Clinical manufacturing and toxicology testing of an adenoviral-based RSV vaccine

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

? DESCRIPTION (provided by applicant): Respiratory viruses are the most common cause of death in infants and children worldwide. Respiratory syncytial virus (RSV), a negative, single-stranded RNA virus in the paramyxoviridae family, is the most frequent cause of hospitalization due to viral respiratory tract disease. The global RSV disease burden is estimated at 64 million cases and 160,000 deaths per year. The spectrum of clinical illness ranges from mild upper respiratory tract disease to severe bronchiolitis and pneumonia. Treatments are limited; prophylactic administration of antibodies against RSV is expensive and impractical in most countries, and the efficacy of anti-viral drug therapy (ribavirin) is controversial due to its high cost and inability to prevent disease. No vaccine is currently available, which is a significant an serious gap in preventive medicine. Intensive new efforts toward vaccine development, such as the one proposed in this application, are clearly needed to close this gap. We have recently generated and tested both in vitro and in vivo the recombinant adenoviral vaccine encoding RSV fusion protein (Ad5.RSV-F). Significantly, one possible reason for the limited efficacy of a recombinant DNA RSV vaccine based on F antigen is poor in vivo expression caused by the presence of premature polyadenylation sites within the F protein open reading frame. We were able to genetically engineer the RSV F protein, which resulted in a robust expression of the F protein, desirable for vaccine application. In vivo efficacy studies of Ad5.RSV-F vaccine were performed on cotton rats. These studies demonstrated the ability of Ad5.RSV-F vaccine to induce a neutralizing immunity five to seven log superior to the vaccination with live RSV virus (golden standard) which result in complete protection and no viral shedding detected in the nose and the lung after RSV challenge. In order to advance this promising RSV vaccine candidate to a phase I clinical study, here we propose a three year centralized and integrated clinical vaccine manufacturing endeavor.