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- alpha / beta response, was deleted from RSV vaccine candidates by use of reverse genetics.


METHODS
Three NS2 gene-deleted RSV vaccine candidates were studied: rA2cp Delta NS2, rA2cp248/404 Delta NS2, and rA2cp530/1009 Delta NS2. rA2cp Delta NS2, which had the fewest attenuating mutations, was evaluated in adults and RSV-seropositive children. rA2cp248/404 Delta NS2 and rA2cp530/1009 Delta NS2 were evaluated in adults and RSV-seropositive and RSV-seronegative children.


RESULTS
At a high dose (10(7.0) pfu), rA2cp Delta NS2 was not shed by adults, and only 13% of them had an immune response. The other vaccine candidates, rA2cp248/404 Delta NS2 and rA2cp530/1009 Delta NS2, had greatly decreased infectivity 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 strategy of developing live respiratory tract virus vaccines in which the virus's ability to inhibit the human innate immune system is blocked. rA2cp248/404 Delta NS2 should be studied in children at a higher input titer, because it was more infectious and immunogenic than was rA2cp530/1009 Delta NS2.
Wright
Peter F
PF
Division of Pediatric Infectious Disease, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Peter.Wright@Vanderbilt.edu
Karron
Ruth A
RA
Madhi
Shabir A
SA
Treanor
John J
JJ
King
James C
JC
O'Shea
Alice
A
Ikizler
Mine R
MR
Zhu
Yuwei
Y
Collins
Peter L
PL
Cutland
Clare
C
Randolph
Valerie B
VB
Deatly
Anne M
AM
Hackell
Jill G
JG
Gruber
William C
WC
Murphy
Brian R
BR
D000328:Adult; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007372:Interferons / Q000819:agonists*; D018357:Respiratory Syncytial Virus Infections / Q000821:virology*; D018113:Respiratory Syncytial Virus, Human / Q000737:chemistry / Q000472:pathogenicity*; D014611:Vaccination; D017361:Viral Nonstructural Proteins / Q000633:toxicity*; D014774:Virulence / Q000502:physiology*; D017201:Virus Shedding
D017361:Viral Nonstructural Proteins; D007372:Interferons