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Novel multivalent nanoparticle-based vaccines

A nanoparticle and subunit technology, applied in the field of new multivalent vaccines based on nanoparticles, can solve problems such as antibody difficulties

Pending Publication Date: 2017-12-01
US DEPT OF HEALTH & HUMAN SERVICES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, robust eliciting of these antibodies with such a heterologous neutralization profile by vaccination is difficult [Steel, J. et al. MBio 1, e0018 (2010); Wang, T.T. et al. PLoS Pathog 6, e1000796 (2010); Wei , C.J. et al. Science 329, 1060-1064(2010)]

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0167] Example 1: Production of heterogeneous nanoparticles

[0168] A. Gene synthesis and vector construction

[0169] All genes used in the study were human codon optimized. The gene encoding the H. pylori-bullfrog hybrid ferritin was constructed by incorporating a point mutation (N8Q) at residue 8 of the bullfrog (Rana catesbeiana) ferritin lower subunit (UniProt: P07797) to eliminate potential N-glycosylation site) residues 2-9 with Helicobacter pylori non-heme ferritin (UniProt: Q9ZLI1, residues 3-167) (at residue 7 (I7E) and residue 19 ( N19Q) has mutations to form a salt bridge and eliminate a potential N-glycosylation site) fusion to 6R of bullfrog ferritin, respectively. In some cases, there is an additional GS residue at the carboxyl terminus of H. pylori ferritin. A secreted encapsulin gene was constructed by fusing the human CD5 signal to Thermotoga maritima encapsulin (UniProt:Q9WZP2, residues 1-264). The gene encoding the HA RBD (residues 56-264, H3 numbering...

Embodiment 2

[0174] Example 2: Immunoprecipitation analysis of purified nanoparticles expressing influenza HA protein RBD

[0175] HA RBD nanoparticles expressing RBD from NC99, CA09 or both (CoAsmbl 2) were prepared and purified as described in Example 1 . 4 μg of purified RBD nanoparticles were incubated with 4 μg of anti-NC99 (3u-u), anti-pandemic H1N1HA (2D1) or anti-HA stem region (C179) monoclonal antibodies for 30 min at room temperature. The immune complexes were then captured using protein G-coupled magnetic beads and washed extensively with PBS containing 0.01% Tween 20. The washed pellet was resuspended in 20 μl of Laemmli buffer without reducing agent and analyzed on SDS-PAGE. 5 μg of each protein was loaded. NC99, Type A / New Caledonia / 20 / 1999; CA09, Type A / California / 04 / 2009; WS33, Type A / Wilson-Smith / 1933; AB48, Type A / Albany / 4835 / 1948; BR07 , Type A / Brisbane / 59 / 2007; IA43, Type A / Iowa / 1943; HK77, Type A / Hong Kong / 117 / 1977; FM47, Type A / Fort Monmouth / 1 / 1947. The results o...

Embodiment 3

[0176] Example 3: Immunization of Mice Using Purified Nanoparticles

[0177] The ability of compositions comprising purified monovalent, mixed or heterogeneous nanoparticles to elicit a neutralizing immune response was tested in mice. BALB / c mice aged 6 to 8 weeks were divided into 9 groups (N=5). In the presence of the Sigma Adjuvant System (SAS), at weeks 0 and 3 each group was administered a composition comprising 2 μg of: a) monovalent (i.e., expressing a single HA RBD) nanoparticles, b) various nanoparticles Mixtures of particles, or co-assembled nanoparticles as indicated in c). The administered immunogens and dosing regimens are shown in Table 3 below.

[0178] table 3

[0179]

[0180] 1 Balb / c mice (N=5)

[0181] 2 Type A / New Caledonia / 20 / 99(NC99); Type A / California / 04 / 09(CA09); Type A / Wilson-Smith / 33(WS33); Type A / Albany / 4835 / 48( AB48); Type A / Brisbane / 59 / 07(BR07); Type A / Iowa / 43(IA43); Type A / Hong Kong / 117 / 77(HK77); Type A / Fort Monmouth / 1 / 47 (FM47)

[0...

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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.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application No. 62 / 098,755, filed December 31, 2014, the entire contents of which are incorporated herein by reference. Summary of the invention [0003] The present invention provides novel, nanoparticle-based vaccines that are easy to manufacture, are potent, and that elicit broadly neutralizing antibodies against infectious agents such as influenza virus, HIV, and human papillomavirus. Specifically, the present invention provides novel nanoparticles (nps) whose surface displays a heterogeneous population of immunogenic portions of proteins from infectious agents. Such nanoparticles comprise fusion proteins each comprising a monomeric subunit of ferritin linked to one or more immunogenic moieties of a protein from an infectious agent. When such nanoparticles are administered to an individual, they elicit an immune response against proteins from a wide range of infe...

Claims

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Application Information

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IPC IPC(8): A61K39/12
CPCA61K39/12A61K2039/6031A61K2039/6068A61K2039/6075C12N2760/16134A61P31/16A61K9/167A61K39/145A61K2039/70C12N2760/16171A61K2039/575C12N7/00Y02A50/30
Inventor B.S.格雷厄姆M.卡内基约H.M.亚辛
Owner US DEPT OF HEALTH & HUMAN SERVICES
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