Scientific Publications by FDA Staff

J Virol 2014 May;88(9):5100-8.

Development of an adenovirus-based respiratory syncytial virus vaccine: preclinical evaluation of efficacy, immunogenicity, and enhanced disease in a cotton rat model.

Kim E, Okada K, Beeler JA, Crim RL, Piedra PA, Gilbert BE, Gambotto A

The lack of a vaccine against respiratory syncytial virus (RSV) is a challenging and serious gap in preventive medicine. Herein, we characterize the immunogenicity and protection following immunization with an adenoviral-based RSV vaccine encoding for the fusion protein F (Ad5.RSV-F) and assess its potential for producing enhanced disease in a cotton rat (CR) model. Animals were immunized intranasally (IN) and/or intramuscularly (IM) and subsequently challenged with RSV/A/Tracy (IN) to assess protection. Robust immune responses were seen in CRs vaccinated with Ad5.RSV-F given IM or IN, which correlated with reduced replication of virus in noses and lungs after challenge. Neutralizing antibody responses following immunization with a single dose of Ad5.RSV-F at 1×1011 viral particles (v.p.) elicited antibody titers 64- to 256- fold greater than those seen after natural infection. CRs boosted with Ad5.RSV-F IN 28 days after an IM dose also had significant increases in neutralizing antibody titers. Antibody affinity for different F protein antigenic sites revealed substantial differences between antibodies elicited by Ad5.RSV-F as compared with those seen after RSV infection; differences in antibody profiles were also seen in CRs given Ad5.RSV-F IM vs. IN. Ad5.RSV-F priming did not result in enhanced disease following live virus challenge in contrast with histopathology seen in CRs given formalin-inactivated-RSV/A/Burnett vaccine. IMPORTANCE: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in infants and young children and a serious health threat in the immunocompromised and the elderly. Infection severity increased in children in an immunization trial, hampering the over four decades-long quest for a successful RSV vaccine. In this study, we show that a genetically-engineered RSV-F encoding adenoviral vector provides protective immunity against RSV challenge without enhanced lung disease in cotton rats (CRs). CRs were vaccinated under a number of different regimens and intramuscular-intranasal prime-boost immunity induced by the recombinant adenoviral RSV vaccine may provide the best protection for young infants and children at risk of RSV infection, since this population is naïve to adenoviral preformed immunity. Overall, this manuscript describes a potential RSV vaccine candidate that merits further evaluation in a phase I clinical study in humans.