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  • 1
    Language: English
    In: Science (New York, N.Y.), 12 August 2011, Vol.333(6044), pp.843-50
    Description: 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 therapies.
    Keywords: Antibodies, Monoclonal -- Immunology ; Antibodies, Neutralizing -- Immunology ; Antibodies, Viral -- Immunology ; Antigens, Viral -- Immunology ; Hemagglutinin Glycoproteins, Influenza Virus -- Immunology ; Influenza A Virus -- Immunology
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 25 November 2014, Vol.111(47), pp.16820-5
    Description: Bispecific antibodies have therapeutic potential by expanding the functions of conventional antibodies. Many different formats of bispecific antibodies have meanwhile been developed. Most are genetic modifications of the antibody backbone to facilitate incorporation of two different variable domains into a single molecule. Here, we present a bispecific format where we have fused two full-sized IgG antibodies via their C termini using sortase transpeptidation and click chemistry to create a covalently linked IgG antibody heterodimer. By linking two potent anti-influenza A antibodies together, we have generated a full antibody dimer with bispecific activity that retains the activity and stability of the two fusion partners.
    Keywords: Antibody Engineering ; Immunotherapy ; Influenza ; Click Chemistry ; Antibodies, Bispecific -- Biosynthesis ; Influenza A Virus -- Immunology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 3
    Language: English
    In: PLoS ONE, 2010, Vol.5(5), p.e10645
    Description: The highly pathogenic avian influenza (HPAI) virus H5N1 causes multi-organ disease and death in poultry, resulting in significant economic losses in the poultry industry. In addition, it poses a major public health threat as it can be transmitted directly from infected poultry to humans with very high (60%) mortality rate. Effective vaccination against HPAI H5N1 would protect commercial poultry and would thus provide an important control measure by reducing the likelihood of bird-to-bird and bird-to-human transmission. ; In the present study we evaluated the vaccine potential of recombinant soluble trimeric subtype 5 hemagglutinin (sH5) produced in mammalian cells. The secreted, purified sH5 was biologically active as demonstrated by its binding to ligands in a sialic acid-dependent manner. It was shown to protect chickens, in a dose-dependent manner, against a lethal challenge with H5N1 after a single vaccination. Protected animals did not shed challenge virus as determined by a quantitative RT-PCR on RNA isolated from trachea and cloaca swabs. Also in mice, vaccination with sH5 provided complete protection against challenge with HPAI H5N1. ; Our results demonstrate that sH5 constitutes an attractive vaccine antigen for protection of chickens and mammals against HPAI H5N1. As these recombinant soluble hemagglutinin preparations can be produced with high yields and with relatively short lead time, they enable a rapid response to circulating and potentially pandemic influenza viruses.
    Keywords: Research Article ; Virology ; Virology -- Animal Models Of Infection ; Virology -- Vaccines
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: 2012, Vol.7(8), p.e44447
    Description: Highly pathogenic avian influenza virus (HPAIV) causes a highly contagious often fatal disease in poultry, resulting in significant economic losses in the poultry industry. HPAIV H5N1 also poses a major public health threat as it can be transmitted directly from infected poultry to humans. One effective way to combat avian influenza with pandemic potential is through the vaccination of poultry. Several live vaccines based on attenuated Newcastle disease virus (NDV) that express influenza hemagglutinin (HA) have been developed to protect chickens or mammalian species against HPAIV. However, the zoonotic potential of NDV raises safety concerns regarding the use of live NDV recombinants, as the incorporation of a heterologous attachment protein may result in the generation of NDV with altered tropism and/or pathogenicity. ; In the present study we generated recombinant NDVs expressing either full length, membrane-anchored HA of the H5 subtype (NDV-H5) or a soluble trimeric form thereof (NDV-sH5). A single intramuscular immunization with NDV-sH5 or NDV-H5 fully protected chickens against disease after a lethal challenge with H5N1 and reduced levels of virus shedding in tracheal and cloacal swabs. NDV-sH5 was less protective than NDV-H5 (50% vs 80% protection) when administered via the respiratory tract. The NDV-sH5 was ineffective in mice, regardless of whether administered oculonasally or intramuscularly. In this species, NDV-H5 induced protective immunity against HPAIV H5N1, but only after oculonasal administration, despite the poor H5-specific serum antibody response it elicited. ; Although NDV expressing membrane anchored H5 in general provided better protection than its counterpart expressing soluble H5, chickens could be fully protected against a lethal challenge with H5N1 by using the latter NDV vector. This study thus provides proof of concept for the use of recombinant vector vaccines expressing a soluble form of a heterologous viral membrane protein. Such vectors may be advantageous as they preclude the incorporation of heterologous membrane proteins into the viral vector particles.
