Influenza hemagglutinin protein-based vaccines
Inventors
Nabel, Gary J. • Kanekiyo, Masaro • Wei, Chih-jen • MCTAMNEY, Patrick M. • YASSINE, Hadi M. • BOYINGTON, Jeffrey C.
Assignees
US Department of Health and Human Services
Publication Number
US-9441019-B2
Publication Date
2016-09-13
Expiration Date
2032-09-24
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Abstract
Novel vaccines are provided that elicit broadly neutralizing anti-influenza antibodies. Some vaccines comprise nanoparticles that display hemagglutinin trimers from influenza virus on their surface. The nanoparticles comprise fusion proteins comprising a monomeric subunit of ferritin joined to at least a portion of an influenza hemagglutinin protein. Some portions comprise the ectodomain while some portions are limited to the stem region. The fusion proteins self-assemble to form the hemagglutinin-displaying nanoparticles. Some vaccines comprise only the stem region of an influenza hemagglutinin protein joined to a trimerization domain. Such vaccines can be used to vaccinate an individual against infection by heterologous influenza viruses and influenza virus that are antigenically divergent from the virus from which the nanoparticle hemagglutinin protein was obtained. Also provided are fusion proteins and nucleic acid molecules encoding such proteins.
Core Innovation
The invention provides novel influenza hemagglutinin protein-based vaccines comprising nanoparticles that display hemagglutinin trimers from influenza virus on their surface. These nanoparticles comprise fusion proteins consisting of a monomeric ferritin subunit joined to at least a portion of an influenza hemagglutinin protein. The fusion proteins self-assemble into nanoparticles that present hemagglutinin trimers, enabling potent and broad elicitation of neutralizing anti-influenza antibodies.
The hemagglutinin portions can include the entire ectodomain or be limited to specific regions such as the stem region. Some vaccines include only the stem region fused to a trimerization domain. Such vaccines confer immune responses not only against homologous influenza strains but also against heterologous and antigenically divergent influenza viruses.
The problem addressed by this invention is the limited efficacy and manufacturing challenges of current influenza vaccines. Traditional vaccines are strain-specific, time-consuming to produce in embryonated eggs, and show limited protection against emerging pandemic and drifted strains. Current alternatives such as virus-like particles have limitations relating to immunogenicity and safety, and recombinant hemagglutinin proteins often fail to form native trimers or elicit robust neutralizing antibody titers.
Claims Coverage
The patent includes four independent claims encompassing nanoparticles, methods for vaccine production and vaccination, as well as fusion proteins. The main inventive features relate to the composition and structure of the nanoparticles, their broad immunogenicity, and methods of using and producing them.
Nanoparticles comprising fusion proteins of monomeric ferritin subunits joined to influenza hemagglutinin proteins
The nanoparticles comprise fusion proteins where a monomeric ferritin subunit protein is joined to an influenza hemagglutinin (HA) protein, such that the nanoparticle presents influenza virus HA protein trimers on its surface.
Method of producing vaccines using fusion protein expression and nanoparticle formation
The method comprises expressing a fusion protein comprising a monomeric ferritin protein joined to an influenza hemagglutinin protein under conditions that allow self-assembly into nanoparticles displaying hemagglutinin trimers, followed by recovering the nanoparticles.
Method of vaccinating individuals with nanoparticles eliciting broad immune responses
Administering the nanoparticles to an individual to elicit an immune response against influenza virus, including strains heterologous or antigenically divergent from the source of the hemagglutinin protein in the nanoparticle, optionally using a prime-boost regimen with an HA-stabilized stem-ferritin fusion protein.
Fusion proteins comprising monomeric ferritin subunits joined to specific influenza hemagglutinin regions
Fusion proteins include a monomeric ferritin subunit joined to influenza HA proteins or portions thereof, including regions corresponding to ectodomains, stem regions, or sequences capable of trimerization, and include variants or sequences from defined SEQ ID NOs that elicit broad neutralizing antibodies.
The claims collectively cover compositions of nanoparticles presenting influenza HA as trimers via ferritin fusion proteins, methods for their production and vaccination, and specific fusion protein constructs designed to elicit broadly neutralizing immune responses against diverse influenza virus strains and subtypes.
Stated Advantages
The vaccines of the invention are easily manufactured and potent.
They elicit broadly neutralizing influenza antibodies capable of providing protection against heterologous and antigenically divergent viruses.
Nanoparticle presentation enhances immunogenicity over current TIV vaccines and trimeric HA alone.
Preexisting immunity to ferritin does not diminish HA-specific antibody responses.
Multivalent vaccine formulations do not exhibit antigenic competition and maintain robust immune responses to all included strains.
Vaccination with these nanoparticles provides cross-protective immunity superior to TIV in animal models such as ferrets, including faster viral clearance and reduced clinical signs.
The ferritin subunit chosen (Helicobacter pylori) reduces the risk of autoimmunity due to low sequence homology with mammalian ferritin.
Documented Applications
Vaccination of individuals against infection by influenza virus, including protection against heterologous and antigenically divergent strains and subtypes.
Use of the nanoparticles and fusion proteins as broad-spectrum influenza vaccines.
Combination in multivalent vaccines comprising multiple distinct influenza hemagglutinin proteins for enhanced protective breadth.
Using prime-boost immunization protocols combining HA-ferritin nanoparticles and HA-stabilized stem-ferritin fusion proteins to enhance broadly neutralizing antibody responses.
Production of vaccines by recombinant expression of fusion proteins forming nanoparticles.
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