The Interferon Antagonist NS2 Protein of Respiratory Syncytial Virus Is an Important Virulence Determinant for Humans

• Published in: The Journal of infectious diseases Vol. 193; no. 4; pp. 573 - 581
• Main Authors: Wright, Peter F., Karron, Ruth A., Madhi, Shabir A., Treanor, John J., King, James C., O’Shea, Alice, Ikizler, Mine R., Zhu, Yuwei, Collins, Peter L., Cutland, Clare, Randolph, Valerie B., Deatly, Anne M., Hackell, Jill G., Gruber, William C., Murphy, Brian R.
• Format: Journal Article
• Language: English
• Published: United States The University of Chicago Press 15.02.2006; University of Chicago Press; Oxford University Press
• Subjects: Adult; Adults; Antibodies; Child; Child, Preschool; Diseases; Dosage; Human respiratory syncytial virus; Humans; Interferons - agonists; Respiratory syncytial virus; Respiratory Syncytial Virus Infections - virology; Respiratory syncytial virus vaccines; Respiratory Syncytial Virus, Human - chemistry; Respiratory Syncytial Virus, Human - pathogenicity; Respiratory syncytial viruses; Transcriptional regulatory elements; Vaccination; Viral Nonstructural Proteins - toxicity; Virulence - physiology; Virus Shedding; Viruses
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/499600

BackgroundRespiratory syncytial virus (RSV) is targeted for vaccine development, because it causes severe respiratory tract illness in the elderly, young children, and infants. A primary strategy has been to derive live attenuated viruses for use in intranasally administered vaccines that will induce a protective immune response. In the present study, the NS2 gene, whose encoded protein antagonizes the host’s interferon-α/β response, was deleted from RSV vaccine candidates by use of reverse genetics MethodsThree NS2 gene–deleted RSV vaccine candidates were studied: rA2cpΔNS2, rA2cp248/404ΔNS2, and rA2cp530/1009ΔNS2. rA2cpΔNS2, which had the fewest attenuating mutations, was evaluated in adults and RSV-seropositive children. rA2cp248/404ΔNS2 and rA2cp530/1009ΔNS2 were evaluated in adults and RSV-seropositive and RSV-seronegative children ResultsAt a high dose (107.0 pfu), rA2cpΔNS2 was not shed by adults, and only 13% of them had an immune response. The other vaccine candidates, rA2cp248/404ΔNS2 and rA2cp530/1009ΔNS2, had greatly decreased infectivity in RSV-seronegative children, compared with that of their immediate parent strains, which possess an intact NS2 gene ConclusionsDeletion of the NS2 gene attenuates RSV in subjects of all ages studied. This validates the strategy of developing live respiratory tract virus vaccines in which the virus's ability to inhibit the human innate immune system is blocked. rA2cp248/404ΔNS2 should be studied in children at a higher input titer, because it was more infectious and immunogenic than was rA2cp530/1009ΔNS2