Nie S.,University of Massachusetts Medical School |
Nie S.,Biomedical Research Models, Inc. |
Lin S.-J.,University of Massachusetts Medical School |
Lin S.-J.,Chang Gung University |
And 3 more authors.
American Journal of Pathology | Year: 2010
Heterologous immunity associated with cross-reactive T-cell responses is proposed to contribute to variations among individuals in the pathogenesis of human viral infections. In genetically identical mice with similar infection histories, marked variations in the magnitude and specificities of T-cell responses under conditions of heterologous immunity occur and have been linked to the private specificity of T-cell repertoires in individual immune mice. Variations in immunopathology in the form of panniculitis are observed in lymphocytic choriomeningitis virus-immune mice after vaccinia virus infection. By adoptively transferring splenocytes from individual lymphocytic choriomeningitis virus-immune donors into paired recipients, we show here that, on vaccinia virus infection, similar levels of panniculitis were generated in recipients from a single donor, but the severity of panniculitis varied among recipients receiving cells from different donors. This indicates that virus-induced immunopathology under conditions of heterologous immunity is a function of the private specificity of the immune repertoire. Copyright © American Society for Investigative Pathology.
Yang K.,Biomedical Research Models, Inc. |
Varga S.M.,University of Iowa
Current Opinion in Virology | Year: 2014
Respiratory syncytial virus (RSV) is a leading cause of severe respiratory disease in infants, young children, immune-compromised and elderly populations worldwide. Natural RSV infection in young children does not elicit long-lasting immunity and individuals remain susceptible to repeated RSV infections throughout life. Because RSV infection is restricted to the respiratory tract, an RSV vaccine should elicit mucosal immunity at upper and lower respiratory tracts in order to most effectively prevent RSV reinfection. Although there is no safe and effective RSV vaccine available, significant progress has been recently made in basic RSV research and vaccine development. This review will discuss recent advances in the identification of a new neutralizing antigenic site within the RSV fusion (F) protein, understanding the importance of mucosal immune responses against RSV infection, and the development of novel mucosal vaccination strategies. © 2014 Elsevier B.V.
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 583.20K | Year: 2011
DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) affects ~ 2 million Americans with devastating impact on multiple organs, especially the skin, joints, kidney, and brain. Therapeutic strategies for lupus are largely palliative orimmunosuppressive with serious toxicities. No new drugs for SLE have been approved in decades. Thus, novel therapeutic approaches to lupus - particularly therapeutics that treat the underlying causes of the disease - are in great demand. Our goals are totranslate insights in the molecular mechanisms underlying SLE into the therapeutic arena. With phase 1 support we will sufficiently characterize a novel set of candidate small molecule lupus therapeutics to warrant the investment of further resources for drug development. SLE is characterized by the production of autoantibodies, many of which have specificity for nuclear antigens, in particular, DNA. These anti-DNA antibodies are now known to cross-react avidly with non-DNA (e.g., protein) antigens and thiscross-reactivity contributes to lupus pathogenesis. Dr. Diamond, Head, Center for Autoimmune and Musculoskeletal Diseases (Feinstein) has performed pioneering studies on the induction and pathogenicity of anti-DNA antibodies in both clinical lupus and invarious mouse animal models and identified a specific pentapeptide (DWEYS) that is present in the N methyl D aspartate receptor (NMDAR) as a cross- reactive protein antigen for the anti-dsDNA autoantibodies that are common in lupus patients. Exogenously supplied DWEYS peptide blocks the pathogenic deposition of anti-DNA antibodies in critical target tissues. Our hypothesis is that lupus peptidomimetics that preferentially bind to and neutralize this subset of anti-DNA autoantibodies will be effective therapeutics in patients. Since exogenous peptides like DWEYS have short half-lives in vivo, the Feinstein initiated a structural peptidomimetic program to create non-peptide organic compounds that will work analogously, but with preferred characteristics, to the DWEYS peptide. Feinstein and Biomedical Research Models, Inc (BRM), a small business with expertise in drug development testing and a particular emphasis in autoimmune models, now propose a joint venture to begin assessing the drug-like properties of these small molecule therapeutics. BRM will establish whether Feinstein's candidate lupus peptidomimetic small molecules possess valid drug-like properties to support preparation of a pre- investigational new drug (pre-IND) package. The Specific Aims are: 1.Synthesize new peptide/DNA mimetope small molecules and determine their rank order of efficacy in in vitro assays. 2. Characterize the lead and back-up lead in terms of tissue distribution, pharmacokinetics, immunogenicity, as well as residual host immunocompetence, using acute and chronic treatment. 3. Initiate preclinical evaluation of small molecule peptidomimetics in spontaneous and genetic murine models of lupus: NZB/W, MRL/lpr. The net result of this effort will be to develop a novel treatment for SLEand improve the lives of Americans. PUBLIC HEALTH RELEVANCE: Systemic lupus erythematosus (SLE) affects multiple organs, especially the skin, joints, kidney, and brain in ~ 2 million Americans. Current SLE therapeutics treat disease symptoms and have serious side-effects. Herein, we describe a novel therapeutic approach to lupus that will treat the underlying cause of the disease, rather than its many symptoms and will result in a novel therapy for Americans.
