of low-antigen vaccines. Delayed availability of a matched vaccine could be partially alleviated by using a 1-dose vaccination program with increased coverage and reduced time to full protection. Although less immunogenic, an overall attack rate of up to 6% lower than a 2-dose program could be achieved. However, if prevalence at vaccination is above 1%, effectiveness is much reduced, emphasizing the need for other control measures

Use of probiotics in preventing antibiotic associated diarrhoea and Clostridium difficile associated diarrhoea in spinal injury centres: An international survey of four western European countries

Probiotics may prevent antibiotic-associatedand Clostridium difficile-associated- diarrhoea (AAD/CDAD). Many spinal cord injury centres (SCICs) practitioners consider probiotics generically and may not realise that efficacy can be strain-, dose-, and disease-specific. One to four SCICs per country (depending on population size) were contacted (UK:4; the Netherlands:3; Belgium: I; Republic of Ireland: 1) to (a) determine if they stocked probiotics; (b) determine whether the use of those probiotics was evidence-based; and (c) document their C. difficile infection (CDI) practices. All nine SCICs responded to the survey (7 physicians, 3 microbiologists, 1 nurse and 2 dietitians). Five (55.5%) stocked probiotics; five different probiotics were identified. Four probiotics were preferred choice prevention o f AAD/CDAD were Lactobacillus casei Shirota (44.4%), L. casei D N -114001 (22.2%), L. acidophilus (22.2%) and a mixed-strains probiotic (Ecologic Pro-AD) (11.1%). Only one evidence base study was identified supporting the use of probiotic for prevention of AAD in SCI patients. Mean CDI cases per 10,000 patient-days were 0.307 (s.d: 0.486, range 0.00 to 1.08). Definitions of diarrhoea and CDI varied among SCICs. Stocking probiotics for the prevention of AAD / CDAD is not common. There is only one single study showing efficiency of a particular strain in SCI populations. The study highlighted the importance of using a standardised definition o f diarrhoea when conducting AAD/CDAD research

The impact of donor policies in Europe: a steady increase, but not everywhere

<p>Abstract</p> <p>Background</p> <p>Transplantable organs are scarce everywhere. Therefore, countries have developed policies to support the efficient use of potential donors. Nevertheless, the shortage of organs remains. Were these policies in vain? The aim of this study is to assess the impact of donor policies on donor procurement in 10 Western European countries from 1995 to 2005.</p> <p>Method</p> <p>To assess the impact of the donor policies we studied the conversion of potential donors into effectuated donors. 80% of the donors died from CVAs or a (traffic) accident. We considered these mortality rates to be a good proxy for potential donors. Here we call the conversion of potential donors into actual donors 'the donor efficiency rate by proxy'.</p> <p>Results</p> <p>The mortality rates for CVA and (traffic) accidents have decreased in the countries under study. At the same time, in most countries the donor efficiency rates have steadily increased. The variance in donor efficiency rates between countries has also increased from 1995 to 2005. Four countries introduced a new consent system or changed their existing system, without (visible) long-term effects.</p> <p>Conclusion</p> <p>The overall increase in donor efficiency means that the efforts to improve donor policies have paid off. However, substantial differences between countries were found. The success of donor policies in terms of the number of absolute donors is blurred by the success of policies on traffic safety and CVA treatment. It remains unclear which specific policy measures are responsible for the increase in donor efficiency rates. This increase is not related to having a presumed consent system. Furthermore, an analysis of countries that introduced a new consent system or changed their system showed no effect on donor efficiency.</p

Broad Clade 2 Cross-Reactive Immunity Induced by an Adjuvanted Clade 1 rH5N1 Pandemic Influenza Vaccine

The availability of H5N1 vaccines that can elicit a broad cross-protective immunity against different currently circulating clade 2 H5N1 viruses is a pre-requisite for the development of a successful pre-pandemic vaccination strategy. In this regard, it has recently been shown that adjuvantation of a recombinant clade 1 H5N1 inactivated split-virion vaccine with an oil-in-water emulsion-based adjuvant system also promoted cross-immunity against a recent clade 2 H5N1 isolate (A/Indonesia/5/2005, subclade 2.1). Here we further analyse the cross-protective potential of the vaccine against two other recent clade 2 isolates (A/turkey/Turkey/1/2005 and A/Anhui/1/2005 which are, as defined by WHO, representatives of subclades 2.2 and 2.3 respectively).Two doses of the recombinant A/Vietnam/1194/2004 (H5N1, clade 1) vaccine were administered 21 days apart to volunteers aged 18-60 years. We studied the cross-clade immunogenicity of the lowest antigen dose (3.8 microg haemagglutinin) given with (N = 20) or without adjuvant (N = 20). Immune responses were assessed at 21 days following the first and second vaccine doses and at 6 months following first vaccination. Vaccination with two doses of 3.8 microg of the adjuvanted vaccine induced four-fold neutralising seroconversion rates in 85% of subjects against A/turkey/Turkey/1/2005 (subclade 2.2) and 75% of subjects against A/Anhui/1/2005 (subclade 2.3) recombinant strains. There was no response induced against these strains in the non-adjuvanted group. At 6 months following vaccination, 70% and 60% of subjects retained neutralising antibodies against the recombinant subclade 2.2 and 2.3 strains, respectively and 40% of subjects retained antibodies against the recombinant subclade 2.1 A/Indonesia/5/2005 strain.In addition to antigen dose-sparing, adjuvantation of inactivated split H5N1 vaccine promotes broad and persistent cross-clade immunity which is a pre-requisite for a pre-pandemic vaccine.ClinicalTrials.gov NCT00309634

