Wyeth

Wyeth Holdings Corporation

The United States of America, As Represented by the Secretary, Department of Health and Human Services

Stephen Alexander Udem

Robert M Chanock

Christopher Lee Parks

John Hayward Eldridge

Timo Vesikari

David Kirkwood Clarke

Timothy Joseph Zamb

Gerald R Kovacs

Roger Michael Hendry

Mohinderjit S Sidhu

Nikolaos Vasilakis

Xiaoyan Mo

Shridhara C Murthy

Peng Tian

J Erik Johnson

Timothy J Zamb

Mohinder S Sidhu

Ruth S Rappaport

Bruce B Mason

Robert A Lerch

Alice F Georgiu

Deborah A Buonagurio

Sangeeta Bhargava

Zimra R Israel

Albert Kapikian

The present invention broadly relates to the synergistic attenuation of vesicular stomatitis virus (VSV), More particularly, the invention relates to the identification of combined mutation classes which synergistically attenuate the pathogenicity of VSV vectors in mammals and immunogenic compositions thereof.

Synergistic attenuation of vesicular stomatitis virus, vectors thereof and immunogenic compositions thereof

The present invention broadly relates to the synergistic attenuation of vesicular stomatitis virus (VSV). More particularly, the invention relates to the identification of combined mutation classes which synergistically attenuate the pathogenicity of VSV vectors in mammals and immunogenic compositions thereof.

Self-propagating, fusogenic blebs are produced from cells infected with a population of Venezuelan Equine Encephalitis virus replicon particles (VRP). The self-propagating, fusogenic nature of the blebs is derived from expression of heterologous genes encoding viral fusion proteins that are incorporated into the replication defective replicon particles. The resulting blebs can be harvested from supernatants of cells displaying severe cytopathic effects. The blebs are used to make immunogenic compositions and devise methods of immunizing mammals against paramyxoviruses such as parainfluenza virus type 3.

Fusogenic, self-propagating blebs as immunogenic compositions

Isolated nucleic acid molecules comprising a gene segment from a rhesus rotavirus (RRV) or from one of three rhesus: human reassortant viruses are disclosed, including isolated nucleic acid molecules having a sequence selected from the group consisting of: SEQ ID NO: 1-14, inclusive, and isolated nucleic acid molecules encoding a protein having a sequence selected from the group consisting of SEQ ID NO: 15-28, inclusive, as well as variants of the isolated nucleic acid molecules.

Sequence analysis of the tetravalent rotavirus vaccine

This invention relates to a method for recombinantly producing, via rescue of mumps virus, a nonsegmented, negative-sense, single-stranded RNA virus, and immunogenic compositions formed therefrom. Additional embodiments relate to methods of producing the mumps virus as an attenuated and/or infectious virus. The recombinant viruses are prepared from cDNA clones, and, accordingly, viruses having defined changes, including nucleotide/polynucleotide deletions, insertions, substitutions and re-arrangements, in the place of the genome are obtained.

Rescue of mumps virus from cDNA

The nonstructural protein 4 (NSP4) in the SA11 ATCC rotavirus strain has a histidine at amino acid position 47. This substituted form is more cytotoxic than the NSP4 of the Australia rotavirus strain, which has an asparagine at amino acid position 47. The histidine at amino acid position 47 is mutagenized to another amino acid to produce an alternative form of NSP4 which has reduced toxicity, while retaining its antigenicity and immunogenicity. NSP4 having a glutamic acid at amino acid position 48 is more cytotoxic than NSP4 having a lysine at amino acid position 48. The lysine at amino acid position 48 is mutagenized to another amino acid other than glutamic acid to produce an alternative form of NSP4 which has reduced toxicity, while retaining its antigenicity and immunogenicity.

Differential cytotoxicity of alternative forms of rotavirus nonstructural protein 4

This invention relates to improved methods for producing nonsegmented, negative-sense, single-stranded RNA viruses of the Order designated Mononegavirales virus, including embodiments relating to methods of producing such viruses as attenuated and/or infectious viruses, such as Measles virus (MV) and respiratory syncytial virus (RSV). One method for producing a recombinant virus from the Order Mononegavirales comprises (a) in at least one host cell, conducting transfection of a rescue composition which comprises (i) a transcription vector comprising an isolated nucleic acid molecule which comprises polynucleotide sequence encoding a genome or antigenome of a nonsegmented, negative-sense, single stranded RNA virus of the Order Mononegavirales and (ii) at least one expression vector which comprises at least one isolated nucleic acid molecule encoding the trans-acting proteins necessary for encapsidation, transcription and replication; in a host cell under conditions sufficient to permit the co-expression of these vectors and the production of the recombinant virus; (b) heating the transfected rescue composition to an effective heat shock temperature under conditions sufficient to increase the recovery of the recombinant virus; and optionally, (c) harvesting the resulting recombinant virus.

Methods for rescue of RNA viruses

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New York, NY, United States of America

Stephen Alexander Udem