Biomedical Research Models, Inc. | Date: 2011-03-09
The invention provides methods and kits for immunizing animals (e.g. mammals) against viral antigens, including herpes-simplex virus type 2. The protective immune response elicited by the methods and kits of the invention is characterized by robust humoral, cellular, and mucosal immunity. In particular, the invention provides a heterologous immunization method comprising a priming DNA vaccine encoding an antigen and a boosting protein vaccine, in which the protein form of the antigen is encapsulated in liposomes. Methods of preventing primary acute, latent and recurrent viral infections, such as that caused by HSV-2 virus, and methods of providing passive protective immunity against a viral pathogen such as HSV-2 virus to a mammal are also disclosed.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 600.00K | Year: 2012
DESCRIPTION (provided by applicant): Human respiratory syncytial virus (RSV) is a highly infectious member of the paramyxovirus family causing upper and lower respiratory tract infections. RSV infection is the leading cause of pulmonary disease of the lower respiratory tract (bronchiolitis, pneumonia and respiratory failure) in infants due to virus-induced airway damage and complex inflammatory processes and responsible for an estimated 160,000 deaths annually worldwide. RSV also causes morbidity and mortality to the immunocompromised and elderly populations. In the United States, an estimated 70,000 to 125,000 infants are hospitalized annually with RSV pneumonia or bronchiolitis resulting in costs that may well exceed US 400 million annually. Because of either low immunogenicity and/or for safety reasons, previous attempts to formulate a vaccine to prevent RSV-mediated disease have not been successful. The formalin-inactivated vaccine candidate (FI-RSV) induced severe disease upon subsequent natural infection with RSV. Vaccinated children were found to suffer from enhanced disease severity and even death upon subsequent RSV infection concomitant with pulmonary eosinophilia. Severe lung inflammatory responses characterized by a skewed CD4+ T-cell response (inthe absence of neutralizing antibodies) and the influx of eosinophils in the lung were detected. Because of the unmet need of a safe and effective RSV vaccine, novel approaches are desperately needed. We have developed a patented mucosal vaccination platform that has demonstrated potent immune responses and protection against two different, mucosally challenged viruses. This powerful vaccine regimen can generate a Th1 biased, broad and potent humoral, mucosal and T cell responses including substantial mucosal secretory IgA and CTL. The uniqueness of our patented immunization regimen are:1) both mucosal (especially mucosal neutralizing antibodies), systemic immune responses and complete mucosal protection were raised without using any virus vectors and/or toxic adjuvants; 2) no immunopathology or vaccine- enhanced diseases have been detected in virus challenged animals. Two patents on the platform technology have been granted. Mucosal HSV-2 vaccine patents are pending and being licensed to a vaccine developerfor further product development. Therefore, this mucosal vaccine platform is an ideal candidate for developing a mucosal vaccine that protects against pathogens which enter at mucosal surfaces, as is the case for RSV. Using this patented mucosal immunization strategy, a safe and effective RSV vaccine will be developed. A strong scientific team involves four collaborating Institutes including: Biomedical Research Models, Inc., St. Jude Children's Research Hospital, University of Iowa and Sigmovir Biosystem, Inc. will: 1) prepare and optimize vaccine formulations to be tested in both BALB/c mice and cotton rats, 2) perform immunogenicity and protection studies in both mice and cotton rats of RSV intranasal infection, 3) test the durability of immune protection and the cross-subtype protection, 4) evaluate the safety (pulmonary histopathology) of the RSV vaccine candidate in both BALB/c mouse and the cotton rat models. PUBLIC HEALTH RELEVANCE: The Public Health Service (PHS) has recognized the significant public health issues caused by RSV. Due to the seriousness of RSV infection caused morbidity and mortality and the lack of a safe and effective RSV vaccine, development of novel approaches to RSV vaccination is desperately needed. The development of asafe and effective Respiratory Syncytial Virus (RSV) vaccine would provide protection to infants and elderly populations under the threat of RSV infection. The reduced incidence of disease in the lower respiratory tract would reduce the amount of medicalcosts directly associated with the infection.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 452.43K | Year: 2012