    Keywords: Research Article ; Biology ; Medicine ; Veterinary Science ; Virology ; Immunology ; Infectious Diseases ; Public Health And Epidemiology ; Biochemistry
    E-ISSN: 1932-6203
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  • 5
    Language: English
    In: Vaccine, 2009, Vol.27(28), pp.3704-3718
    Description: Porcine reproductive and respiratory syndrome virus (PRRSV) continues to be a threat for the pig industry. Vaccines have been developed, but these failed to provide sustainable disease control, in particular against genetically unrelated strains. Here we give an overview of current knowledge and gaps in our knowledge that may be relevant for the development of a future generation of more effective vaccines. PRRSV replicates in cells of the monocyte/macrophage lineage, induces apoptosis and necrosis, interferes with the induction of a proinflammatory response, only slowly induces a specific antiviral response, and may cause persistent infections. The virus appears to use several evasion strategies to circumvent both innate and acquired immunity, including interference with antigen presentation, antibody-mediated enhancement, reduced cell surface expression of viral proteins, and shielding of neutralizing epitopes. In particular the downregulation of type I interferon-α production appears to interfere with the induction of acquired immunity. Current vaccines are ineffective because they suffer both from the immune evasion strategies of the virus and the antigenic heterogeneity of field strains. Future vaccines therefore must “uncouple” the immune evasion and apoptogenic/necrotic properties of the virus from its immunogenic properties, and they should induce a broad immune response covering the plasticity of its major antigenic sites. Alternatively, the composition of the vaccine should be changed regularly to reflect presently and locally circulating strains. Preferably new vaccines should also allow discriminating infected from vaccinated pigs to support a virus elimination strategy. Challenges in vaccine development are the incompletely known mechanisms of immune evasion and immunity, lack of knowledge of viral sequences that are responsible for the pathogenic and immunosuppressive properties of the virus, lack of knowledge of the forces that drive antigenic heterogeneity and its consequences for immunogenicity, and a viral genome that is relatively intolerant for subtle changes at functional sites.
    Keywords: Porcine Reproductive and Respiratory Syndrome Virus ; Vaccination ; Vaccine Development ; Immune Evasion ; Medicine ; Biology ; Veterinary Medicine ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0264-410X
    E-ISSN: 1873-2518
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  • 6
    Language: English
    In: The Journal of infectious diseases, 15 December 2009, Vol.200(12), pp.1870-3
    Description: New strategies to prevent and treat influenza virus infections are urgently needed. A recently discovered class of monoclonal antibodies (mAbs) neutralizing an unprecedented spectrum of influenza virus subtypes may have the potential for future use in humans. Here, we assess the efficacies of CR6261, which is representative of this novel class of mAbs, and oseltamivir in mice. We show that a single injection with 15 mg/kg CR6261 outperforms a 5-day course of treatment with oseltamivir (10 mg/kg/day) with respect to both prophylaxis and treatment of lethal H5N1 and H1N1 infections. These results justify further preclinical evaluation of broadly neutralizing mAbs against influenza virus for the prevention and treatment of influenza virus infections.
    Keywords: Antibodies, Monoclonal -- Therapeutic Use ; Antibodies, Neutralizing -- Therapeutic Use ; Antibodies, Viral -- Therapeutic Use ; Antiviral Agents -- Therapeutic Use ; Orthomyxoviridae Infections -- Drug Therapy ; Oseltamivir -- Therapeutic Use
    ISSN: 00221899
    E-ISSN: 1537-6613
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  • 7
    Language: English
    In: Journal of Biomechanics, 2008, Vol.41, pp.S79-S79
    Keywords: Medicine ; Engineering ; Anatomy & Physiology
    ISSN: 0021-9290
    E-ISSN: 1873-2380
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  • 8
    Language: English
    In: Journal of Biomechanics, 2008, Vol.41(4), pp.845-853
    Description: Pressure-related deep tissue injury (DTI) represents a severe pressure ulcer, which initiates in compressed muscle tissue overlying a bony prominence and progresses to more superficial tissues until penetrating the skin. Individual subjects with impaired motor and/or sensory capacities are at high risk of developing DTI. Impaired diffusion of critical metabolites in compressed muscle tissue may contribute to DTI, and impaired diffusion of tissue damage biomarkers may further impose a problem in developing early detection blood tests. We hypothesize that compression of muscle tissue between a bony prominence and a supporting surface locally influences the diffusion capacity of muscle. The objective of this study was therefore, to determine the effects of large compression strains on free diffusion in a tissue-engineered skeletal muscle model. Diffusion was measured with a range of fluorescently labeled dextran molecules (10, 20, 150 kDa) whose sizes were representative of both hormones and damage biomarkers. We used fluorescence recovery after photobleaching (FRAP) to compare diffusion coefficients ( ) of the different dextrans between the uncompressed and compressed (48–60% strain) states. In a separate experiment, we simulated the effects of local partial muscle ischemia , by reducing the temperature of compressed specimens from 37 to 34 °C. Compared to the in the uncompressed model system, values in the compressed state were significantly reduced by 47±22% ( 〈0.02). A 3 °C temperature decrease further reduced in the compressed specimens by 10±6% ( 〈0.05). , the effects of large strains and ischemia are likely to be summative, and hence, the present findings suggest an important role of impaired diffusion in the etiology of DTI, and should also be considered when developing biochemical screening methods for early detection of DTI.
