Significant progress has been made in the development of a live attenuated subgroup A RSV vaccine as well as in the understanding of the genetic basis of attenuation of the biologically-derived, live- attenuated virus vaccine candidates. Toward this goal, a set of five missense mutations previously identified by nucleotide sequence analysis of subgroup A cold-passaged (cp) respiratory syncytial virus (RSV) have been introduced into a recombinant wildtype strain of RSV. This recombinant virus, designated rA2cp, caused significantly less rhinorrhea and cough and replicated less efficiently in the upper and lower respiratory tracts of seronegative chimpanzees than wildtype RSV. These findings confirm the role of the cp mutations in attenuation of RSV and identify their usefulness for inclusion in future live attenuated recombinant RSV vaccine candidates. Deletion of the SH and NS2 genes attenuates RSV for chimpanzees, with the NS2 gene providing the greater level of attenuation.Respiratory syncytial virus (RSV) cpts248/404 is a live-attenuated, temperature-sensitive (ts) vaccine candidate derived from cold-passaged cpRSV by two rounds of chemical mutagenesis and biological selection. In addition to the cp mutations, the cpts248/404 candidate vaccine possessed two attenuating ts mutations, one in L and one in the M2 gene start signal sequence. An additional attenuating ts mutation was identified in the L gene, the 1030 mutation, which was added to the cpts248/404 candidate vaccine and a more attenuated derivative was made. This derivative, termed cpts248/404/1030 will be evaluated in humans this year. A series of new recombinant viruses containing various combinations of cp, ts, or deletion mutations is being constructed. A cpts248/404/1030 recombinant has been made that contains the RSV subgroup B G and F protective antigens substituted for those of the RSV subgroup A, and this antigenic chimeric recombinant virus appeared to be satisfactorily attenuated and immunogenic for chimpanzees. - respiratory syncytial virus, pneumonia, bronchiolitis, vaccines, live-attenuated virus vaccines, childhood immunization
