Progress has been made toward the development of a trivalent live attenuated virus vaccine consisting of (1) a respiratory syncytial virus (RSV) subgroup A component; (2) an RSV subgroup B component; and (3) a parainfluenza virus type 3 (PIV3) vaccine component. After evaluation of five live attenuated subgroup A virus vaccine candidates, the RSV A2 subgroup A candidate cpts248/404 has been found to be satisfactorily attenuated, phenotypically stable, poorly transmissible, and immunogenic in seronegative infants and children over the age of six months. As a consequence of this favorable constellation of properties, we initiated studies in the target population of one month old infants for the first time in our live attenuated RSV vaccine program. The cpts248/404 vaccine candidate retained some residual mild reactogenicity for the upper respiratory tract of infants and a more attenuated derivative will need to be generated. However, the cpts248/404 virus did not cause fever, otitis media, pneumonia or bronchiolitis so we are close to achieving the level of attenuation needed for this target age group. Young infants infected with vaccine virus developed an immune response sufficient to restrict replication of a second dose of vaccine. The candidate vaccine was, for the most part, phenotypically stable. Thus, the human neonate can develop a protective immune response induced by a live attenuated vaccine candidate that is effective against RSV, albeit an attenuated version of RSV. The RSV subgroup B candidate vaccine, RSV B1 cp23, was found to be under-attenuated for use in fully susceptible infants and children and for this reason will not be pursued further. RSV subgroup B vaccines of the future will need to be chimeric recombinant viruses bearing the RSV subgroup B F and G protective antigens on a background of an attenuated subgroup A virus that was from cDNA. A live attenuated PIV3 candidate vaccine, JS cp45, produced by NIH was satisfactorily attenuated, immunogenic, and phenotypically stable in seronegative infants and children, and studies with simian Vero cell-grown vaccine produced by our CRADA partner, Wyeth-Lederle-Praxis, have been initiated this past year. The two preparations appear to be comparable in their behavior in seronegative infants and children. Once fully acceptable monovalent vaccines are identified, studies with bivalent or trivalent vaccines will be initiated.
