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ROCKVILLE, MD, United States

Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 225.00K | Year: 2014

Project Summary Human respiratory syncytial virus (RSV) is recognized as the single most important viral cause of acute respiratory disease in infants and young children worldwide. Elderly populations and immunocompromised individuals are also at significant risk for serious RSV disease. Despite this very substantial disease burden imposed by RSV worldwide, there are no vaccines available. Several problems have impeded RSV vaccine development. First is safety. An early formalin-inactivated vaccine (FI-RSV)predisposed infants to more severe disease upon natural exposure to live virus resulting in concerns about the safety of all subsequently developed RSV vaccines, particularly nonreplicating vaccines. A second problem is a lack of understanding of requirements for stimulation protective responses making efficacy of new vaccine candidates difficult to predict. A third problem is the failure of RSV infections as well as many vaccine candidates to stimulate long-term, protective immune responses. This propos

Blanco J.C.G.,Sigmovir Biosystems, Inc. | Boukhvalova M.S.,Sigmovir Biosystems, Inc. | Perez D.R.,University of Maryland University College | Vogel S.N.,University of Maryland, Baltimore | Kajon A.,Lovelace Respiratory Research Institute
Journal of Antivirals and Antiretrovirals | Year: 2014

For over three decades, cotton rats have been a preferred model for human Respiratory Syncytial Virus (RSV) infection and pathogenesis, and a reliable model for an impressive list of human respiratory pathogens including adenoviruses, para influenza virus, measles, and human metapneumo virus. The most significant contribution of the cotton rat to biomedical research has been the development of anti-RSV antibodies for prophylactic use in high-risk infants. More recently, however, the cotton rat model has been further explored as a model for infection with other respiratory viral pathogens including influenza and rhinovirus. Together with RSV, these viruses inflict the greatest impact on the human respiratory health. This review will focus on the characteristics of these new models and their potential contribution to the development of new therapies. © 2014 Blanco JCG, et al.

Shirey K.A.,University of Maryland, Baltimore | Lai W.,University of Maryland, Baltimore | Pletneva L.M.,Sigmovir Biosystems, Inc. | Finkelman F.D.,Cincinnati Veterans Affairs Medical Center | And 5 more authors.
Journal of Leukocyte Biology | Year: 2014

RSV is the most significant cause of serious lower respiratory tract infection in infants and young children worldwide. There is currently no vaccine for the virus, and antiviral therapy (e.g., ribavirin) has shown no efficacy against the disease. We reported that alternatively activated macrophages (AAMs) mediate resolution of RSV-induced pathology. AAM differentiation requires macrophage-derived IL-4 and-13, autocrine/paracrine signaling through the type I IL-4 receptor, and STAT6 activation. Based on these findings, we reasoned that it would be possible to intervene therapeutically in RSV disease by increasing AAM differentiation, thereby decreasing lung pathology. Mice treated with the IL-4/anti-IL-4 immune complexes, shown previously to sustain levels of circulating IL-4, increased the RSVinduced AAM markers arginase-1 and mannose receptor and decreased the lung pathology. Induction of PPARΓ, shown to play a role in AAM development, by the PPARΓagonist rosiglitazone or treatment of mice with the macrolide antibiotic AZM, also reported to skew macrophage differentiation to an AAM phenotype, increased the AAM markers and mitigated RSV-induced lung pathology. Collectively, our data suggest that therapeutic manipulation of macrophage differentiation to enhance the AAM phenotype is a viable approach for ameliorating RSV-induced disease. © Society for Leukocyte Biology.

Hubner M.P.,Uniformed Services University of the Health Sciences | Hubner M.P.,University of Bonn | Killoran K.E.,Uniformed Services University of the Health Sciences | Rajnik M.,Uniformed Services University of the Health Sciences | And 11 more authors.
PLoS Neglected Tropical Diseases | Year: 2012

Background: Chronic helminth infections induce a Th2 immune shift and establish an immunoregulatory milieu. As both of these responses can suppress Th1 immunity, which is necessary for control of Mycobacterium tuberculosis (MTB) infection, we hypothesized that chronic helminth infections may exacerbate the course of MTB. Methodology/Principal Findings: Co-infection studies were conducted in cotton rats as they are the natural host for the filarial nematode Litomosoides sigmodontis and are an excellent model for human MTB. Immunogical responses, histological studies, and quantitative mycobacterial cultures were assessed two months after MTB challenge in cotton rats with and without chronic L. sigmodontis infection. Spleen cell proliferation and interferon gamma production in response to purified protein derivative were similar between co-infected and MTB-only infected animals. In contrast to our hypothesis, MTB loads and occurrence and size of lung granulomas were not increased in co-infected animals. Conclusions/Significance: These findings suggest that chronic filaria infections do not exacerbate MTB infection in the cotton rat model. While these results suggest that filaria eradication programs may not facilitate MTB control, they indicate that it may be possible to develop worm-derived therapies for autoimmune diseases that do not substantially increase the risk for infections.

Boukhvalova M.,Sigmovir Biosystems, Inc. | Blanco J.C.G.,Sigmovir Biosystems, Inc. | Falsey A.R.,Rochester General Hospital | Mond J.,ADMA Biologics
Bone Marrow Transplantation | Year: 2016

Respiratory syncytial virus (RSV) is a significant cause of bronchiolitis and pneumonia in several high health risk populations, including infants, elderly and immunocompromised individuals. Mortality in hematopoietic stem cell transplant recipients with lower respiratory tract RSV infection can exceed 80%. It has been shown that RSV replication in immunosuppressed individuals is significantly prolonged, but the contribution of pulmonary damage, if any, to the pathogenesis of RSV disease in this susceptible population is not known. In this work, we tested RI-002, a novel standardized Ig formulation containing a high level of RSV-neutralizing Ab, for its ability to control RSV infection in immunocompromised cotton rats Sigmodon hispidus. Animals immunosuppressed by repeat cyclophosphamide injections were infected with RSV and treated with RI-002. Prolonged RSV replication, characteristic of immunosuppressed cotton rats, was inhibited by RI-002 administration. Ab treatment reduced detection of systemic dissemination of viral RNA. Importantly, pulmonary interstitial inflammation and epithelial hyperplasia that were significantly elevated in immunosuppressed animals were reduced by RI-002 administration. These results indicate the potential of RI-002 to improve outcome of RSV infection in immunocompromised subjects not only by controlling viral replication, but also by reducing damage to lung parenchyma and epithelial airway lining, but further studies are needed. © 2016 Macmillan Publishers Limited. All rights reserved.

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