A conservative approach to leveraging external evidence for effective clinical trial design.

Prior probabilities of clinical hypotheses are not systematically used for clinical trial design yet, due to a concern that poor priors may lead to poor decisions. To address this concern, a conservative approach to Bayesian trial design is illustrated here, requiring that the operational characteristics of the primary trial outcome are stronger than the prior. This approach is complementary to current Bayesian design methods, in that it insures against prior-data conflict by defining a sample size commensurate to a discrete design prior.

What is the expected benefit of patient-centric clinical development in oncology?

The identification and quantification of predictive biomarkers characterize personalized medicine approaches and patient-centric clinical development. In practice, the sponsor needs evaluating whether biomarker-informed clinical development strategies are more likely to benefit current and future patients. To this end, a simple metric is proposed and assessed here quantifying the expected clinical benefit (ECB) of clinical development programmes.

Estimation of invasive Group B Streptococcus disease risk in young infants from case-control serological studies.

Background: Group B Streptococcus (GBS) infections are a major cause of invasive disease (IGbsD) in young infants and cause miscarriage and stillbirths. Immunization of pregnant women against GBS in addition to intrapartum antibiotic prophylaxis could prevent disease. Establishing accurate serological markers of protection against IGbsD could enable use of efficient clinical trial designs for vaccine development and licensure, without needing to undertake efficacy trials in prohibitively large number of mother-infant dyads.

Retrospective Identification of a Broad IgG Repertoire Differentiating Patients With Skin and Soft Tissue Infections From Controls.

Although the relevance of humoral immunity for protection against skin and soft tissue infections (SSTIs) has been suggested by several animal and human studies, the question of which human antibodies may be protective has so far impeded the development of a safe and effective vaccine. Because most adults have developed certain anti- antibodies due to colonization or infection, we hypothesized that the titers of antibodies to in uninfected controls would differ from those in infected patients and would also differ in infected patients from the time of acute infection to a 40-day convalescent serum. To test these hypotheses, we measured human antibody levels against a panel of 134 unique antigens comprising the surfome and secretome in subjects with active culture-confirmed SSTIs (cases) and in controls with no infection, using a novel protein microarray.

Functional activity of maternal and cord antibodies elicited by an investigational group B Streptococcus trivalent glycoconjugate vaccine in pregnant women.

Objectives: The main aim of this exploratory study was to evaluate functional activity of antibodies elicited by a maternal Group B Streptococcus (GBS) investigational vaccine composed of capsular polysaccharides Ia, Ib, and III conjugated to genetically detoxified Diphtheria toxin CRM. The second objective was to investigate the relationship between serotype-specific IgG concentrations and functional activity in maternal and cord sera.

Methods: Maternal and cord sera collected at baseline and at delivery from vaccine and placebo recipients during a double-blind placebo-controlled Phase II study (www.

Core values for vaccine evaluation.

Currently, most health economic modelling approaches tend to inadequately incorporate crucial disease-specific criteria and other attributes of benefit resulting from vaccination, which limits their utility for evaluating vaccines and, in consequence, for optimally guiding vaccine decision-making. Additionally, vaccine evaluation methods are frequently poorly standardised and non-transparent, leading to a potentially low level of accountability that can hinder acceptance of resulting decisions. To address these issues, we have considered whether it is possible to identify a set of universal vaccine-disease considerations, which we have called Core Values.

The Protective Value of Maternal Group B Streptococcus Antibodies: Quantitative and Functional Analysis of Naturally Acquired Responses to Capsular Polysaccharides and Pilus Proteins in European Maternal Sera.

Background: Group B Streptococcus (GBS) is a major cause of neonatal sepsis and meningitis. A vaccine targeting pregnant women could protect infants through placentally transferred antibodies. The association between GBS maternal antibody concentrations and the risk of neonatal infection has been investigated in US and African populations.

Expression of factor H binding protein in meningococcal strains can vary at least 15-fold and is genetically determined.

Factor H binding protein (fHbp) is a lipoprotein of Neisseria meningitidis important for the survival of the bacterium in human blood and a component of two recently licensed vaccines against serogroup B meningococcus (MenB). Based on 866 different amino acid sequences this protein is divided into three variants or two families. Quantification of the protein is done by immunoassays such as ELISA or FACS that are susceptible to the sequence variation and expression level of the protein.

Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2.

The sleep disorder narcolepsy is linked to the HLA-DQB1*0602 haplotype and dysregulation of the hypocretin ligand-hypocretin receptor pathway. Narcolepsy was associated with Pandemrix vaccination (an adjuvanted, influenza pandemic vaccine) and also with infection by influenza virus during the 2009 A(H1N1) influenza pandemic. In contrast, very few cases were reported after Focetria vaccination (a differently manufactured adjuvanted influenza pandemic vaccine).

