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WORCESTER, MA, United States

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. Source


Grant
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


Grant
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.


Grant
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.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 2.56M | Year: 2009

DESCRIPTION (provided by applicant): Approximately 1 out of every 5 Americans is infected with herpes simplex virus type 2 (HSV-2). Localized genital infection by HSV-2 results in painful recurring genital lesions while disseminated infection can involve multiple visceral organs and lethal encephalitis. Using Phase 1 funding we have developed a new heterologous immunization protocol composed of a glycoprotein D (gD) DNA vaccine followed by a liposome-encapsulated gD boost. This protocol induces robust serum IgG antigen-specific antibodies, mucosal IgG and secretory IgA and a T helper type 1 (Th1)-biased immune response. Mice immunized with this protocol are protected from disease after infection with 100 times the lethal dose of virus. Use of a higher priming dose of DNA revealed sterilizing immunity in 80% of immunized mice. We are requesting Phase 2 funding to complement and extend the studies in preparation for preclinical safety testing. The requested funding will be used to further characterize immune mediators induced by the novel HSV-2 vaccine. Funding will also be used to evaluate commercial suppliers of vaccine components and establish quality control parameters. Dosing of components will be further optimized in preparation for human use and toxicity testing. Guinea pigs will be used to demonstrate efficacy of the vaccine in a second animal model and to test the ability of the vaccine to prevent establishment of latency and/or reactivation of latent virus. The end result of these experiments will be the establishment of a novel vaccine for HSV-2. PUBLIC HEALTH RELEVANCE: This vaccine would clearly have an impact on the greater than 1.6 billion spent annually on direct medical costs associated with HSV-2. The Public Health Service (PHS) has recognized the significant public health issues caused by herpes simplex virus. The PHS publication, Healthy People 2010 , has set sexually transmitted diseases as a national priority with a goal to reduce the number of adults infected with human papilloma virus and HSV-2.

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