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Journal of Virology, October 2000, p. 9317-9321, Vol. 74, No. 19
0022-538X/00/$04.00+0

Recombinant Respiratory Syncytial Virus That Does Not Express the NS1 or M2-2 Protein Is Highly Attenuated and Immunogenic in Chimpanzees

Michael N. Teng,1 Stephen S. Whitehead,1 Alison Bermingham,1 Marisa St. Claire,2 William R. Elkins,3 Brian R. Murphy,1 and Peter L. Collins1,*

Respiratory Viruses Section1 and Experimental Primate Virology Section,3 Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, 20892, and Bioqual, Inc., Rockville, Maryland, 208502

Received 11 May 2000/Accepted 28 June 2000

Mutant recombinant respiratory syncytial viruses (RSV) which cannot express the NS1 and M2-2 proteins, designated rA2Delta NS1 and rA2Delta M2-2, respectively, were evaluated as live-attenuated RSV vaccines. The rA2Delta NS1 virus contains a large deletion that should have the advantageous property of genetic stability during replication in vitro and in vivo. In vitro, rA2Delta NS1 replicated approximately 10-fold less well than wild-type recombinant RSV (rA2), while rA2Delta M2-2 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 rA2Delta NS1 and rA2Delta M2-2 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, rA2Delta NS1 and rA2Delta M2-2 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 rA2Delta NS1 or rA2Delta M2-2 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.

* Corresponding author. Mailing address: LID, NIAID, 7 Center Dr., MSC 0720, Bethesda, MD 20892-0720. Phone: (301) 496-4205. Fax: (301) 496-8312. E-mail: pcollins{at}niaid.nih.gov.

Journal of Virology, October 2000, p. 9317-9321, Vol. 74, No. 19
0022-538X/00/$04.00+0


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