title: Implication of respiratory syncytial virus (RSV) F transgene sequence heterogeneity observed in Phase 1 evaluation of MEDI-534, a live attenuated parainfluenza type 3 vectored RSV vaccine.
abstract: MEDI-534 is the first live vectored RSV vaccine candidate to be evaluated in seronegative children. It consists of the bovine parainfluenza virus type 3 (PIV3) genome with substituted human PIV3 F and HN glycoproteins engineered to express RSV F protein. A Phase 1 study of 49 healthy RSV and PIV3 seronegative children 6 to <24 months of age demonstrated an acceptable safety profile at the following doses: 10(4), 10(5) and 10(6)TCID50. After 3 doses of MEDI-534 at 10(6)TCID50, administered at 0, 2 and 4 month intervals, 100% of subjects seroresponded to PIV3, whereas only 50% seroresponded to RSV. To investigate the discordance in seroresponse rates, the RSV F transgene and its flanking non-coding nucleotides were sequenced from shed virus recovered from the nasal washes of 24 MEDI-534-vaccinated children. Eleven out of 24 samples contained no nucleotide changes in the analyzed region. The other 13 samples contained mixtures of variant subpopulations. Fifty-five percent exhibited changes in the transcription termination poly A gene sequences of the upstream bPIV3N gene while 21% had variant subpopulations in the RSV F open reading frame that resulted in pre-mature stop codons. Both types of changes are expected to reduce RSV F expression. Evaluation of the administered vaccine by dual immunofluorescence staining showed ~2.5% variants with low or no RSV F expression while single nucleotide primer extension detected ~1% variation at nucleotide 2045 that resulted in a pre-mature translational termination at codon 85. An association between shedding of variants and lower RSV F serological response was observed but it was not possible to establish a definitive clinical significance due to the small number of subjects in this study.
authors.affiliation: MedImmune, 297 North Bernardo Avenue, Mountain View, CA 94043, United States. yangc@medimmune.com
authors.forename: Chin-Fen
authors.initials: CF
authors.lastname: Yang
authors.forename: C Kathy
authors.initials: CK
authors.lastname: Wang
authors.forename: Elissa
authors.initials: E
authors.lastname: Malkin
authors.forename: Jeanne H
authors.initials: JH
authors.lastname: Schickli
authors.forename: Cindy
authors.initials: C
authors.lastname: Shambaugh
authors.forename: Fengrong
authors.initials: F
authors.lastname: Zuo
authors.forename: Mark S
authors.initials: MS
authors.lastname: Galinski
authors.forename: Filip
authors.initials: F
authors.lastname: Dubovsky
authors.forename: Roderick S
authors.initials: RS
authors.lastname: Tang
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D002417:Cattle; D015331:Cohort Studies; D006801:Humans; D007223:Infant; D029101:Parainfluenza Virus 3, Bovine / Q000235:genetics / Q000276:immunology; D010224:Parainfluenza Virus 3, Human / Q000235:genetics* / Q000276:immunology; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology / Q000517:prevention & control*; D012136:Respiratory Syncytial Viruses / Q000235:genetics* / Q000276:immunology; D017422:Sequence Analysis, DNA; D019076:Transgenes; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology; D014765:Viral Vaccines / Q000235:genetics* / Q000276:immunology; D017201:Virus Shedding
chemical_list: D000914:Antibodies, Viral; D014613:Vaccines, Attenuated; D014765:Viral Vaccines