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
| Autor: | Cindy Shambaugh, Elissa Malkin, C. Kathy Wang, Roderick Tang, Mark S. Galinski, Chin-Fen Yang, Jeanne H. Schickli, Filip Dubovsky, Fengrong Zuo |
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| Rok vydání: | 2013 |
| Předmět: |
Translational termination
Respiratory Syncytial Virus Infections Biology medicine.disease_cause Antibodies Viral Vaccines Attenuated Virus Serology Cohort Studies medicine Animals Humans Transgenes Gene Parainfluenza Virus 3 Bovine General Veterinary General Immunology and Microbiology Immunogenicity Public Health Environmental and Occupational Health Infant Viral Vaccines Sequence Analysis DNA respiratory system Virology Stop codon Parainfluenza Virus 3 Human Respiratory Syncytial Viruses Virus Shedding Open reading frame Infectious Diseases Respiratory syncytial virus (RSV) Molecular Medicine Cattle |
| Zdroj: | Vaccine. 31(26) |
| ISSN: | 1873-2518 |
| Popis: | 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 to24 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. |
| Databáze: | OpenAIRE |
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