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PubMed | National Institute of Allergy and Infectious Diseases, Sigmovir Biosystems, Inc., Children's Healthcare Of Atlanta, University of North Carolina at Chapel Hill and Baylor College of Medicine
Type: Journal Article | Journal: Journal of virology | Year: 2016

Although respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants, a safe and effective vaccine is not yet available. Live-attenuated vaccines (LAVs) are the most advanced vaccine candidates in RSV-naive infants. However, designing an LAV with appropriate attenuation yet sufficient immunogenicity has proven challenging. In this study, we implemented reverse genetics to address these obstacles with a multifaceted LAV design that combined the codon deoptimization of genes for nonstructural proteins NS1 and NS2 (dNS), deletion of the small hydrophobic protein (SH) gene, and replacement of the wild-type fusion (F) protein gene with a low-fusion RSV subgroup B F consensus sequence of the Buenos Aires clade (BAF). This vaccine candidate, RSV-A2-dNS-SH-BAF (DB1), was attenuated in two models of primary human airway epithelial cells and in the upper and lower airways of cotton rats. DB1 was also highly immunogenic in cotton rats and elicited broadly neutralizing antibodies against a diverse panel of recombinant RSV strains. When vaccinated cotton rats were challenged with wild-type RSV A, DB1 reduced viral titers in the upper and lower airways by 3.8 log10 total PFU and 2.7 log10 PFU/g of tissue, respectively, compared to those in unvaccinated animals (P < 0.0001). DB1 was thus attenuated, highly immunogenic, and protective against RSV challenge in cotton rats. DB1 is the first RSV LAV to incorporate a low-fusion F protein as a strategy to attenuate viral replication and preserve immunogenicity.RSV is a leading cause of infant hospitalizations and deaths. The development of an effective vaccine for this high-risk population is therefore a public health priority. Although live-attenuated vaccines have been safely administered to RSV-naive infants, strategies to balance vaccine attenuation with immunogenicity have been elusive. In this study, we introduced a novel strategy to attenuate a recombinant RSV vaccine by incorporating a low-fusion, subgroup B F protein in the genetic background of codon-deoptimized nonstructural protein genes and a deleted small hydrophobic protein gene. The resultant vaccine candidate, DB1, was attenuated, highly immunogenic, and protective against RSV challenge in cotton rats.


Blanco J.C.G.,Sigmovir Biosystems, Inc. | Boukhvalova M.S.,Sigmovir Biosystems, Inc. | Pletneva L.M.,Sigmovir Biosystems, Inc. | Shirey K.A.,University of Maryland, Baltimore | Vogel S.N.,University of Maryland, Baltimore
Vaccine | Year: 2014

We previously demonstrated that the severe cytokine storm and pathology associated with RSV infection following intramuscular vaccination of cotton rats with FI-RSV Lot 100 could be completely abolished by formulating the vaccine with the mild TLR4 agonist and adjuvant, monophosphoryl lipid A (MPL). Despite this significant improvement, the vaccine failed to blunt viral replication in the lungs. Since MPL is a weak TLR4 agonist, we hypothesized that its adjuvant activity was mediated by modulating the innate immune response of respiratory tract resident macrophages. Therefore, we developed a new vaccine preparation with purified, baculovirus expressed, partially purified, anchorless RSV F protein formulated with synthetic MPL that was administered to cotton rats intranasally, followed by an intradermal boost. This novel formulation and heterologous "prime/boost" route of administration resulted in decreased viral titers compared to that seen in animals vaccinated with F protein alone. Furthermore, animals vaccinated by this route showed no evidence of enhanced lung pathology upon RSV infection. This indicates that MPL acts as an immune modulator that protects the host from vaccine-enhanced pathology, and reduces RSV replication in the lower respiratory tract when administered by a heterologous prime/boost immunization regimen. © 2013 Elsevier Ltd.


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.


