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

Institute for Research in Biomedicine

The State University of New York

The United States of America

Codagenix, Inc.

Other

University System of Maryland

The University of North Carolina at Chapel Hill

The United States of America As Represented by the Department of Health

Pharmacia & Upjohn Company

Rush University Medical Center

Apath, LLC

Mueller, Steffen

Wimmer, Eckard

Peter L Collins

Brian R Murphy

Ursula J Buchholz

Mario H Skiadopoulos

Stephen Whitehead

Shirin Munir

Steffen Mueller

Anna P Durbin

Christine D Krempl

Peter D Kwong

Cindy Luongo

Bo Liang

Antonio Lanzavecchia

Davide Corti

Baoshan Zhang

Michael Gordon Joyce

Yongping Yang

Guillaume Stewart-Jones

Alexander A Bukreyev

Alexander C Schmidt

Tao Tao

Cyril Le Nouën

Linda G Brock

Barney S Graham

Eckard Wimmer

Jason Scott McLellan

Joshua Marc DiNapoli

Anne Schaap Nutt

Natalie Mackow

Paul D Olivo

Gail W Wertz

Mark Edward Peeples

Siba K Samal

Katalin Juhasz

Michael N Teng

Jane E Bailly

Alison Bermingham

Thomas Charles McCarty

Cyril Lenouen

Brian P Murphy

Sondra Schlesinger

Stephane Biacchesi

Jason T Newman

Matthias Lingemann

Sheila Nolan

Cindy L Luongo

Joshua Marc Dinapoli

Paul David Olivo

Metapneumovirus (MPV) F proteins stabilized in a prefusion conformation, nucleic acid molecules and vectors encoding these proteins, and methods of their use and production are disclosed. In several embodiments, the MPV F proteins and/or nucleic acid molecules can be used to generate an immune response to MPV in a subject. In additional embodiments, the therapeutically effective amount of the MPV F ectodomain trimers and/or nucleic acid molecules can be administered to a subject in a method of treating or preventing MPV infection.

Recombinant metapneumovirus f proteins and their use

Respiratory syncytial virus (RSV) infection may lead to severe respiratory illness in young children. Thus, there is a need for a live attenuated vaccine, which would mimic the natural course of infection without causing illness; however, restricting viral replication also reduces the immune response. Reported herein is a method of vaccination using a single dose of a recombinant RSV lacking the M2-2 protein that surprisingly induced a stronger immune response to RSV than previous vaccine candidates despite being more restricted in replication.

Method of vaccination with an attenuated RSV vaccine formulation

Disclosed are live, chimeric non-human Mononegavirales vectors that allow a cell to express at least one protein from at least one human pathogen. In addition, compositions comprising the vectors, methods and kits for eliciting an immune response in a host, and methods of making the vectors are disclosed, in accordance with embodiments of the invention.

Chimeric vectors

Described herein are RSV polynucleotide sequences that make use of multiple codons that are containing silent nucleotide substitutions engineered in multiple locations in the genome, wherein the substitutions introduce a numerous synonymous codons into the genome. Due to the large number of defects involved, the attenuated viruses disclosed herein provide a means of producing attenuated, live vaccines against RSV.

Attenuation of human respiratory syncytial virus by genome scale codon-pair deoptimization

Reported herein are presumptively de-attenuating mutations that are useful, either individually or in combinations that may include other known mutations, in producing recombinant strains of human respiratory syncytial virus (RSV) exhibiting attenuation phenotypes. Also described herein is a novel RSV construct, Min_L-NPM2-1(N88K)L, which exhibits an attenuated phenotype, is stable and is as immunogenic as wild type RSV. The recombinant RSV strains described here are suitable for use as live-attenuated RSV vaccines. Exemplary vaccine candidates are described. Also provided are polynucleotide sequences capable of encoding the described viruses, as well as methods for producing and using the viruses.

Vaccine candidates for human respiratory syncytial virus (RSV) having attenuated phenotypes

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.

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

Recombinant chimeric bovine/human parainfluenza virus 3 (rB/HPIV3) vectors expressing Respiratory Syncytial Virus (RSV) G protein or a recombinant RSV G protein, as well as methods of their use and manufacture, are provided. The rB/HPIV3 vector comprises a genome comprising a heterologous gene encoding the RSV G protein or the recombinant RSV G protein. Nucleic acid molecules comprising the sequence of the genome or antigenome of the disclosed rB/HPIV3 vectors are also provided. The disclosed rB/HPIV3 vectors can be used, for example, to induce an immune response to RSV and HPIV3 in a subject.

Recombinant chimeric bovine/human parainfluenza virus 3 expressing rsv g and its use

Reported herein are novel recombinant respiratory syncytial viruses (RSV) having an attenuated phenotype in which the native positions of the NS1 and/or NS2 genes in the RSV genome are shifted to a higher position, that is at positions that are more distal to the promoter. The changes in the gene positions may be present in combination with mutations at other loci to achieve desired levels of attenuation and immunogenicity. The recombinant RSV strains described here are suitable for use as live-attenuated RSV vaccines. Also provided are polynucleotide sequences capable of encoding the described viruses, as well as methods for producing and using the viruses.

Recombinant respiratory syncytial virus strains comprising NS1 and NS2 gene shifts

Recombinant metapneumovirus F proteins and their use

Recombinant human/bovine parainfluenza virus 1 (HPIV1) expressing a chimeric RSV/HPIV1 F protein and uses thereof

Embodiments of a method for inhibiting viral infection in a subject are provided herein. In some embodiments, the method comprises administration of a competitive antagonist of ouabain binding to ATP1A1 to inhibit respiratory syncytial virus infection in the subject.

Use of ouabain antagonists to inhibit viral infection

Provided herein are novel recombinant respiratory syncytial viruses (RSV) having an attenuated phenotype that contain mutations in the M2-2 open reading frame that interfere with the expression of the M2-2 protein. The M2-2 mutations may be present in combination with mutations at other loci. Using methods described herein, combinations of mutations are provided to achieve desired levels of attenuation. The recombinant RSV strains described here are suitable for use as live-attenuated RSV vaccines. Also provided are polynucleotide sequences of the described viruses, as well as methods for producing and using the viruses.

Recombinant respiratory syncytial virus strains with mutations in the M2-2 ORF providing a range of attenuation phenotypes

Recombinant chimeric bovine/human parainfluenza virus 3 expressing RSV G and its use

Growing community of inventors

Silver Spring, MD, United States of America

Peter L Collins