DESCRIPTION (provided by applicant): Rheumatoid arthritis is a chronic inflammatory disorder that afflicts at least 2.5 million Americans. This autoimmune disease is 2-3 times more common in women and typically affects the small joints in the hands and feet. Current therapeutic strategies include steroids and analgesics for the pain, while preventative strategies include disease modifying anti-rheumatic drugs (DMARDs). Unfortunately both steroids and DMARDs are not always effective, can result in serious toxicities, and are often costly. Thus, novel therapeutic approaches to rheumatoid arthritis, particularly cost-effective, steroid-sparing small molecule therapies, are in great demand. The broad long-term objective of this proposal is to advance a small molecule rheumatoid arthritis therapeutic into clinical service. This technology, being developed at the academic partner (The Feinstein Institute for Medical Research), targets macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine whose dysregulation underlies many autoimmune diseases. In addition to being the only cytokine that lends itself to small molecule intervention, MIF is known to counteract glucocorticoid action. Thus MIF intervention will be steroid-sparing. Feinstein and Biomedical Research Models, Inc. (BRM) - a small business with expertise in drug development testing and a particular emphasis in autoimmune models - now propose a joint venture to begin assessing the therapeutic efficacy of small molecule MIF inhibitors using BRM's validated preclinical models of rheumatoid arthritis. We will accomplish our goals by pursuing two Specific Aims: 1. Select a lead and back-up lead MIF inhibitor using established in vitro assays. Feinstein has developed five (5) proprietary MIF inhibitors which exhibit enhanced potency relative to a well- characterized positive control. Each of these drug candidates will be screened for their ability to inhibit (i) pro-inflammatory cytokine release from monocytes and (ii) the invasion of synovial fibroblast-like cells into a collagen matrix. 2. Perform dose efficacy studies on the lead and back-up lead in industry-accepted mouse and rat rheumatoid arthritis models. Following scale-up synthesis, these critical in vivo studies will be carried out at BRM. Dose finding studies and PK profiling will first be performed with a preference for oral dosing. An optimized dose and route of administration will then be chosen to test the therapeutic efficacy of two lead compounds in the RA models PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis (RA) is one of the most common and costly of autoimmune diseases in humans. It affects ~ 1% of the US population and is predominant in females. This project will potentially improve clinical practice in the treatment of RA by advancing a novel cost-effective therapy.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 594.14K | Year: 2010
DESCRIPTION (provided by applicant): Autoimmune diseases comprise the third most common category of illness in the United States affecting an estimated 22 million Americans. To date, therapeutic and preventive strategies for human autoimmune diseases (based on the restoration of immune tolerance) have been largely disappointing. Experimental animal models greatly facilitate the study of the pathogenesis and complications of autoimmune disease. They permit the evaluation of treatment protocols that pose ethical issues and safety risks in humans. They provide populations of genetically identical subjects that can be maintained under controlled environmental conditions. With them, new pharmaceutical agents, dietary regimens etc. can be tested to determine therapeutic benefit while detecting potential toxicity and unanticipated worsening of disease prior to human application. Preclinical testing of new agents and diets therefore represents a multimillion-dollar commercial market that would embrace a new, well-characterized rat model of multiple autoimmune diseases including, especially, T1D and rheumatoid arthritis. In our preliminary studies we report that LEW.1WR1 rats are 1) susceptible to virus-triggered autoimmune diabetes and experimental allergic encephalomyelitis, 2) susceptible to adjuvant arthritis, and 