Shirey K.A.,University of Maryland, Baltimore | Lai W.,University of Maryland, Baltimore | Pletneva L.M.,Sigmovir Biosystems, Inc. | Karp C.L.,Cincinnati Childrens Hospital Research Foundation | And 3 more authors.
Mucosal Immunology | Year: 2014

Resolution of severe Respiratory Syncytial Virus (RSV)-induced bronchiolitis is mediated by alternatively activated macrophages (AA-M/) that counteract cyclooxygenase (COX)-2-induced lung pathology. Herein, we report that RSV infection of 5-lipoxygenase (LO)/ and 15-LO/ macrophages or mice failed to elicit AA-M/ differentiation and concomitantly exhibited increased COX-2 expression. Further, RSV infection of 5-LO/ mice resulted in enhanced lung pathology. Pharmacologic inhibition of 5-LO or 15-LO also blocked differentiation of RSV-induced AA-M/ in vitro and, conversely, treatment of 5-LO/ macrophages with downstream products, lipoxin A4 and resolvin E1, but not leukotrieneB4 or leukotrieneD4, partially restored expression ofAA-M/markers. Indomethacin blockade ofCOXactivity in RSV-infected macrophages increased 5-LO and 15-LO, as well as arginase-1 mRNA expression. Treatment of RSV-infected mice with indomethacin also resulted not only in enhanced lung arginase-1 mRNA expression and decreased COX-2, but also decreased lung pathology in RSV-infected 5-LO/ mice. Treatment of RSV-infected cotton rats with aCOX-2-specific inhibitor resulted in enhanced lung 5-LOmRNAandAA-M/ markerexpression.Together, these data suggest a novel therapeutic approach for RSV that promotes AA-M/ differentiation by activating the 5-LO pathway. © 2014 Society for Mucosal Immunology.


PubMed | Sigmovir Biosystems, Inc., University of Milan Bicocca, University of Lyon and University of Maryland, Baltimore
Type: | Journal: Scientific reports | Year: 2017

Dysregulated Toll-like receptor (TLR)-4 activation is involved in acute systemic sepsis, chronic inflammatory diseases, such as atherosclerosis and diabetes, and in viral infections, such as influenza infection. Thus, therapeutic control of the TLR4 signalling pathway is of major interest. Here we tested the activity of the small-molecule synthetic TLR4 antagonist, FP7, in vitro on human monocytes and monocyte-derived dendritic cells (DCs) and in vivo during influenza virus infection of mice. Our results indicate that FP7 antagonized the secretion of proinflammatory cytokines (IL-6, IL-8, and MIP-1) by monocytes and DCs (IC


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.


Grant
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


Boukhvalova M.S.,Sigmovir Biosystems, Inc. | Blanco J.C.G.,Sigmovir Biosystems, Inc.
Current Topics in Microbiology and Immunology | Year: 2013

The cotton rat Sigmodon hispidus is a New World rodent that has become an important model of respiratory syncytial virus (RSV) infection. This small animal is relatively permissive to RSV and can be infected throughout life. It recapitulates the pathology associated with the FI-RSV vaccine-enhanced disease, the phenomenon of maternally transmitted immunity and the ability of passive immunity to suppress efficacy of RSV vaccines. Different highly susceptible human cohort scenarios have been modeled in the cotton rat, including RSV disease in infants, elderly, and immunosuppressed individuals. The cotton rat has accurately predicted efficacy and dose of antibody immunoprophylaxis, and the lack of efficacy of antibody immunotherapy for disease treatment. With the recent development of molecular reagents and tools for the model, the cotton rat is an important model of RSV infection to consider for vaccine and drug testing, and will continue to advance our understanding of RSV disease pathogenesis. © Springer-Verlag Berlin Heidelberg 2013.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 546.44K | Year: 2012

