Wisconsin Alumni Research Foundation

The University of Tokyo

Flugen, Inc.

Yoshihiro Kawaoka

Gabriele Neumann

Shinji Watanabe

Jihui Ping

Tokiko Watanabe

Makoto Ozawa

Taisuke Horimoto

Shin Murakami

Shinya Yamada

Shiho Chiba

Satoshi Fukuyama

Yuri Furusawa

Kosuke Takada

Huihui Kong

Seiya Yamayoshi

Masaki Imai

Luke D Jasenosky

Pamuk Bilsel

Yasuko Hatta

Masato Hatta

Hatice Akarsu

Kiyoko Iwatsuki-Horimoto

Shuji Hatakeyama

Stefan Hamm

Hideki Ebihara

Peter J Halfmann

The invention provides a recombinant biologically contained influenza virus that is a PB2 knockout virus, e.g., one that is useful to generate a multivalent vaccine, and methods of making and using that virus.

Influenza viruses with mutant PB2 gene segment as live attenuated vaccines

The invention provides a composition useful to prepare high titer influenza B viruses, e.g., in the absence of helper virus, which includes internal genes from an influenza B virus vaccine strain or isolate, e.g., one that is safe in humans, for instance, one that does not result in significant disease, that confer enhanced growth in cells in culture, such as MDCK cells, or in eggs.

Influenza B virus replication for vaccine development

Modified influenza virus neuraminidases are described herein that have stabilized NA tetramers which may improve vaccine production efficiency, thus improving the yield of vaccine viruses.

Recombinant influenza viruses with stabilized NA

The invention provides a vaccine comprising a recombinant biologically contained filovirus and methods of making and using those viruses.

Recombinant biologically contained filovirus vaccine

The invention provides a composition useful to prepare influenza vaccine viruses, e.g., in the absence of helper virus, which includes internal viral segments from an influenza virus vaccine strain or isolate, e.g., one that is safe in humans, for instance, one that does not result in significant disease, and encodes a heterologous antigen.

Recombinant multivalent influenza viruses

A mammalian or avian cell line that expresses high levels of human influenza virus receptors is provided. In one embodiment, the cell line supports human influenza virus, e.g., human A/H3 influenza virus, isolation and growth much more effectively than corresponding conventional (unmodified) cells or in corresponding human virus receptor-overexpressing cells, and the propagated viruses may maintain higher genetic stability than in the corresponding cells.

Humanized cell line

Modified influenza virus neuraminidases are described herein that improve viral replication, thus improving the yield of vaccine viruses. Expression of such modified. neuraminidases by influenza virus may also stabilize co-expressed hemagglutinins so that the hemagglutinins do not undergo mutation.

Recombinant influenza viruses with stabilized HA for replication in eggs

Methods of preparing influenza viruses having altered immunodominant epitopes in HA, e.g., having one or more residues in one or more of antigenic sites A-E in HA altered, and viral vectors, e.g., influenza virus VLPs or non-influenza viruses or VLPs thereof expressing or having influenza HAs with altered immunogenicity as a result of altered immunodominant epitopes therein are provided.

Vectors for eliciting immune responses to non-dominant epitopes in the hemagglutinin (HA) protein

An isolated recombinant influenza virus is provided having PA, PB1, PB2, NP, NS, M, NA and HA viral segments, wherein the PB1 viral segment encodes a PB1 with a residue other than isoleucine at position 711 or the M viral segment encodes a M1 with a residue other than methionine at position 128, wherein the recombinant influenza virus has enhanced replication relative to a corresponding influenza virus having a PB1 viral segment that encodes a PB1 with an isoleucine at position 711 or having a M viral segment that encodes a M1 with methionine at position 128, as well as methods of making and using the virus.

Influenza virus replication for vaccine development

The invention provides a vaccine comprising an effective amount of an isolated recombinant influenza virus comprising a mutant M gene segment that is mutated so that upon viral replication the mutant M gene expresses a functional M1 protein and a mutant M2 protein with a deletion of the cytoplasmic tail and either lacking a transmembrane domain or having a mutated transmembrane domain.

Vaccines comprising mutant attenuated influenza viruses

Modified influenza virus neuraminidases are described herein that improve viral replication, thus improving the yield of vaccine viruses. Expression of such modified neuraminidases by influenza virus may also stabilize co-expressed hemagglutinins so that the hemagglutinins do not undergo mutation or decrease the need for HA binding to cells.

The disclosure provides for an isolated recombinant influenza virus having at least one of: a PA gene segment encoding PA with a residue at position 443 that is not arginine, a PB1 gene segment encoding PB1 with a residue at position 737 that is not lysine, a PB2 gene segment encoding PB2 with a residue at position 25 that is not valine or a residue at position 712 that is not glutamic acid, a NS gene segment encoding a NS1 with a residue at position 167 that is not proline, a HA gene segment encoding a HA with a residue at position 380 that is not threonine, or any combination thereof, and methods of making and using the virus.

Growing community of inventors

Middleton, WI, United States of America

Yoshihiro Kawaoka