New Class of Monoclonal Antibodies against Severe Influenza: Prophylactic and Therapeutic Efficacy in Ferrets

Background: The urgent medical need for innovative approaches to control influenza is emphasized by the widespread resistance of circulating subtype H1N1 viruses to the leading antiviral drug oseltamivir, the pandemic threat posed by the occurrences of human infections with highly pathogenic avian H5N1 viruses, and indeed the evolving swine-origin H1N1 influenza pandemic. A recently discovered class of human monoclonal antibodies with the ability to neutralize a broad spectrum of influenza viruses (including H1, H2, H5, H6 and H9 subtypes) has the potential to prevent and treat influenza in humans. Here we report the latest efficacy data for a representative antibody of this novel class. Methodology/Principal Findings: We evaluated the prophylactic and therapeutic efficacy of the human monoclonal antibody CR6261 against lethal challenge with the highly pathogenic avian H5N1 virus in ferrets, the optimal model of human influenza infection. Survival rates, clinically relevant disease signs such as changes in body weight and temperature, virus replication in lungs and upper respiratory tract, as well as macro- and microscopic pathology were investigated. Prophylactic administration of 30 and 10 mg/kg CR6261 prior to viral challenge completely prevented mortality, weight loss and reduced the amount of infectious virus in the lungs by more than 99.9%, abolished shedding of virus in phar

Current and next generation influenza vaccines: Formulation and production strategies

AbstractVaccination is the most effective method to prevent influenza infection. However, current influenza vaccines have several limitations. Relatively long production times, limited vaccine capacity, moderate efficacy in certain populations and lack of cross-reactivity are important issues that need to be addressed. We give an overview of the current status and novel developments in the landscape of influenza vaccines from an interdisciplinary point of view. The feasibility of novel vaccine concepts not only depends on immunological or clinical outcomes, but also depends on biotechnological aspects, such as formulation and production methods, which are frequently overlooked. Furthermore, the next generation of influenza vaccines is addressed, which hopefully will bring cross-reactive influenza vaccines. These developments indicate that an exciting future lies ahead in the influenza vaccine field

Computers and types of control in relation to work stress and learning

© 2014 © 2014 Taylor & Francis. Traditional machine-paced work shows adverse effects on worker health and learning. It is hardly known whether technological pacing shows the same effects in computer work. Hypotheses on work stress and learning were formulated regarding the effects of technological pacing, in the context of computer work performed during at least half of the working day, especially. Further, method-order (m-o) autonomy was conceived as another control and standardisation mechanism and taken into account as a potentially important modifier of the effects. As hypothesised, this study's secondary analyses of a European survey of 18,723 employees revealed that the level of adverse work stress for technological pacing among computer workers was almost equal to the level found for traditionally machine-paced workers. Distinct interactions with m-o autonomy were also shown. For instance, lack hereof was especially problematic for work stress among technologically paced computer workers. Software's flexible nature and its relatively easy adaptability to chosen work organisation modes may explain this. Lastly, in technologically paced work, m-o autonomy appeared to reinforce learning. In sum, many hypotheses were supported especially on the main and interaction effects regarding work stress, but less so regarding learning. Recommendations for future research and practical implications are discussed.status: publishe

Haemagglutinin quantification and identification of influenza A&B strains propagated in PER.C6 cells: a novel RP-HPLC method

The major antigenic determinant of influenza A and B virus is haemagglutinin (HA). The HA content is an important specification of influenza vaccines. HA in vaccines has typically been quantified by single-radial-immunodiffusion (SRID). However, SRID is a laborious and low throughput assay. Moreover, sensitivity, accuracy, and precision, especially for non-purified (in-process) influenza virus is relatively low. We present a novel method for quantification of HA in influenza viral cultures as well as for the identification of HA from individual influenza strains in trivalent vaccines. The method is based on the separation of HA(1), the hydrophilic subunit of HA, from the more hydrophobic viral and matrix components by reversed-phase high performance liquid chromatography (RP-HPLC). The HA(1) peak area is demonstrated to be proportional to the level of HA in non-purified, semi-purified and purified vaccine products of various epidemic and pandemic influenza A and B strains propagated in PER.C6((R)) cell cultures. The RP-HPLC assay selectivity allows for the simultaneous identification and quantification of HA(1) from influenza A and B strains in the yearly revised trivalent vaccines for epidemic outbreak

A highly conserved neutralizing epitope on group 2 influenza A viruses

Current flu vaccines provide only limited coverage against seasonal strains of influenza viruses. The identification of V(H)1-69 antibodies that broadly neutralize almost all influenza A group 1 viruses constituted a breakthrough in the influenza field. Here, we report the isolation and characterization of a human monoclonal antibody CR8020 with broad neutralizing activity against most group 2 viruses, including H3N2 and H7N7, which cause severe human infection. The crystal structure of Fab CR8020 with the 1968 pandemic H3 hemagglutinin (HA) reveals a highly conserved epitope in the HA stalk distinct from the epitope recognized by the V(H)1-69 group 1 antibodies. Thus, a cocktail of two antibodies may be sufficient to neutralize most influenza A subtypes and, hence, enable development of a universal flu vaccine and broad-spectrum antibody therapie

Prophylactic efficacy of CR6261 against lethal H5N1 challenge.

<p>Groups of 6 ferrets received 30, 10, 3, or 1 mg/kg of mAb CR6261 or 30 mg/kg control mAb by intravenous injection and were challenged 24 hours later with 10⁵ TCID₅₀ of influenza A/Indonesia/5/2005 (H5N1). Ferrets were monitored for 5 days or until death. Panel A: Kaplan–Meier survival probability curves. Panel B: Change in body weight at the end of study (or at death if the event occurred earlier) expressed as percentage from baseline body weight. Panel C: Maximal body temperature observed during the day after challenge. Panel D: Viral shedding of infectious virus in the upper respiratory tract. The graph shows the proportion of ferrets alive with infectious virus detected in nasal and/or throat swabs. Panel E: Viral load in lung tissue as determined by virus titration on MDCK cells. Panel F: lung weights as determined after necropsy. Dots in panels B, C, E and F represent individual animals; group means are indicated by the horizontal lines.</p