Biomedical Research Models, Inc. — Department of Health and Human Services SBIR Phase I: NIAID

Description

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