Significant progress has been made in the development of a live attenuated bivalent vaccine against RSV by introducing additional attenuating mutations into mutants that were not completely attenuated for seonegative humans. Several promising candidate RSV subgroup A vaccine candidates have been produced and evaluated. The cpts 248/955, 248/404, 530/1009, and 530/1030 mutants were selected from a large panel of mutants for further study because they are attenuated, stable genetically, immunogenic, and efficacious in rodents or chimpanzees. Importantly, these mutants are able to induce a high level of resistance to wild type virus challenge even in chimpanzees passively infused with RSV antibodies at the time of immunization, a situation that simulates that of the human infant with passively acquired RSV antibodies. Progress toward the development of a subgroup B RSV vaccine has also been made this year. We have demonstrated that the cpRSV B1/2B5 candidate vaccine virus sustained three independent mutations that contribute to its attenuation phenotype for cotton rats. The attenuation phenotype of this mutant is highly stable even after prolonged replication in immunosuppressed cotton rats. Both components of a bivalent subgroup A and B vaccine were able to replicate in vivo without apparent interference. Studies with the cpts-248/955 vaccines have been initiated in humans. The CD8+ T-cell epitope, amino acids 82-90, of the M2 protein of RSV was shown to be the sole mediator of resistance induced by immunization of BALB/c mice with a vaccinia recombinant expressing the M2 protein. A neutralizing human monoclonal Fab specific for the RSV fusion glycoprotein exhibited significant therapeutic efficacy in RSV-infected mice when introduced directly into the lower respiratory tract at the height of RSV replication in this site. The observed therapeutic efficacy of RSV human monoclonal antibody Fabs generated by antigen selection from a random combinatorial library and produced in E. coli, signals a major advance in the immunotherapy of viral respiratory tract disease.
