Recombinant human parainfluenza virus type 1 expressing a chimeric RSV/HPIV1 f protein and uses thereof

Inventors

Collins, Peter • Liang, Bo • Munir, Shirin • Nutt, Anne Schaap • Buchholz, Ursula • Mackow, Natalie • Kwong, Peter • Graham, Barney • McLellan, Jason

Assignees

US Department of Health and Human Services

Abstract

Recombinant paramyxoviruses including a viral genome encoding a heterologous gene are provided. In several embodiments, the recombinant paramyxovirus is a recombinant parainfluenza virus, such as a recombinant PIV3 including a viral genome encoding a heterologous respiratory syncytial virus F ectodomain linked to the transmembrane domain and the cytoplasmic tail of the F protein from the PIV3. Nucleic acid molecules including the genome of a recombinant paramyxoviruses are also provided. The recombinant viruses may advantageously be used in vaccine formulations, such as for vaccines against parainfluenza virus and respiratory syncytial virus.

Core Innovation

This invention provides recombinant paramyxoviruses that include viral genomes encoding heterologous genes, specifically encoding antigens from heterologous viruses such as respiratory syncytial virus (RSV) fusion (F) protein. In particular, the recombinant paramyxovirus can be a recombinant parainfluenza virus (PIV) incorporating a viral genome with a heterologous gene encoding a RSV F ectodomain linked to the transmembrane domain (TM) and cytoplasmic tail (CT) of the paramyxovirus F protein. This chimeric configuration enhances the incorporation of the RSV F ectodomain into the paramyxovirus envelope, thereby increasing immunogenicity when administered to a subject.

The background establishes that RSV and human parainfluenza viruses (HPIVs) are leading causes of severe respiratory infections with significant morbidity, especially among infants, children, the elderly, and immunocompromised individuals. Development of effective vaccines against RSV and PIVs remains elusive, with challenges including suboptimal immunogenicity and issues related to vector stability and antigen expression. Prior attempts to express RSV F protein in related paramyxovirus vectors resulted in poor incorporation of RSV F into vector particles and required deletion of vector F protein to improve packaging, which is undesirable as it removes important vector protective antigens and impairs infectious virus production.

The core innovation involves engineering a recombinant paramyxovirus that expresses a chimeric RSV F protein in which the TM and CT domains of the RSV F protein are replaced with the corresponding domains from the paramyxovirus F protein. This modification leads to a multi-fold increase in RSV F ectodomain incorporation into the viral envelope, resulting in dramatically enhanced elicitation of immune responses against the RSV F ectodomain, including increased quantity and quality of virus-neutralizing serum antibodies. Various embodiments include the use of codon-optimized RSV F genes with amino acid substitutions (such as DS-Cav1 and HEK assignments) to stabilize the prefusion conformation and enhance expression or incorporation. The heterologous gene can be positioned in different locations within the paramyxovirus genome, typically between the genomic promoter and N gene or between N and P genes.

Claims Coverage

The patent claims include 19 independent inventive features related to recombinant HPIV1 expressing chimeric RSV F protein and methods of use.

The claims define recombinant HPIV1 viruses encoding a chimeric RSV F protein with TM and CT from HPIV1 F protein, specific amino acid substitutions for prefusion stabilization and expression enhancement, insertion of the gene at defined genome positions, variants with attenuating mutations, viral particles with RSV F ectodomain on the envelope, immunogenic compositions comprising such recombinant viruses, and methods for eliciting protective immune responses, especially in young subjects.

Stated Advantages

Documented Applications