The empirical replicability of task-based fMRI as a function of sample size

Replicating results (i.e. obtaining consistent results using a new independent dataset) is an essential part of good science. As replicability has consequences for theories derived from empirical studies, it is of utmost importance to better understand the underlying mechanisms influencing it. A popular tool for non-invasive neuroimaging studies is functional magnetic resonance imaging (fMRI). While the effect of underpowered studies is well documented, the empirical assessment of the interplay between sample size and replicability of results for task-based fMRI studies remains limited. In this work, we extend existing work on this assessment in two ways. Firstly, we use a large database of 1400 subjects performing four types of tasks from the IMAGEN project to subsample a series of independent samples of increasing size. Secondly, replicability is evaluated using a multi-dimensional framework consisting of 3 different measures: (un)conditional test-retest reliability, coherence and stability. We demonstrate not only a positive effect of sample size, but also a trade-off between spatial resolution and replicability. When replicability is assessed voxelwise or when observing small areas of activation, a larger sample size than typically used in fMRI is required to replicate results. On the other hand, when focussing on clusters of voxels, we observe a higher replicability. In addition, we observe variability in the size of clusters of activation between experimental paradigms or contrasts of parameter estimates within these

Use of antibiotics and the prevalence of antibiotic-associated diarrhoea in patients with spinal cord injuries: an international, multi-centre study

BACKGROUND: Little is known about the use of antibiotics and the extent of antibiotic-associated diarrhoea (AAD) in patients with spinal cord injuries (SCIs). AIMS: To record the use of antibiotics, establish the prevalence of AAD and Clostridium difficile infection (CDI), and assess if there was any seasonal variation in antibiotic use and incidence of AAD in patients with SCIs. METHODS: A retrospective study was conducted in six European SCI centres between October 2014 and June 2015. AAD was defined as two or more watery stools (Bristol Stool Scale type 5, 6 or 7) over 24 h. FINDINGS: In total, 1267 adults (median age 54 years, 30.7% female) with SCIs (52.7% tetraplegia, 59% complete SCI) were included in this study. Among the 215 (17%) patients on antibiotics, the top three indications for antibiotics were urinary tract infections (UTIs), infected pressure ulcers and other skin infections. Thirty-two of these 215 (14.9%) patients developed AAD and two patients out of the total study population (2/1267; 0.16%) developed CDI. AAD was more common in summer than in spring, autumn or winter (30.3% vs 3.8%, 7.4% and 16.9%, respectively; P<0.01). AAD was associated with age ≥65 years, tetraplegia, higher body mass index, hypoalbuminaemia, polypharmacy, multiple antibiotic use and high-risk antibiotic use. Summer and winter seasons and male sex were identified as independent predictors for the development of AAD. CONCLUSION: This survey found that AAD is common in patients with SCIs, and UTI is the most common cause of infection. Summer and winter seasons and male sex are unique predictors for AAD. Both AAD and UTIs are potentially preventable; therefore, further work should focus on preventing the over-use of antibiotics, and developing strategies to improve hospital infection control measures

A phase II, open-label, multicentre study to evaluate the immunogenicity and safety of an adjuvanted prepandemic (H5N1) influenza vaccine in healthy Japanese adults

