Enhanced pulmonary pathology was observed in cotton rats immunized with formalin-inactivated respiratory syncytial virus (RSV) or purified RSV fusion (F) protein and challenged intranasally with RSV 3 or 6 months later. This constitutes the first evidence that immunization with the F glycoprotein alone can induce a potentiated pathological response to subsequent RSV infection. Enhanced pulmonary pathology was not observed previously when animals immunized with purified RSV F were challenged with RSV one month later. These observations indicate the importance of the interval between immunization and subsequent virus infection in the occurrence of enhanced pulmonary pathology. A similar situation was observed almost 25 years ago with the licensed inactivated measles virus vaccine and thus, caution should be exercised in the evaluation of a purified RSV F glycoprotein vaccine in humans. Also, passively acquired RSV F antibodies can suppress the neutralizing antibody response of cotton rats to purified RSV F glycoprotein. With lower doses of F (0.2 ug to 1.7 ug) there was a 7 to 8 fold suppression, while with high doses of F (5 to 15 (mu)g) suppression was significantly less, i.e., 2 fold. The efficiency of topical immunotherapy for RSV infection was significantly increased by two modifications of previous methodology. First, a mixture of RSV F monoclonal antibodies directed at the major conserved neutralization epitopes on this glycoprotein was highly effective in topical immunotherapy of RSV infection in the cotton rat. Second, delivery of RSV antibodies directly into the lungs in a small particle aerosol (< 2 mu) was also effective therapeutically. The use of monoclonal antibodies should decrease the amount of IgG required for therapy by 2 orders of magnitude. In other studies in cotton rats, parainfluenza virus type 3 (PIV3) antibodies were shown to be protective as well as therapeutic. Thus, usefulness of topical immunotherapy is not limited to RSV. It is likely that this approach will prove to be effective for other respiratory viral pathogens whose pathogenic effects are also limited to the cells that line the lumen of the lower respiratory tract.
