A gene deletion that up-regulates viral gene expression yields an attenuated RSV vaccine with improved antibody responses in children

• Published in: Science translational medicine 2015-11, Vol.7 (312), p.312ra175-312ra175
• Main Authors: Karron, Ruth A, Luongo, Cindy, Thumar, Bhagvanji, Loehr, Karen M, Englund, Janet A, Collins, Peter L, Buchholz, Ursula J
• Format: Article
• Language: English
• Subjects: Adult; Antibodies, Viral - immunology; Antibody Formation - immunology; Child, Preschool; Gene Deletion; Gene Expression Regulation, Viral; Humans; Infant; Respiratory syncytial virus; Respiratory Syncytial Virus Vaccines - immunology; Respiratory Syncytial Viruses - genetics; Respiratory Syncytial Viruses - immunology; Vaccines, Attenuated - genetics; Vaccines, Attenuated - immunology; Viral Proteins - genetics
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.aac8463

Respiratory syncytial virus (RSV) is the leading viral cause of severe pediatric respiratory illness, and a safe and effective vaccine for use in infancy and early childhood is needed. We previously showed that deletion of the coding sequence for the viral M2-2 protein (ΔM2-2) down-regulated viral RNA replication and up-regulated gene transcription and antigen synthesis, raising the possibility of development of an attenuated vaccine with enhanced immunogenicity. RSV MEDI ΔM2-2 was therefore evaluated as a live intranasal vaccine in adults, RSV-seropositive children, and RSV-seronegative children. When results in RSV-seronegative children were compared to those achieved with the previous leading live attenuated RSV candidate vaccine, vaccine virus shedding was significantly more restricted, yet the postvaccination RSV-neutralizing serum antibody achieved [geometric mean titer (GMT) = 1:97] was significantly greater. Surveillance during the subsequent RSV season showed that several seronegative RSV MEDI ΔM2-2 recipients had substantial antibody rises without reported illness, suggesting that the vaccine was protective yet primed for anamnestic responses to RSV. Rational design appears to have yielded a candidate RSV vaccine that is intrinsically superior at eliciting protective antibody in RSV-naïve children and highlights an approach for the development of live attenuated RSV vaccines.