<p>Abstract</p> <p>Background</p> <p>Promising clinical data and significant antigen-sparing have been demonstrated for a pandemic H5N1 influenza split-virion vaccine adjuvanted with AS03_A, an α-tocopherol-containing oil-in-water emulsion-based Adjuvant System. Although studies using this formulation have been reported, there have been no data for Japanese populations. This study therefore aimed to assess the immunogenicity and tolerability of a prepandemic (H5N1) influenza vaccine adjuvanted with AS03_Ain Japanese adults.</p> <p>Methods</p> <p>This open-label, single-group study was conducted at two centres in Japan in healthy Japanese males and females aged 20-64 years (n = 100). Subjects received two doses of vaccine, containing 3.75 μg haemagglutinin of the A/Indonesia/5/2005-like IBCDC-RG2 Clade 2.1 (H5N1) strain adjuvanted with AS03_A, 21 days apart. The primary endpoint evaluated the humoral immune response in terms of H5N1 haemagglutination inhibition (HI) antibody titres against the vaccine strain (Clade 2.1) 21 days after the second dose. Ninety five percent confidence intervals for geometric mean titres, seroprotection, seroconversion and seropositivity rates were calculated. Secondary and exploratory endpoints included the assessment of the humoral response in terms of neutralising antibody titres, the response against additional H5N1 strains (Clade 1 and Clade 2.2), as well as the evaluation of safety and reactogenicity.</p> <p>Results</p> <p>Robust immune responses were elicited after two doses of the prepandemic influenza vaccine adjuvanted with AS03_A. Overall, vaccine HI seroconversion rates and seroprotection rates were 91% 21 days after the second vaccination. This fulfilled all regulatory acceptance criteria for the vaccine-homologous HI antibody level. A substantial cross-reactive humoral immune response was also observed against the virus strains A/turkey/Turkey/1/2005 (Clade 2.2) and A/Vietnam/1194/2004 (Clade 1) after the second vaccine administration. A marked post-vaccination response in terms of neutralising antibody titres was demonstrated and persistence of the immune response was observed 6 months after the first dose. The vaccine was generally well tolerated and there were no serious adverse events reported.</p> <p>Conclusions</p> <p>The H5N1 candidate vaccine adjuvanted with AS03_Aelicited a strong and persistent immune response against the vaccine strain A/Indonesia/5/2005 in Japanese adults. Vaccination with this formulation demonstrated a clinically acceptable reactogenicity profile and did not raise any safety concerns in this population.</p> <p>Trial registration</p> <p>Clinicaltrials.gov NCT00742885</p

Second international congress on immunopharmacology : delivery systems and current strategies for drug design

The 2nd International Congress on Immunopharmacology was held in June of 2011 at the Conference Center of Plaza America in Varadero, Cuba. The main goal of this meeting was to provide state-of-the-art communications for scientists, manufacturers, regulators and healthcare workers, to accelerate progress in the development of biological and biotechnological products and to promote exchange/scientific cooperation between researchers. 300 delegates from 22 countries attended the conference. The wide-ranging programme commenced with a plenary session and then split into a series of parallel workshops and symposia, covering “Advances in Immunopharmacology”, “Neuroimmunology”, “Therapeutic Biological Products”, “Prophylaxis and Treatment of Helicobacter pylori”, “Pharmacology of Cytochrome P450”, “Hereditary Ataxias” and “Delivery Systems and Current Strategies for Drug Design”. In this last Symposium, a substantial body of data was presented relating to the development of delivery systems with adjuvant and vaccine potential and also to strategies focused in therapeutic and prophylactic approaches against tuberculosis. This issue is dedicated to some of the results presented in this area

Confounders in the assessment of the renal effects associated with low-level urinary cadmium: an analysis in industrial workers

<p>Abstract</p> <p>Background</p> <p>Associations of proteinuria with low-level urinary cadmium (Cd) are currently interpreted as the sign of renal dysfunction induced by Cd. Few studies have considered the possibility that these associations might be non causal and arise from confounding by factors influencing the renal excretion of Cd and proteins.</p> <p>Methods</p> <p>We examined 184 healthy male workers (mean age, 39.5 years) from a zinc smelter (n = 132) or a blanket factory (n = 52). We measured the concentrations of Cd in blood (B-Cd) and the urinary excretion of Cd (U-Cd), retinol-binding protein (RBP), protein HC and albumin. Associations between biomarkers of metal exposure and urinary proteins were assessed by simple and multiple regression analyses.</p> <p>Results</p> <p>The medians (interquartile range) of B-Cd (μg/l) and U-Cd (μg/g creatinine) were 0.80 (0.45-1.16) and 0.70 (0.40-1.3) in smelter workers and 0.66 (0.47-0.87) and 0.55 (0.40-0.90) in blanket factory workers, respectively. Occupation had no influence on these values, which varied mainly with smoking habits. In univariate analysis, concentrations of RBP and protein HC in urine were significantly correlated with both U-Cd and B-Cd but these associations were substantially weakened by the adjustment for current smoking and the residual influence of diuresis after correction for urinary creatinine. Albumin in urine did not correlate with B-Cd but was consistently associated with U-Cd through a relationship, which was unaffected by smoking or diuresis. Further analyses showed that RBP and albumin in urine mutually distort their associations with U-Cd and that the relationship between RBP and Cd in urine was almost the replicate of that linking RBP to albumin</p> <p>Conclusions</p> <p>Associations between proteinuria and low-level urinary Cd should be interpreted with caution as they appear to be largely driven by diuresis, current smoking and probably also the co-excretion of Cd with plasma proteins.</p