A series of progressively more attenuated cold-passaged (cp), temperature-sensitive (ts) intranasally administered RSV vaccines are being evaluated in placebo-controlled, randomized, double-blinded trials in young children. In all preclinical testing, including administration to chimpanzees, the current vaccine candidate, cpts248/404, was more highly attenuated than the strains recently described by Karron et al (JID 176:1428-36, 1997). The vaccine failed to infect 15 seropositive children, 15-59 months of age. The vaccine was safe, infectious, immunogenic and genetically stable in 45 seronegative 6-24 month old children at doses of 104 pfu(16) and 105 pfu(29). Results were similar in 16 children 3-5 months of age at 105. We next administered 2 doses of vaccine 8 weeks apart at 104 (10 children) or 105 (25 children) in the target age group of 4-12 week old infants. The first dose of vaccine was infectious at both dosage levels with all 7 vaccinees shedding virus following a 104 dose and 76% (13/17 vaccinees) shedding at a 105 dose. The amount of virus detected in nasopharyngeal washes was equal to that in older children (peak mean titer ≥ 4 log10 pfu/ml for both dosages). Two isolates showed a drift in their ts shut-off temperature from 36 to 37°C, indicating a very high level of genetic stability. At either dosage, vaccine caused mild to moderate nasal congestion without fever or any signs of lower respiratory tract involvement between 7-10 days after vaccine administration. With the second dose of vaccine virus there were no clinical symptoms and shedding was markedly curtailed (0/7 at the 104 dose) and(4/15 at 105) indicating protection conferred by the first dose of vaccine. Preliminary results suggest that protection occurs in the absence of detectable serum neutralizing antibody responses. Administration of cpts 248/404 live, attenuated RSV vaccine to 1-2 month old infants was accompanied by URI symptoms that will necessitate a slightly more attenuated vaccine. Nevertheless, for the first time a vaccine was administered to the target age group and induced protective immunity.