title: A gene deletion that up-regulates viral gene expression yields an attenuated RSV vaccine with improved antibody responses in children.
abstract: 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.
authors.affiliation: Center for Immunization Research, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. rkarron@jhu.edu.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Karron
authors.affiliation: RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy, Immunology, and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Luongo
authors.affiliation: Center for Immunization Research, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
authors.forename: Bhagvanji
authors.initials: B
authors.lastname: Thumar
authors.affiliation: Center for Immunization Research, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Loehr
authors.affiliation: Seattle Children's Research Institute, University of Washington, Seattle, WA 98101, USA.
authors.forename: Janet A
authors.initials: JA
authors.lastname: Englund
authors.affiliation: RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy, Immunology, and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Collins
authors.affiliation: RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy, Immunology, and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ursula J
authors.initials: UJ
authors.lastname: Buchholz
mesh_terms: D000328:Adult; D000914:Antibodies, Viral / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology; D002675:Child, Preschool; D017353:Gene Deletion; D015967:Gene Expression Regulation, Viral; D006801:Humans; D007223:Infant; D022261:Respiratory Syncytial Virus Vaccines / Q000276:immunology*; D012136:Respiratory Syncytial Viruses / Q000235:genetics / Q000276:immunology; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics*
chemical_list: D000914:Antibodies, Viral; C507355:M2-2 protein, respiratory syncytial virus; D022261:Respiratory Syncytial Virus Vaccines; D014613:Vaccines, Attenuated; D014764:Viral Proteins