Optimization of a mucosal RSV vaccine

Period of Performance: 07/01/2016 - 06/30/2017

$214K

Phase 1 SBIR

Recipient Firm

Biomedical Research Models, Inc.
Worcester, MA 01606
Principal Investigator

Abstract

Abstract Human respiratory syncytial virus (RSV) is a highly infectious member of the paramyxovirus family causingupper and lower respiratory tract infections. RSV is the leading cause of pulmonary disease of the lowerrespiratory tract (bronchiolitis, pneumonia and respiratory failure) in infants due to virus-induced airwaydamage and complex inflammatory processes and responsible for an estimated 160,000 deaths annuallyworldwide. RSV also causes morbidity/mortality to immunocompromised and elderly populations. In the USA,treatment of RSV pneumonia and bronchiolitis annual health care costs exceed $400 million. Because of eitherlow 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) inducedsevere disease upon subsequent natural infection with RSV wherein vaccinated children were found to sufferfrom enhanced disease severity and even death. Severe lung inflammatory responses characterized by askewed CD4+ T-cell response (in the absence of neutralizing antibodies) and an influx of eosinophils in thelung were detected. Because of the unmet need of a safe and effective RSV vaccine, novel approaches are inhigh demand. Since it is important for an RSV vaccine to protect the upper and lower respiratory tracts fromsubsequent RSV infection, the ideal RSV vaccine candidate should elicit a durable mucosal response andprotection as the first line of defense in the host. Vaccines that are able to induce durable RSV-specificmucosal IgA responses in the respiratory tract may be more protective than those that generate a systemicantibody response alone. Fortunately, one of the most exciting advances in RSV research was made by a co-investigator on thisgrant. Specifically, a newly discovered antigenic site (Ø) was identified on stabilize the pre-fusion F (pre-F)protein and this pre-F, with all four neutralizing antigen sites (Ø, I, II, and IV), was proven to be a far moreimmunogenic antigen than the post-fusion F (post-F) with three neutralizing antigen sites (I, II, and IV) thathave been previously employed in vaccination approaches. To develop a safe and effective mucosal RSVvaccine, in this proposal we plan to combine the merits of this novel antigen and our patented mucosalvaccination platform, and optimize the best vaccination conditions in mice and cotton rats. This platform hasalready demonstrated potent immune responses and significant protection against two different, mucosallychallenged viruses such as HSV-2 and RSV. This powerful vaccine regimen can generate a Th1 biased, broadand potent humoral, mucosal and T cell responses including substantial mucosal IgA and CTL. Theuniqueness of our patented immunization regimen are:1) both mucosal (especially mucosal neutralizingantibodies), systemic immune responses and complete mucosal protection were raised without using any virusvectors and/or toxic adjuvants; 2) no immunopathology or vaccine-enhanced diseases have been detected invirus challenged animals. Therefore, this mucosal vaccine platform is an ideal candidate for developing amucosal 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 RSVvaccine that was developed in a previously funded SBIR grant and further optimize by extensively testing andcomparing the pre-F and the post-F antigens in mice and cotton rats. A very strong scientific team includingfour collaborating Institutes: Biomedical Research Models, Inc., Dartmouth College, University of Iowa andSigmovir Biosystem, Inc. will: 1) prepare and optimize vaccine formulations to be tested in both BALB/c miceand cotton rats, 2) optimize the best immunization dose and schedule for comparing pre-F vs. post F in elicitingthe immune responses and protection in mice, 3) Optimize the best conditions for immunization of cotton ratswith 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 thegrant, we expect: 1) complete or significant protection of animals from virus replication in both lung and nasalpassage; 2) no vaccine-enhanced pulmonary diseases; 3) durable mucosal and protective immunity. The bestantigen, optimal formulation/dose, and immunization schedule will be identified for further development. Thisstudy is a critical step before we can advance with phase II studies, which will require key partners for cGMPmanufacturing the best vaccine antigen formulation, performing toxicology studies, and testing of the mucosalRSV vaccine in the African Green Monkey model and eventually filing the IND for clinical trials.