Recombinant parainfluenza virus vaccines attenuated by deletion or ablation of non-essential gene

Abstract

Provided are recombinant parainfluenza viruses (PIV) in which the expression of C, D and / or V translation reading frames (ORFs) is reduced or eliminated and new PIV vaccine candidates are generated. Reducing or eliminating expression of the C, D, and / or V ORFs by altering a recombinant PIV genome or antigenome, e.g., by introducing a stop codon, mutations of an RNA editing site, mutations that change the amino acid defined by the start codon , or frameshift mutations in the target ORF. Alternatively, the C, D and / or V ORF is completely or partially deleted, rendering the protein encoded by it partially or completely non-functional, or completely destroying protein expression at the same time. C, D and / or V ORF deletion or knockout mutants have phenotypic characteristics that are very good in vaccine development. These deletion or knockout mutations specifically result in the production of one or more desired phenotypes in the resulting viral or subviral particles. The resulting vaccine candidates exhibit changes in viral growth properties, attenuation, plaque size, and / or cytopathological changes, as well as other novel phenotypes. Various mutations and nucleotide modifications present in C, D and / or VORF deletion or removal mutant PIVs of the invention are also provided to obtain good phenotypic and structural effects.

Description

Background of the invention [0001] Human parainfluenza virus type 3 (HPIV3) is a common cause of severe lower respiratory tract infection in young children and children under 1 year of age. It is second only to respiratory syncytial virus (RSV) in causing hospital admissions for viral lower respiratory disease in children of this age (Collins et al., p1205-1243 in B.N. Fields (Knipe et al. eds) Fields Virology, 3 rd ed., vol.1., Lippincott-Raven Publishers, Philadelphia, 1996; Crowe et al., Vaccine 13:415-421, 1995; Marx, J. Infect. Dis. 176:1423-1427, 1997). Infection with this virus causes significant disease in children under 3 years of age. HPIV1 and HPIV2 are the major causes of laryngotracheobronchitis (croup) and can also cause severe pneumonia and bronchiolitis (Collins et al., 3 rd ed. In"Fields Virology" , B.N. Fields, D.M. Knipe, P.M. Howley, R.M. Chanock, J.L. Melnick, T.P. Monath, B. Roizman, and S.E. Straus, Eds., Vol. 1, p1205-1243, Lippincott-Raven Pu...

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