3) can develop diabetes during treatment to induce arthritis. These characteristics make the LEW.1WR1 rat an attractive commercial candidate for a test bed for studying both the efficacy of therapies for autoimmune disease prevention and reversal as well as screening for unanticipated adverse effects that would compromise the safety of such medications. We are therefore requesting funding to enhance the drug-platform-testing utility and commercial value of the LEW.1WR1 rat model of autoimmune diseases. In Phase 1 we will fully evaluate the autoimmune susceptibilities of these animals in response to perturbation of innate immunity and viral infection. In Phase 2, we will identify the genetic basis of the susceptibility of LEW.1WR1 rats to the different forms of autoimmunity characterized in Phase 1. Our specific aims are: 1: Identify the immunological and viral perturbants that increase the penetrance of disease in the LEW.1WR1 rat model of type 1 diabetes 2. Establish the LEW.1WR1 rat as a model of rheumatoid arthritis 3. Determine if the diabetic LEW.1WR1 rat develops thyroiditis, celiac disease, adrenal insufficiency, and sialadentis for use as a model of these disorders. PUBLIC HEALTH RELEVANCE: No preventative or curative therapies have been identified for the multiple autoimmune diseases that affect 22 million Americans. Progress in the development of new therapeutics is hampered by the lack of appropriate animal models. We have identified a novel autoimmune-susceptible rat strain that is poised to develop multiple autoimmune syndromes in response to environmental pertubants. This unique model is ideally suited for science-based preclinical safety evaluation that is needed before new therapies can be tested in humans.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 3.00M | Year: 2014
DESCRIPTION (provided by applicant): Globally, an estimated 16.2% of the human population is infected with HSV-2 including gt17% of the U.S. adult population. Genital herpes is associated with an increased risk of HIV acquisition and transmission and HSV-2infection can cause neonatal herpes with high infant mortality. HSV-2 infection in the adult population has increased substantially in the past two decades despite the availability of antiviral drugs. Although long-term antiviral drug treatment can lowerthe frequency of viral shedding and severity of recurrences, compliance and potential decreases in HSV-specific immune responses are problematic. The failure of antiviral drugs to prevent the spread of HSV-2 and the sheer magnitude of the public health problem associated with HSV-2 infection indicates a need for a safe and effective vaccine. The consensus of experts who attended the HSV workshop (Bethesda, October 2012) is that antibody response alone is not sufficient for protective immunity; mucosal a
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 213.86K | Year: 2016
Abstract Human respiratory syncytial virus RSV is a highly infectious member of the paramyxovirus family causing upper and lower respiratory tract infections RSV is the leading cause of pulmonary disease of the lower respiratory tract bronchiolitis pneumonia and respiratory failure in infants due to virus induced airway damage and complex inflammatory processes and responsible for an estimated deaths annually worldwide RSV also causes morbidity mortality to immunocompromised and elderly populations In the USA treatment of RSV pneumonia and bronchiolitis annual health care costs exceed $ million Because of either low immunogenicity and or for safety reasons previous attempts to formulate a vaccine to prevent RSV mediated disease have not been successful The formalin inactivated vaccine candidate FI RSV induced severe disease upon subsequent natural infection with RSV wherein vaccinated children were found to suffer from enhanced disease severity and even death Severe lung inflammatory responses characterized by a skewed CD T cell response in the absence of neutralizing antibodies and an influx of eosinophils in the lung were detected Because of the unmet need of a safe and effective RSV vaccine novel approaches are in high demand Since it is important for an RSV vaccine to protect the upper and lower respiratory tracts from subsequent RSV infection the ideal RSV vaccine candidate should elicit a durable mucosal response and protection as the first line of defense in the host Vaccines that are able to induce durable RSV specific mucosal IgA responses in the respiratory tract may be more protective