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

• Published in: Vaccine Vol. 31; no. 26; pp. 2822 - 2827
• Main Authors: Yang, Chin-Fen, Wang, C. Kathy, Malkin, Elissa, Schickli, Jeanne H., Shambaugh, Cindy, Zuo, Fengrong, Galinski, Mark S., Dubovsky, Filip, Tang, Roderick S.
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 10.06.2013; Elsevier; Elsevier Limited
• Subjects: Age; Allergy and Immunology; Animals; Antibodies, Viral - blood; Applied microbiology; Biological and medical sciences; Bovine parainfluenza virus 3; Bovine respirovirus 3; Cattle; children; Cohort Studies; Deoxyribonucleic acid; DNA; fluorescent antibody technique; Fundamental and applied biological sciences. Psychology; Glycoproteins; Heterogeneity; Humans; Immunization; Immunogenicity; Infant; Microbiology; nose; nucleotides; open reading frames; Parainfluenza virus; Parainfluenza Virus 3, Bovine - genetics; Parainfluenza Virus 3, Bovine - immunology; Parainfluenza Virus 3, Human - genetics; Parainfluenza Virus 3, Human - immunology; Polymerase chain reaction; Proteins; Respiratory syncytial virus; Respiratory syncytial virus (RSV); Respiratory Syncytial Virus Infections - immunology; Respiratory Syncytial Virus Infections - prevention & control; Respiratory Syncytial Viruses - genetics; Respiratory Syncytial Viruses - immunology; RSV F expression; Sequence Analysis, DNA; stop codon; Subpopulations; Transgenes; Vaccines; Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies (general aspects); Vaccines, Attenuated - genetics; Vaccines, Attenuated - immunology; Viral Vaccines - genetics; Viral Vaccines - immunology; Virus Shedding; Virus variants; viruses; Virus variants; Respiratory syncytial virus (RSV); RSV F expression; Immunogenicity; Human; Retroviridae; Vaccine; Virus; Human syncytial virus; Spumavirus; Phase I trial; Attenuated strain; Child; Vector
• ISSN: 0264-410X; 1873-2518; 1873-2518
• DOI: 10.1016/j.vaccine.2013.04.006

•The live RSV vaccine virus was primarily detected in young children post dose 1.•About half of the shed vaccine viruses (13/24) contained sequence changes.•These sequence changes may result in lower RSVF protein expression.•These changes may have been selected during replication in humans.•The presence of vaccine variants may be associated with lower RSVF sero-responses. 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: 104, 105 and 106TCID50. After 3 doses of MEDI-534 at 106TCID50, 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.