Identification of a recombinant live attenuated respiratory syncytial virus vaccine candidate that is highly attenuated in infants.
BACKGROUND
Recombination technology can be used to create live attenuated respiratory syncytial virus (RSV) vaccines that contain combinations of known attenuating mutations.


METHODS
Two live attenuated, recombinantly derived RSV vaccine candidates, rA2cp248/404 Delta SH and rA2cp248/404/1030 Delta SH, were evaluated in 31 adults and in 95 children >/=6 months old. rA2cp248/404/1030 Delta SH was subsequently evaluated in 44 infants 1-2 months old. These vaccine candidates share 4 attenuating genetic elements and differ only in a missense mutation (1030) in the polymerase gene.


RESULTS
Both vaccines were highly attenuated in adults and RSV-seropositive children and were well tolerated and immunogenic in RSV-seronegative children. Compared with that of rA2cp248/404 Delta SH, replication of rA2cp248/404/1030 Delta SH was restricted in RSV-seronegative children (mean peak titer, 10(4.3) vs. 10(2.5) plaque-forming units [pfu]/mL), indicating that the 1030 mutation had a potent attenuating effect. Although rA2cp248/404/1030 Delta SH was well tolerated in infants, only 44% of infants who received two 10(5.3)-pfu doses of vaccine had detectable antibody responses. However, replication after administration of the second dose was highly restricted, indicating that protective immunity was induced. At least 4 of 5 attenuating genetic elements were retained in recovered vaccine viruses.


CONCLUSIONS
rA2cp248/404/1030 Delta SH is the first RSV vaccine candidate to be sufficiently attenuated in young infants. Additional studies are needed to determine whether rA2cp248/404/1030 Delta SH can induce protective immunity against wild-type RSV.
Karron
Ruth A
RA
Center for Immunization Research, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA. rkarron@jhsph.edu
Wright
Peter F
PF
Belshe
Robert B
RB
Thumar
Bhagvanji
B
Casey
Roberta
R
Newman
Frances
F
Polack
Fernando P
FP
Randolph
Valerie B
VB
Deatly
Anne
A
Hackell
Jill
J
Gruber
William
W
Murphy
Brian R
BR
Collins
Peter L
PL
D000328:Adult; D019943:Amino Acid Substitution; D000914:Antibodies, Viral / Q000097:blood*; D002675:Child, Preschool; D012321:DNA-Directed RNA Polymerases / Q000235:genetics / Q000276:immunology; D004311:Double-Blind Method; D005814:Genes, Viral; D006801:Humans; D007223:Infant; D020125:Mutation, Missense; D018357:Respiratory Syncytial Virus Infections / Q000517:prevention & control*; D022261:Respiratory Syncytial Virus Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D012136:Respiratory Syncytial Viruses / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000821:virology; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology; D014779:Virus Replication; D017201:Virus Shedding
D000914:Antibodies, Viral; D022261:Respiratory Syncytial Virus Vaccines; D014613:Vaccines, Attenuated; D014614:Vaccines, Synthetic; D017361:Viral Nonstructural Proteins; D012321:DNA-Directed RNA Polymerases