Multivalent nanoparticle-based vaccines
Inventors
Graham, Barney S. • Kanekiyo, Masaru • YASSINE, Hadi M.
Assignees
US Department of Health and Human Services
Publication Number
US-11191727-B2
Publication Date
2021-12-07
Expiration Date
2035-12-31
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Abstract
Novel, nanoparticle-based vaccines are provided that elicit an immune response to a broad range of infectious agents, such as influenza viruses. The nanoparticles comprise a heterogeneous population of fusion proteins, each comprising a monomeric subunit of a self-assembly protein, such as ferritin, joined to one or more immunogenic portions of a protein from an infectious agent, such as influenza virus. The fusion proteins self-assemble to form nanoparticles that display a heterogeneous population of immunogenic portions on their surface. When administered to an individual, such nanoparticles elicit an immune response to different strains, types, subtypes and species with in the same taxonomic family. Thus, such nanoparticles can be used to vaccinate an individual against infection by different Types, subtypes and/or strains of infectious agents. Also provided are specific fusion proteins, nucleic acid molecules encoding such fusion proteins and methods of using nanoparticles of the invention to vaccinate individuals.
Core Innovation
The invention provides novel, nanoparticle-based vaccines that elicit broadly neutralizing antibodies against infectious agents such as influenza virus, HIV, and human papilloma virus. These nanoparticles comprise a heterogeneous population of fusion proteins, each containing a monomeric subunit of a self-assembly protein (e.g., ferritin) joined to one or more immunogenic portions of proteins from infectious agents. The fusion proteins self-assemble into nanoparticles that display diverse immunogenic portions on their surface, enabling an immune response to a broad range of strains, types, subtypes, and species within the same taxonomic family.
The problem addressed is that current vaccines, particularly influenza vaccines, exhibit highly strain-specific efficacy and are limited by production constraints (e.g., production in embryonated eggs) and the constantly evolving antigenic nature of influenza virus surface proteins such as hemagglutinin (HA). Existing approaches, such as virus-like particles (VLPs) or recombinant HA proteins, do not significantly improve the breadth or potency of protective immunity. There is a need for vaccines that can elicit broadly neutralizing antibodies to protect against diverse and evolving strains of viruses like influenza.
The invention overcomes these limitations by creating nanoparticles that display a heterogeneous population of immunogenic portions from corresponding proteins of at least two infectious agents within the same taxonomic family. These multivalent nanoparticles elicit broader and more potent immune responses than monovalent nanoparticles or mixtures of monovalent nanoparticles. The nanoparticle design includes fused self-assembling monomeric subunits linked to immunogenic portions, spaced to optimize B-cell receptor crosslinking and selection of cross-reactive B cells, thereby inducing broad neutralization.
Claims Coverage
The claims include two independent claims covering nanoparticles with fused self-assembling subunits displaying heterogeneous immunogenic portions and a kit comprising such nanoparticles.
Nanoparticle displaying at least four ferritin-based fusion proteins with distinct influenza HA RBD immunogenic portions
A nanoparticle comprising at least four species of fusion proteins, each consisting of a self-assembling, monomeric ferritin protein linked to an immunogenic portion of the receptor binding domain (RBD) of an influenza virus HA protein, optionally including protease sites and linker sequences, wherein each fusion protein differs from others by at least one amino acid in the immunogenic portion, and each fusion protein has at least 80% identity to SEQ ID NO:97. The nanoparticle displays these immunogenic portions on its surface.
Nanoparticle comprising at least two species of fusion proteins with distinct immunogenic portions from influenza HA RBD
A nanoparticle comprising at least two species of fusion proteins, each comprising a self-assembling monomeric subunit protein joined to an immunogenic portion of the receptor binding domain from an influenza virus HA protein, optionally with protease sites or linker sequences, differing by at least one amino acid in the immunogenic portion among species, with each fusion protein at least 80% identical to SEQ ID NO:97. The nanoparticle displays these immunogenic portions on its surface.
Kit comprising the described nanoparticle
A kit comprising the nanoparticle of claim 1, i.e., the nanoparticle displaying at least four species of ferritin-based fusion proteins with distinct influenza HA RBD immunogenic portions.
The claims cover multivalent nanoparticles formed from self-assembling fusion proteins displaying diverse influenza HA receptor binding domain immunogenic portions with sequence variation, including specifically ferritin-based assemblies, and kits containing such nanoparticles. These claims emphasize the structure of the fusion proteins, their heterogeneity in immunogenic portions, surface display, and sequence identity to a specified sequence.
Stated Advantages
The nanoparticles elicit a broadly neutralizing and more potent immune response compared to single-species or admixed nanoparticles.
They are easily manufactured and overcome limitations of current influenza vaccines, including strain specificity and production capacity.
Documented Applications
Vaccination of individuals against infection by multiple types, subtypes, strains, or species of infectious agents such as influenza viruses using nanoparticles displaying heterogeneous immunogenic portions.
Induction of broadly neutralizing antibodies against influenza virus and other infectious agents in humans or animals.
Use in prime/boost vaccination protocols to provide protection against evolving seasonal and pandemic influenza virus strains.
Formulation into vaccines containing adjuvants and other pharmaceutical components for administration via various routes to elicit humoral and cellular immune responses.
Use as medicaments and kits comprising nanoparticles, nucleic acid molecules, fusion proteins, and related components for vaccination against influenza virus and other infectious agents.
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