title: Recombinant respiratory syncytial virus that does not express the NS1 or M2-2 protein is highly attenuated and immunogenic in chimpanzees.
abstract: Mutant recombinant respiratory syncytial viruses (RSV) which cannot express the NS1 and M2-2 proteins, designated rA2DeltaNS1 and rA2DeltaM2-2, respectively, were evaluated as live-attenuated RSV vaccines. The rA2DeltaNS1 virus contains a large deletion that should have the advantageous property of genetic stability during replication in vitro and in vivo. In vitro, rA2DeltaNS1 replicated approximately 10-fold less well than wild-type recombinant RSV (rA2), while rA2DeltaM2-2 had delayed growth kinetics but reached a final titer similar to that of rA2. Each virus was administered to the respiratory tracts of RSV-seronegative chimpanzees to assess replication, immunogenicity, and protective efficacy. The rA2DeltaNS1 and rA2DeltaM2-2 viruses were 2,200- to 55,000-fold restricted in replication in the upper and lower respiratory tracts but induced a level of RSV-neutralizing antibody in serum that was only slightly reduced compared to the level induced by wild-type RSV. The replication of wild-type RSV in immunized chimpanzees after challenge was reduced more than 10,000-fold at each site. Importantly, rA2DeltaNS1 and rA2DeltaM2-2 were 10-fold more restricted in replication in the upper respiratory tract than was the cpts248/404 virus, a vaccine candidate that retained mild reactogenicity in the upper respiratory tracts of 1-month-old infants. Thus, either rA2DeltaNS1 or rA2DeltaM2-2 might be appropriately attenuated for this age group, which is the major target population for an RSV vaccine. In addition, these results show that neither NS1 nor M2-2 is essential for RSV replication in vivo, although each is important for efficient replication.
authors.affiliation: Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, 20892, USA.
authors.forename: M N
authors.initials: MN
authors.lastname: Teng
authors.forename: S S
authors.initials: SS
authors.lastname: Whitehead
authors.forename: A
authors.initials: A
authors.lastname: Bermingham
authors.forename: M
authors.initials: M
authors.lastname: St Claire
authors.forename: W R
authors.initials: WR
authors.lastname: Elkins
authors.forename: B R
authors.initials: BR
authors.lastname: Murphy
authors.forename: P L
authors.initials: PL
authors.lastname: Collins
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology*; D015707:HN Protein; D009154:Mutation; D002679:Pan troglodytes; D011995:Recombination, Genetic; D012136:Respiratory Syncytial Viruses / Q000235:genetics* / Q000276:immunology*; D014759:Viral Envelope Proteins; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics* / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D015707:HN Protein; D014759:Viral Envelope Proteins; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C116204:attachment protein G