DESCRIPTION (provided by applicant): Seasonal influenza leads to an annual average of over 200,000 cases of hospitalizations and 36,000 deaths in the United States alone. Of all influenza-associated deaths, 90% occur in adults over the age of 65 years. Current approaches to vaccination of human elderly against seasonal influenza are inadequate. The task of developing an improved influenza intervention for the elderly is complicated by the absence of an appropriate animal model of influenza disease in the aged. Infection with unadapted seasonal influenza viruses is easily achieved in the cotton rat S.hispidus, an animal with high translational value for research on respiratory viruses. Aging in cotton rats significantly alters pathogenesis of respiratory viral infections, with seasonal influenza infection causing a more severe disease in the aged cotton rats. Efficacy of human influenza vaccines has been demonstrated in younger cotton rats using trivalent inactivated vaccine FluLaval. In this work, we will validate the aged cotton rat model of human seasonal influenza vaccines by demonstrating age-related decline in immunogenicity of both trivalent inactivated (FluLaval, GSK) and live attenuated (FluMist, MedImmune) vaccines. Vaccine efficacy will be evaluatedagainst immunologic parameters reported to characterize aging in humans and expanded to define biomarkers of severe seasonal influenza disease in human elderly and their modification by various vaccination regimes. Validation of this platform would yield avaluable translational model that can be used to improve existing methods of seasonal influenza vaccination of human elderly and to devise novel effective vaccines. PUBLIC HEALTH RELEVANCE: Disease caused by seasonal influenza carries a deadly toll on human elderly. Current approaches to vaccination of elderly against influenza are not effective and cannot be improved in the absence of an appropriate animal model. The cotton rat S.hispidus is susceptible to infection with unadapted influenza viruses and shows age-related alterations in influenza pathogenesis leading to a more severe disease. In this proposal we will use the aged cotton rats to recapitulate deficiencies of trivalent inactivated and live attenuated influenza vaccines as reported forhuman elderly. Creation of a translational animal model of influenza vaccines for elderly would facilitate design of a more effective vaccination approaches and reduce disease burden in this fast-growing population.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase II | Award Amount: 933.96K | Year: 2016

DESCRIPTION provided by applicant Respiratory syncytial virus RSV is a substantial threat to human health most severely affecting three large populations infants young children and the elderly Despite the significance of RSV disease in these different populations there are no vaccines available The goal of this Phase II STTR project is to continue preclinical testing of a novel RSV vaccine candidate a candidate unlike any previously tested This candidate is a virus like particle VLP built on the Newcastle disease virus core proteins M and NP and containing the RSV A F and G proteins inserted into the membrane of the particle The objective is to determine the potential of VLPs as a vaccine for each of the human populations at risk for serious disease using well characterized cotton rats models as surrogates for these groups Specific aim Optimize protective responses in young animals Children from years of age comprise a substantial proportion of RSV illness burden and likely provide a reservoir for infection of newborns This age group is considered to have less safety constrains than the newborn month age group and is most likely the population where direct vaccination should be seriously considered Thus for use of VLPs as a vaccine for this population the immune responses in young animals will be optimized by testing different routes of VLP delivery and options for VLP formulations for cross protection from RSV B infections Specific aim Determine the efficacy of maternal immunization in protection of neonates Direct vaccination of neonates is likely ineffective due to the immaturity of their immune system safety concerns and inhibition of vaccine protection by maternal antibodies An alternative approach is protection of newborns from RSV infections through maternal vaccination that will enhance and extend passive transfer of maternal neutralizing antibodies to the fetus Thus the protection of cotton rat pups by VLP vaccination of na ve and RSV experienced mothers will be measured by virus titer in the pupsandapos lungs and nasal tissue after RSV challenge In addition safety of maternal immunization in offspring will be determined by measuring lung histology after RSV challenge of pups Specific aim Assess efficacy of VLP immunization in elderly populations Elderly immune systems are less vigorous than younger adult populations thus the responses to a vaccine candidate may be different than those of younger adults Furthermore the elderly population has experienced RSV infections in their lifetime Therefore the protection of both na ve and RSV experienced elderly cotton rats by different doses and routes of VLP immunization will be assessed by serum responses and virus titers in lungs after virus challenge to evaluate different strategies of vaccination in this population PUBLIC HEALTH RELEVANCE Respiratory syncytial virus RSV is one of the most frequent causes of acute respiratory tract infection most severely affecting infants young children and the elderly However after decades of effort no vaccine exists to protect these populations from the virus This project will continue the preclinical development of a completely new RSV vaccine candidate a candidate unlike any previously tested The efficacy of this vaccine candidate in the most vulnerable populations will be tested using the cotton rat as surrogate model for the different targeted human populations The results of the study should provide key data to support future clinical trials of the vaccine safety and efficacy

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