Identification of a recombinant live attenuated respiratory syncytial virus vaccine candidate that is highly attenuated in infants

Ruth A. Karron, Peter F. Wright, Robert B. Belshe, Bhagvanji Thumar, Roberta Casey, Frances Newman, Fernando P. Polack, Valerie B. Randolph, Anne Deatly, Jill Hackell, William Gruber, Brian R. Murphy, Peter L. Collins

Research output: Contribution to journalArticlepeer-review

Abstract

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, rA2cp248/404ΔSH and rA2cp248/404/1030ΔSH, were evaluated in 31 adults and in 95 children ≥6 months old. rA2cp248/404/ 1030ΔSH 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 rA2cp248/404ΔSH, replication of rA2cp248/404/1030ΔSH was restricted in RSV-seronegative children (mean peak titer, 104.3 vs. 10 2.5 plaque-forming units [pfu]/mL), indicating that the 1030 mutation had a potent attenuating effect. Although rA2cp248/404/1030ΔSH was well tolerated in infants, only 44% of infants who received two 105.3-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/ 1030ΔSH is the first RSV vaccine candidate to be sufficiently attenuated in young infants. Additional studies are needed to determine whether rA2cp248/404/1030ΔSH can induce protective immunity against wild-type RSV.

Original languageEnglish (US)
Pages (from-to)1093-1104
Number of pages12
JournalJournal of Infectious Diseases
Volume191
Issue number7
DOIs
StatePublished - Apr 1 2005

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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