Safety, efficacy, and immunogenicity of an inactivated influenza vaccine in healthy adults: a randomized, placebo-controlled trial over two influenza seasons

<p>Abstract</p> <p>Background</p> <p>Seasonal influenza imposes a substantial personal morbidity and societal cost burden. Vaccination is the major strategy for influenza prevention; however, because antigenically drifted influenza A and B viruses circulate annually, influenza vaccines must be updated to provide protection against the predicted prevalent strains for the next influenza season. The aim of this study was to assess the efficacy, safety, reactogenicity, and immunogenicity of a trivalent inactivated split virion influenza vaccine (TIV) in healthy adults over two influenza seasons in the US.</p> <p>Methods</p> <p>The primary endpoint of this double-blind, randomized study was the average efficacy of TIV versus placebo for the prevention of vaccine-matched, culture-confirmed influenza (VMCCI) across the 2005-2006 and 2006-2007 influenza seasons. Secondary endpoints included the prevention of laboratory-confirmed (defined by culture and/or serology) influenza, as well as safety, reactogenicity, immunogenicity, and consistency between three consecutive vaccine lots. Participants were assessed actively during both influenza seasons, and nasopharyngeal swabs were collected for viral culture from individuals with influenza-like illness. Blood specimens were obtained for serology one month after vaccination and at the end of each influenza season's surveillance period.</p> <p>Results</p> <p>Although the point estimate for efficacy in the prevention of all laboratory-confirmed influenza was 63.2% (97.5% confidence interval [CI] lower bound of 48.2%), the point estimate for the primary endpoint, efficacy of TIV against VMCCI across both influenza seasons, was 46.3% with a 97.5% CI lower bound of 9.8%. This did not satisfy the pre-specified success criterion of a one-sided 97.5% CI lower bound of >35% for vaccine efficacy. The VMCCI attack rates were very low overall at 0.6% and 1.2% in the TIV and placebo groups, respectively. Apart from a mismatch for influenza B virus lineage in 2005-2006, there was a good match between TIV and the circulating strains. TIV was highly immunogenic, and immune responses were consistent between three different TIV lots. The most common reactogenicity events and spontaneous adverse events were associated with the injection site, and were mild in severity.</p> <p>Conclusions</p> <p>Despite a good immune response, and an average efficacy over two influenza seasons against laboratory-confirmed influenza of 63.2%, the pre-specified target (lower one-sided 97.5% confidence bound for efficacy > 35%) for the primary efficacy endpoint, the prevention of VMCCI, was not met. However, the results should be interpreted with caution in view of the very low attack rates we observed at the study sites in the 2005-2006 and 2006-2007, which corresponded to relatively mild influenza seasons in the US. Overall, the results showed that TIV has an acceptable safety profile and offered clinical benefit that exceeded risk.</p> <p>Trial registration</p> <p>NCT00216242</p

Self-Organization of Muscle Cell Structure and Function

The organization of muscle is the product of functional adaptation over several length scales spanning from the sarcomere to the muscle bundle. One possible strategy for solving this multiscale coupling problem is to physically constrain the muscle cells in microenvironments that potentiate the organization of their intracellular space. We hypothesized that boundary conditions in the extracellular space potentiate the organization of cytoskeletal scaffolds for directed sarcomeregenesis. We developed a quantitative model of how the cytoskeleton of neonatal rat ventricular myocytes organizes with respect to geometric cues in the extracellular matrix. Numerical results and in vitro assays to control myocyte shape indicated that distinct cytoskeletal architectures arise from two temporally-ordered, organizational processes: the interaction between actin fibers, premyofibrils and focal adhesions, as well as cooperative alignment and parallel bundling of nascent myofibrils. Our results suggest that a hierarchy of mechanisms regulate the self-organization of the contractile cytoskeleton and that a positive feedback loop is responsible for initiating the break in symmetry, potentiated by extracellular boundary conditions, is required to polarize the contractile cytoskeleton

Soft Matrices Suppress Cooperative Behaviors among Receptor-Ligand Bonds in Cell Adhesion

The fact that biological tissues are stable over prolonged periods of time while individual receptor-ligand bonds only have limited lifetime underscores the critical importance of cooperative behaviors of multiple molecular bonds, in particular the competition between the rate of rupture of closed bonds (death rate) and the rate of rebinding of open bonds (birth rate) in a bond cluster. We have recently shown that soft matrices can greatly increase the death rate in a bond cluster by inducing severe stress concentration near the adhesion edges. In the present paper, we report a more striking effect that, irrespective of stress concentration, soft matrices also suppress the birth rate in a bond cluster by increasing the local separation distance between open bonds. This is shown by theoretical analysis as well as Monte Carlo simulations based on a stochastic-elasticity model in which stochastic descriptions of molecular bonds and elastic descriptions of interfacial force/separation are unified in a single modeling framework. Our findings not only are important for understanding the role of elastic matrices in cell adhesion, but also have general implications on adhesion between soft materials

Estimation of Parent Specific DNA Copy Number in Tumors using High-Density Genotyping Arrays