than those that generate a systemic antibody response alone Fortunately one of the most exciting advances in RSV research was made by a co investigator on this grant Specifically a newly discovered antigenic site was identified on stabilize the pre fusion F pre F protein and this pre F with all four neutralizing antigen sites I II and IV was proven to be a far more immunogenic antigen than the post fusion F post F with three neutralizing antigen sites I II and IV that have been previously employed in vaccination approaches To develop a safe and effective mucosal RSV vaccine in this proposal we plan to combine the merits of this novel antigen and our patented mucosal vaccination platform and optimize the best vaccination conditions in mice and cotton rats This platform has already demonstrated potent immune responses and significant protection against two different mucosally challenged viruses such as HSV and RSV This powerful vaccine regimen can generate a Th biased broad and potent humoral mucosal and T cell responses including substantial mucosal IgA and CTL The uniqueness of our patented immunization regimen are both mucosal especially mucosal neutralizing antibodies systemic immune responses and complete mucosal protection were raised without using any virus vectors and or toxic adjuvants no immunopathology or vaccine enhanced diseases have been detected in virus challenged animals Therefore this mucosal vaccine platform is an ideal candidate for developing a mucosal vaccine that protects against pathogens which enter at mucosal surfaces as is the case for RSV Using this patented mucosal immunization strategy we will build on a safe and effective mucosal RSV vaccine that was developed in a previously funded SBIR grant and further optimize by extensively testing and comparing the pre F and the post F antigens in mice and cotton rats A very strong scientific team including four collaborating Institutes Biomedical Research Models Inc Dartmouth College University of Iowa and Sigmovir Biosystem Inc will prepare and optimize vaccine formulations to be tested in both BALB c mice and cotton rats optimize the best immunization dose and schedule for comparing pre F vs post F in eliciting the immune responses and protection in mice Optimize the best conditions for immunization of cotton rats with pre F and post F test and compare the durability of immune responses protection and safety pulmonary histopathology provided by the RSV vaccine candidates in cotton rats At the completion of the grant we expect complete or significant protection of animals from virus replication in both lung and nasal passage no vaccine enhanced pulmonary diseases durable mucosal and protective immunity The best antigen optimal formulation dose and immunization schedule will be identified for further development This study is a critical step before we can advance with phase II studies which will require key partners for cGMP manufacturing the best vaccine antigen formulation performing toxicology studies and testing of the mucosal RSV vaccine in the African Green Monkey model and eventually filing the IND for clinical trials Project Narrative Development and optimization of a safe and effective Respiratory Syncytial Virus RSV vaccine using a patented mucosal immunization strategy described herein would clearly have significant impact on not only the health and well beings of different human populations under the threat of RSV infection caused pulmonary diseases but also the tremendous amount of medical costs directly associated with the infection The Public Health Service PHS has recognized the significant public health issues caused by RSV Due to the seriousness of RSV infection caused morbidity and mortality and the lack of a safe and effective RSV vaccine novel RSV vaccine and vaccination strategy is in high demand
Biomedical Research Models, Inc. | Date: 2014-01-07
The invention provides methods and kits for inducing a therapeutic immunity in animals (e.g. mammals) against viral antigens, including herpes-simplex virus type 2. In particular, the invention provides a method of treating animals with an established HSV-2 infection by administering a therapeutic vaccine comprising a priming dose of a nucleic acid encoding an HSV-2 antigen, an initial or first boosting dose comprising the protein form of the antigen encapsulated in liposomes, and one or more subsequent boosting doses comprising both the nucleic acid encoding the HSV-2 antigen and the liposomal-encapsulated protein antigen.