RSV vaccine development Early in the development of respiratory syncytial virus (RSV) vaccines severe disease occurred in some children after receipt of formalin-inactivated RSV vaccine. The illnesses occurred in children who had not previously experienced RSV infection but had wild-type RSV infection in the winter season subsequent to vaccination. Live attenuated, intranasally administered vaccines offer the potential for a broadly based immune response and, by mimicking the response to natural infection, are unlikely to result in potentiated disease. The continuing efforts to develop an appropriately attenuated and immunogenic live RSV vaccine have provided an opportunity to give assurances that live vaccines are a safe approach to RSV immunization and to provide useful data on the optimal design of subsequent vaccine efficacy trials. Between 1996 and 2003 7 different RSV vaccines were given to 113 6-24 month old children seronegative to RSV at immunization and 2 vaccines to 62 RSV-nave infants 1-3 months of age. In total, 388 vaccinees, placebo recipients and age-matched controls were followed for respiratory illness during the subsequent winter. Nasal wash samples were cultured for RSV with each episode of respiratory disease. For purposes of analysis we focused on: 1) a comparison between all vaccinees and controls - an intent to treat analysis, and 2) for two vaccines given to both 6-24 month olds and 1-3 month olds - a comparison of those who had a response to vaccination (evidence of virus shedding or an immune response) versus controls - a vaccine efficacy analysis. Pre and post-season sera available on 122 of the infants and 143 of the children were examined for serologic evidence of RSV infection. In the intent to treat analysis the rate of RSV-associated upper respiratory tract illness was lower in vaccinated children than in controls (14% versus 20% in the 6-24 month old group and 16% versus 25% in infants). RSV-associated lower respiratory tract illness was infrequent and there was no evidence that vaccination predisposed to more severe illness. The vaccine efficacy analysis of the two leading vaccine candidates (cpts 248404 and rA2cp 2484041030SH) revealed similar trends towards efficacy. RSV serologic rises over the ensuing winter were common in children (31%) and infants (21%) regardless of receipt of vaccine or placebo. This surveillance clearly demonstrated that infection with a live attenuated RSV vaccine did not result in enhanced disease upon infection with wild type RSV. The information on the impact of RSV in the young infants and children during the period of surveillance will assist in designing future efficacy studies with RSV vaccines. Parainfluenza virus (PIV) vaccine development HPIV3cp45 - Studies have been initiated with a human (H) recombinant(r) vaccine virus, designated rHPIV3cp45. Previously, biologically-derived HPIV3cp45 was shown to be satisfactorily attenuated, immunogenic, and genetically stable in the target population of HPIV3 nave subjects. Deriving a virus from a cDNA copy of the HPIV3 genome using defined materials and media generates a virus seed that is free of adventitious contaminants from the previous 45 passages of the virus in primary monkey kidney cultures. The present study was done to demonstrate the bioequivalence of the rHPIV3cp45 and the biologically-derived HPIV3cp45 and to define a dose of vaccine that is safe, infectious, and immunogenic in older and younger HPIV3 nave subjects. These studies are in progress and preliminary results indicate that the two versions of HPIV3cp45 vaccine are comparable. BHPIV3 Studies have been initiated with the chimeric recombinant virus that contains the HPIV3 HN and F protective antigens on a bovine (B) PIV3 backbone that contains multiple attenuating BPIV3 genes. HPIV1 and HPIV2 Live attenuated HPIV1 and HPIV2 vaccine candidates have been identified in preclinical studies and clinical trial materials are being prepared. Trials with this vaccine should be initiated this coming year.