Threshold-free estimation of functional antibody titers of a group B streptococcus opsonophagocytic killing assay.

Opsonophagocytic killing assays (OPKA) are routinely used for the quantification of bactericidal antibodies in blood serum samples. Quantification of the OPKA readout, the titer, provides the basis for the statistical analysis of vaccine clinical trials having functional immune response endpoints. Traditional OPKA titers are defined as the maximum serum dilution yielding a predefined bacterial killing threshold value, and they are estimated by fitting a dose-response model to the dilution-killing curve.

Quantification by LC-MS(E) of outer membrane vesicle proteins of the Bexsero® vaccine.

Meningococcal disease is a major cause of morbidity and mortality worldwide. Its epidemiology is currently dominated by five capsular serogroups (A, B, C, W, and Y). While effective vaccines already exist for serogroups A, C, W and Y, except for under clonal outbreaks, no vaccine was available against serogroup B.

Conjugation of a TLR7 agonist and antigen enhances protection in the S. pneumoniae murine infection model.

Next generation vaccine adjuvants include Toll like receptor agonists, which are mostly extracted from microorganisms, but synthetic small molecule TLR agonists have also been identified. However, their delivery systems have not been optimized for effective administration in conjunction with antigens. Here, we describe a novel approach in which a small molecule TLR agonist was directly conjugated to antigen to ensure effective co-delivery.

Bactericidal antibody against a representative epidemiological meningococcal serogroup B panel confirms that MATS underestimates 4CMenB vaccine strain coverage.

Background: 4CMenB (Bexsero), a vaccine developed against invasive meningococcal disease caused by capsular group B strains (MenB), was recently licensed for use by the European Medicines Agency. Assessment of 4CMenB strain coverage in specific epidemiologic settings is of primary importance to predict vaccination impact on the burden of disease. The Meningococcal Antigen Typing System (MATS) was developed to predict 4CMenB strain coverage, using serum bactericidal antibody assay with human complement (hSBA) data from a diverse panel of strains not representative of any specific epidemiology.

Predicted strain coverage of a meningococcal multicomponent vaccine (4CMenB) in Europe: a qualitative and quantitative assessment.

Background: A novel multicomponent vaccine against meningococcal capsular group B (MenB) disease contains four major components: factor-H-binding protein, neisserial heparin binding antigen, neisserial adhesin A, and outer-membrane vesicles derived from the strain NZ98/254. Because the public health effect of the vaccine, 4CMenB (Novartis Vaccines and Diagnostics, Siena, Italy), is unclear, we assessed the predicted strain coverage in Europe.

Methods: We assessed invasive MenB strains isolated mainly in the most recent full epidemiological year in England and Wales, France, Germany, Italy, and Norway.

A hybrid procedure for detecting global treatment effects in multivariate clinical trials: theory and applications to fMRI studies.

In multivariate clinical trials, a key research endpoint is ascertaining whether a candidate treatment is more efficacious than an established alternative. This global endpoint is clearly of high practical value for studies, such as those arising from neuroimaging, where the outcome dimensions are not only numerous but they are also highly correlated and the available sample sizes are typically small. In this paper, we develop a two-stage procedure testing the null hypothesis of global equivalence between treatments effects and demonstrate its application to analysing phase II neuroimaging trials.

Design and conduct of Caudwell Xtreme Everest: an observational cohort study of variation in human adaptation to progressive environmental hypoxia.

Background: The physiological responses to hypoxaemia and cellular hypoxia are poorly understood, and inter-individual differences in performance at altitude and outcome in critical illness remain unexplained. We propose a model for exploring adaptation to hypoxia in the critically ill: the study of healthy humans, progressively exposed to environmental hypobaric hypoxia (EHH). The aim of this study was to describe the spectrum of adaptive responses in humans exposed to graded EHH and identify factors (physiological and genetic) associated with inter-individual variation in these responses.

Gene expression phenotypes of atherosclerosis.

Objective: Fulfilling the promise of personalized medicine by developing individualized diagnostic and therapeutic strategies for atherosclerosis will depend on a detailed understanding of the genes and gene variants that contribute to disease susceptibility and progression. To that end, our group has developed a nonbiased approach congruent with the multigenic concept of complex diseases by identifying gene expression patterns highly associated with disease states in human target tissues.

Methods And Results: We have analyzed a collection of human aorta samples with varying degrees of atherosclerosis to identify gene expression patterns that predict a disease state or potential susceptibility.