    Keywords: Pressure Ulcer ; Deep Tissue Injury ; Dextran ; Confocal Microscopy ; Frap ; Medicine ; Engineering ; Anatomy & Physiology
    ISSN: 0021-9290
    E-ISSN: 1873-2380
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  • 9
    Language: English
    In: Virology Journal, Sept 5, 2013, Vol.10(1)
    Description: Background Highly pathogenic avian influenza (HPAI) viruses pose a potential human health threat as they can be transmitted directly from infected poultry to humans. During a large outbreak of HPAI H7N7 virus among poultry in The Netherlands in 2003, bird to human transmission was confirmed in 89 cases, of which one had a fatal outcome. Methods To identify genetic determinants of virulence in a mammalian host, we passaged an avian H7N7/03 outbreak isolate in mouse lungs and evaluated the phenotype of the mouse-adapted variant in animal models and in vitro. Results Three passages in mouse lungs were sufficient to select a variant that was highly virulent in mice. The virus had a MLD.sub.50 that was 〉4.3 logs lower than that of its non-lethal parental virus. Sequence analysis revealed a single mutation at position 627 in PB2, where the glutamic acid was changed to a lysine (E627K). The mouse-adapted virus has this mutation in common with the fatal human case isolate. The virus remained highly pathogenic for chickens after its passage in mice. In ferrets, the mouse-adapted virus induced more severe disease, replicated to higher titers in the lower respiratory tract and spread more efficiently to systemic organs compared with the parental virus. In vitro, the PB2 E627K mutation had a promoting effect on virus propagation in mammalian, but not in avian cells. Conclusions Our results show that the E627K mutation in PB2 alone can be sufficient to convert an HPAI H7N7 virus of low virulence to a variant causing severe disease in mice and ferrets. The rapid emergence of the PB2 E627K mutant during mouse adaptation and its pathogenicity in ferrets emphasize the potential risk of HPAI H7N7 viruses for human health. Keywords: Avian influenza virus, Ferret, H7N7, Mouse-adaptation, Pathogenicity, PB2 E627K
    Keywords: Lysine – Analysis ; Disease Transmission – Analysis ; Glutamate – Analysis ; Virulence (Microbiology) – Analysis ; Avian Influenza – Analysis
    ISSN: 1743-422X
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  • 10
    In: Skin Research and Technology, November 2007, Vol.13(4), pp.369-376
    Description: Calcium regulates the proliferation and differentiation of keratinocytes and plays a role in restoration of the epidermal barrier function. The factors that maintain the calcium gradient are still unknown. A numerical model may give more insight into transport processes that maintain the epidermal calcium gradient. In this study, transport of free calcium in the epidermis is described with diffusion, convection and electrophoresis. Binding and release of calcium results in equilibrium between free and bound calcium. The physiological epidermal calcium gradient as well as the calcium concentration in a damaged epidermis are modeled. The typical shape of the calcium gradient in the epidermis, as found in experimental studies, was maintained when separate formulations were used for free and bound calcium. Application of damage results in a decrease of the calcium concentration, especially in the upper living epidermis. Using this model, an estimate could be made about the fraction bound calcium in the epidermis. The typical shape of the gradient is predominantly determined by the bound calcium concentration. For both a normal and a damaged epidermis, the concentration of free calcium is mainly determined by electrophoresis in the living epidermis, whereas in the largest part of the stratum corneum diffusion is the most important factor. The convection that was determined by the transepidermal water loss did not have an effect on the calcium concentration.
    Keywords: Skin ; Epidermis ; Calcium Gradient ; Transport Processes
    ISSN: 0909-752X
    E-ISSN: 1600-0846
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