American Home Products Corporation

National Institutes of Health, a Component of the US Dept. of Health & Human Services

The United States of America

Kuo-Hom L Hsu

Alan R Davis

Michael D Lubeck

Daniel M Teller

Harry R Munson, Jr

Gunnar E Jagdmann, Jr

Ibrahim M Uwaydah

Brian R Murphy

Robert M Chanock

James E Crowe, Jr

Mark Connors

Bernard H Selling

Jehan F Bagli

The respiratory syncytial virus (RSV) is a major cause of lower respiratory tract disease in infants and children throughout the world. RSV is a major cause of pneumonia and bronchiolitis in infants under one year of age, and is a major cause of fatal respiratory tract disease in these infants. The treatment and prevention of RSV infection has been problematic. However, the present invention addresses some of these concerns by providing attenuated RSV strains that are suitable for inclusion in immunizing compositions. Specifically, the present invention is directed toward the introduction of growth restriction mutations into incompletely attenuated host range-restricted cold-passaged respiratory syncytial virus (cpRSV) strains by further passage of the strains at increasingly reduced temperatures to produce derivative strains which are more satisfactorily attenuated. These cold-adaptation (ca) approaches were used to introduce further attenuation in the parental RSV virus cpRSV-3131, which is incompletely attenuated in seronegative children. Mutants of the parental strain were obtained by selecting for large plaque production at reduced temperatures. An RSV cp-3131 derivative, designated D,, was isolated that produces large plaques at 25&deg; C. Biologically cloned virus D1 produces distinctly and uniformly larger plaques at 25&deg; C. as compared to the parental attenuated strain cpRSV-3131 or wild-type strain A2. Thus, D1 is an attenuated cold-adapted, but not temperature-sensitive, RSV mutant. The invention also provides methods for stimulating RSV-specific immune responses in an individual through the administration of said mutants.

Immunogenic compositions comprising cold-adapted attenuated respiratory syncytial virus mutants

The present invention provides vaccine compositions of attenuated respiratory syncytial virus (RSV). More particularly, the attenuated virus may be a derivative of RSV which has been incompletely attenuated by cold-passage or introduction of mutations which produce virus having a temperature sensitive (ts) or cold adapted (ca) phenotype. The invention also provides methods for stimulating the immune system of an individual to induce protection against respiratory syncytial virus by administration of attenuated RSV. The invention also provides pure cultures of attenuated RS virus, wherein the virus has been more completely attenuated by the further derivatization of previously identified incompletely attenuated ts or cp mutants.

Attenuated respiratory syncytial virus vaccine compositions

Antiinfluenza A activity was found in compounds of the formula: ##STR1## wherein X is ##STR2## where one of R.sup.1 and R.sup.2 is H and the other is phenylamino and Z is --SCH.sub.3 or a pharmaceutically acceptable salt thereof.

N-cyanoamidine derivatives as anti-influenza agents

Antiinfluenza A activity was found in compounds of the formula: ##STR1## wherein: X is 2-phenylethyl, 2-furanylmethyl, or ##STR2## where one of R.sup.1 and R.sup.2 is H and the other is phenylamino; Z is --SCH.sub.3 when X is ##STR3## or ##STR4## when X is 2-phenylethyl or 2-furanylmethyl; or a pharmaceutically acceptable salt thereof.

Antiinfluenza A activity was found in compounds of the formula: ##STR1## wherein: X is 2-phenylethyl, 2-furanylmethyl, or ##STR2## where one of R.sup.1 and R.sup.2 is H and the other is phenylamino; Z is --SCH.sub.3 when X is ##STR3## when X is 2-phenylethyl or 2-furanylmethyl; or a pharmaceutically acceptable salt thereof.

Antiviral activity against respiratory syncytial virus has been found in some substituted 6-aminopyrimidines having the formula: ##STR1## wherein R.sup.1 is lower alkyl, preferably methyl or t-butyl, R.sup.2 is halogen or cyano, and R.sup.3 is C.sub.1 -C.sub.6 alkyl or --(CH.sub.2).sub.n R.sup.4 where n is 1 or 2 and R.sup.4 is phenyl, phenyl substituted by lower alkoxy, lower alkyleneoxy, bromo, or 3,4-methylenedioxy; 3 or 4-pyridinyl, pyridinyl substituted by cyano or bromo, thienyl, or di-(C.sub.1 -C.sub.6 alkyl)amino.

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Fort Washington, PA, United States of America

Kuo-Hom L Hsu