Chromosomal gains and losses comprise an important type of genetic change in tumors, and can now be assayed using microarray hybridization-based experiments. Most current statistical models for DNA copy number estimate total copy number, which do not distinguish between the underlying quantities of the two inherited chromosomes. This latter information, sometimes called parent specific copy number, is important for identifying allele-specific amplifications and deletions, for quantifying normal cell contamination, and for giving a more complete molecular portrait of the tumor. We propose a stochastic segmentation model for parent-specific DNA copy number in tumor samples, and give an estimation procedure that is computationally efficient and can be applied to data from the current high density genotyping platforms. The proposed method does not require matched normal samples, and can estimate the unknown genotypes simultaneously with the parent specific copy number. The new method is used to analyze 223 glioblastoma samples from the Cancer Genome Atlas (TCGA) project, giving a more comprehensive summary of the copy number events in these samples. Detailed case studies on these samples reveal the additional insights that can be gained from an allele-specific copy number analysis, such as the quantification of fractional gains and losses, the identification of copy neutral loss of heterozygosity, and the characterization of regions of simultaneous changes of both inherited chromosomes

Plastic accumulation in the Mediterranean Sea

Concentrations of floating plastic were measured throughout the Mediterranean Sea to assess whether this basin can be regarded as a great accumulation region of plastic debris. We found that the average density of plastic (1 item per 4 m2), as well as its frequency of occurrence (100% of the sites sampled), are comparable to the accumulation zones described for the five subtropical ocean gyres. Plastic debris in the Mediterranean surface waters was dominated by millimeter-sized fragments, but showed a higher proportion of large plastic objects than that present in oceanic gyres, reflecting the closer connection with pollution sources. The accumulation of floating plastic in the Mediterranean Sea (between 1,000 and 3,000 tons) is likely related to the high human pressure together with the hydrodynamics of this semi-enclosed basin, with outflow mainly occurring through a deep water layer. Given the biological richness and concentration of economic activities in the Mediterranean Sea, the affects of plastic pollution on marine and human life are expected to be particularly frequent in this plastic accumulation region

Seasonal Influenza Vaccine and Protection against Pandemic (H1N1) 2009-Associated Illness among US Military Personnel

INTRODUCTION: A novel A/H1N1 virus is the cause of the present influenza pandemic; vaccination is a key countermeasure, however, few data assessing prior seasonal vaccine effectiveness (VE) against the pandemic strain of H1N1 (pH1N1) virus are available. MATERIALS AND METHODS: Surveillance of influenza-related medical encounter data of active duty military service members stationed in the United States during the period of April-October 2009 with comparison of pH1N1-confirmed cases and location and date-matched controls. Crude odds ratios (OR) and VE estimates for immunized versus non-immunized were calculated as well as adjusted OR (AOR) controlling for sex, age group, and history of prior influenza vaccination. Separate stratified VE analyses by vaccine type (trivalent inactivated [TIV] or live attenuated [LAIV]), age groups and hospitalization status were also performed. For the period of April 20 to October 15, 2009, a total of 1,205 cases of pH1N1-confirmed cases were reported, 966 (80%) among males and over one-half (58%) under 25 years of age. Overall VE for service members was found to be 45% (95% CI, 33 to 55%). Immunization with prior season's TIV (VE = 44%, 95% CI, 32 to 54%) as well as LAIV (VE = 24%, 95% CI, 6 to 38%) were both found to be associated with protection. Of significance, VE against a severe disease outcome was higher (VE = 62%, 95% CI, 14 to 84%) than against milder outcomes (VE = 42%, 95% CI, 29 to 53%). CONCLUSION: A moderate association with protection against clinically apparent, laboratory-confirmed Pandemic (H1N1) 2009-associated illness was found for immunization with either TIV or LAIV 2008-09 seasonal influenza vaccines. This association with protection was found to be especially apparent for severe disease as compared to milder outcome, as well as in the youngest and older populations. Prior vaccination with seasonal influenza vaccines in 2004-08 was also independently associated with protection

Search for Charged Higgs Bosons in e+e- Collisions at \sqrt{s} = 189 GeV

A search for pair-produced charged Higgs bosons is performed with the L3 detector at LEP using data collected at a centre-of-mass energy of 188.6 GeV, corresponding to an integrated luminosity of 176.4 pb^-1. Higgs decays into a charm and a strange quark or into a tau lepton and its associated neutrino are considered. The observed events are consistent with the expectations from Standard Model background processes. A lower limit of 65.5 GeV on the charged Higgs mass is derived at 95 % confidence level, independent of the decay branching ratio Br(H^{+/-} -> tau nu)

Integrin-Specific Mechanoresponses to Compression and Extension Probed by Cylindrical Flat-Ended AFM Tips in Lung Cells

Cells from lung and other tissues are subjected to forces of opposing directions that are largely transmitted through integrin-mediated adhesions. How cells respond to force bidirectionality remains ill defined. To address this question, we nanofabricated flat-ended cylindrical Atomic Force Microscopy (AFM) tips with ∼1 µm2 cross-section area. Tips were uncoated or coated with either integrin-specific (RGD) or non-specific (RGE/BSA) molecules, brought into contact with lung epithelial cells or fibroblasts for 30 s to form focal adhesion precursors, and used to probe cell resistance to deformation in compression and extension. We found that cell resistance to compression was globally higher than to extension regardless of the tip coating. In contrast, both tip-cell adhesion strength and resistance to compression and extension were the highest when probed at integrin-specific adhesions. These integrin-specific mechanoresponses required an intact actin cytoskeleton, and were dependent on tyrosine phosphatases and Ca2+ signaling. Cell asymmetric mechanoresponse to compression and extension remained after 5 minutes of tip-cell adhesion, revealing that asymmetric resistance to force directionality is an intrinsic property of lung cells, as in most soft tissues. Our findings provide new insights on how lung cells probe the mechanochemical properties of the microenvironment, an important process for migration, repair and tissue homeostasis