Immunogenicity and pathogenicity of temperature‐sensitive modified respiratory syncytial virus in adult volunteers

Abstract

Single temperature-sensitive (ts) mutants of a subgroup A strain of respiratory syncytial (RS) virus whose multiplication is restricted at 39 degrees C in MRC-6 cells and double ts mutants that are restricted at 38 degrees C, were obtained following mutagenesis using 5-fluorouracil and acridine-like compounds. Isolation and propagation of the parental RSS-2 strain of RS virus and its derived ts mutants were carried out entirely in MRC-5 human diploid cells. The immunogenicity and disease-producing ability of four of these mutants and the parental unmodified strain have been assessed by intranasal administration into groups of about 20 adult volunteers. The results of these trials indicate that the capacity of the parental RSS-2 strain to produce upper respiratory tract infection in adults was not diminished by limited propagation in MRC-5 cells. The mutants on the other hand were impaired in this respect to varying extents. The double mutant tslB in particular has characteristics that suggest that it may be suitable for further development as a live RS virus vaccine. It retained near normal immunogenicity and replicative ability in the upper respiratory tract, while exhibiting greatly reduced disease-producing potential.

Parainfluenza Virus Type 3 Expressing the Native or Soluble Fusion (F) Protein of Respiratory Syncytial Virus (RSV) Confers Protection from RSV Infection in African Green Monkeys

“…The first live attenuated RSV vaccines tested in human trials were cold-passaged and/or chemically mutagenized viruses displaying temperature sensitivity. These vaccine candidates failed because they were either over-or underattenuated, and wild-type revertants were often isolated from vaccinees (23,27,28). Cold-passaged, temperature-sensitive viruses 248/ 955 and 530/1009, a more current series of RSV strains, were evaluated in RSV-seronegative children as young as 6 months.…”

Controlled human infection with RSV: The opportunities of experimental challenge

“…Since that time there have been numerous challenge studies of human RSV involving over 300 subjects using both wild-type and attenuated strains without reported serious adverse events (Table 1) [19][20][21][22][23][24][25]. Insights into the influence of route of infection, incubation periods, durations of protective immunity and viral shedding were gained from these studies, but until recently limitations in technology have meant smaller contributions to understanding of immuno-pathogenesis or facilitating the development of effective vaccines.…”

Respiratory Syncytial Virus Vaccines

“…Investigators in the United Kingdom have also developed ts mutants of RSV group A, which were derived from the RSS-2 strain by chemical mutagenesis of virus grown in the MRC-5 human diploid cell line (82,102). Two mutants, designated ts1A and ts19A, were derived by a single round of mutagenesis with 5-fluorouracil (5-FU); ts1B and ts19B were each derived from the respective A viruses by a second round of mutagenesis with ICR 340 or ICR 372; and the ts1C virus was derived from ts1B by a third round of mutagenesis with 5-FU.…”

“…Each of these ts viruses has been evaluated in healthy adult volunteers. Although attenuated in comparison to wt RSV, the ts1A and ts1B viruses caused upper respiratory tract illnesses in adults and were therefore not sufficiently attenuated for further evaluation in children (82). Replication of the ts1C mutant in adults was not associated with illness (102), but evaluation in children is necessary to determine if this candidate vaccine is sufficiently attenuated.…”