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


Background. Respiratory 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-a/b response, was deleted from RSV vaccine candidates by use of reverse genetics. Methods. Three NS2 gene–deleted RSV vaccine candidates were studied: rA2cpDNS2, rA2cp248/404DNS2, and rA2cp530/1009DNS2. rA2cpDNS2, which had the fewest attenuating mutations, was evaluated in adults and RSV-seropositive children. rA2cp248/404DNS2 and rA2cp530/1009DNS2 were evaluated in adults and RSV-seropositive and RSV-seronegative children. Results. At a high dose (107.0 pfu), rA2cpDNS2 was not shed by adults, and only 13 % of them had an immune response. The other vaccine candidates, rA2cp248/404DNS2 and rA2cp530/1009DNS2, had greatly decreased in-fectivity in RSV-seronegative children, compared with that of their immediate parent strains, which possess an intact NS2 gene. Conclusions. Deletion of the NS2 gene attenuates RSV in subjects of all ages studied. This validates the strateg

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