A major goal of the laboratory is the development of a live attenuated bivalent respiratory syncytial virus (RSV) vaccine. The LID/NIAID has entered into a CRADA with Wyeth-Ayerst to accelerate the attainment of this goal. Significant progress has been made in the development of a subgroup A RSV vaccine. Essential to the success of this program has been the chimpanzee which responds to RSV infection in a manner most similar to that of susceptible infants. This means that evaluation of live RSV vaccine candidates for attenuation, immunogenicity and protective efficacy in susceptible chimpanzees provides the most relevant assessment of these virus preparations prior to initiation of clinical trials. A partially attenuated cold-passaged (cp) RSV (designated cpRSV) was further attenuated by the introduction of additional attenuating mutations, specifically temperature sensitive (ts) mutations. Several cpts candidate vaccines were found to be satisfactorily attenuated, immunogenic, stable genetically, and protective in chimpanzees. Importantly, these vaccines were shown to be protective in chimpanzees passively infused with RSV immune globulin to achieve a level of RSV neutralizing antibodies equivalent to that present in the target population for RSV vaccine, i.e., very young infants who possess passively-acquired RSV antibodies derived from their mother. Unexpectedly, chimpanzees immunized in the presence of passively transferred RSV antibodies developed unusually high titers of RSV neutralizing antibodies following challenge with wild type virus. These findings are very encouraging and form the basis for ongoing evaluation of several of these vaccine candidates in humans. Also, wild type and cold-passaged (cp) subgroup B viruses have been evaluated for level of replication and immunogenicity in chimpanzees and African green monkeys. Unfortunately, the subgroup B wild type virus does not replicate to high titer in these non-human primates indicating that these animals are not optimal for the evaluation of RSV subgroup B mutants. Nonetheless, the cp subgroup B RSV was more restricted in its replication in chimpanzees than its parental wild type virus indicating that the cp mutant was attenuated. Evaluation of this candidate mutant in humans will begin shortly.
