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Computationally optimized broadly reactive antigens for H5N1 and H1N1 influenza viruses

A technology for influenza and influenza hemagglutinin, applied in the direction of viral antigen components, antisense single-stranded RNA viruses, viruses, etc., can solve problems such as increasing the risk of infection

Inactive Publication Date: 2018-01-23
UNIVERSITY OF PITTSBURGH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Live virus vaccines should not be given to immunocompromised or pregnant patients because of the increased risk of infection in these patients

Method used

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  • Computationally optimized broadly reactive antigens for H5N1 and H1N1 influenza viruses
  • Computationally optimized broadly reactive antigens for H5N1 and H1N1 influenza viruses
  • Computationally optimized broadly reactive antigens for H5N1 and H1N1 influenza viruses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0114] Example 1: Generation of H5N1 Influenza COBRA Sequences

[0115] This example describes the use of 426 human H5N1 influenza HA sequences from clades 0, 1, 2.1, 2.2, 2.3 and 7 to generate the H5N1 influenza HA COBRA consensus sequence. The resulting COBRA sequence was referred to as "PATH H5N1 COBRA".

[0116] To generate the final H5N1 influenza HA COBRA sequence, three levels of consensus sequences were generated ( figure 1 ). In the first tier, (1) 5 isolates from clade 0; (2) 86 isolates from clade 1; (3) 106 isolates from clade 2.1; (4) 97 isolates from clade 2.2 isolates; (5) 34 clade 2.3 isolates and (6) 1 clade 7 isolate, resulting in 6 independent consensus sequences. In the second level, a clade 2 consensus sequence was generated using the 3 clade 2 consensus sequences generated in the first level (clade 2.1, clade 2.2 and clade 2.3 consensus sequences). Using the individual clade 0, clade 1 and clade 7 consensus sequences generated in the first level and t...

Embodiment 2

[0119] Example 2: Generation of H1N1 Influenza COBRA Sequences

[0120] This example describes the use of 205 human and porcine H1N1 influenza HA sequences to generate the H1N1 influenza HA COBRA consensus sequence. The resulting COBRA sequence is referred to as "PATH H1N1 COBRA".

[0121] To generate the final H1N1 influenza HA COBRA sequence, two levels of consensus sequences were generated ( figure 2 ). In the first tier, (1) 8 human strains isolated in 1933-1934; (2) 13 human strains isolated in 1935-1947; (3) 12 human strains isolated in 1948-1957 were used; ( 4) 123 human strains and (5) 49 porcine strains isolated from 2009-2011, resulting in 5 independent consensus sequences. Using the 5 independent consensus sequences generated in the first tier, a final consensus sequence was generated. The PATH H1N1 COBRA sequence is shown below and presented herein as SEQ ID NO:2.

[0122] PATH H1N1 COBRA HA (SEQ ID NO: 2)

[0123] MKARLLVLLCALAATDADTICIGYHANNSTDTVDTVLEKNVTV...

Embodiment 3

[0124] Example 3: Codon-optimized COBRA gene sequence

[0125] The COBRA amino acid sequence disclosed herein was back translated and optimized for expression in mammalian cells, including codon usage and RNA optimization (GeneArt; Regensburg, Germany). The optimized nucleic acid sequence can be inserted into an appropriate expression vector, such as the pTR600 expression vector (US Patent Application Publication No. 2002 / 0106798; Ross et al., Nat Immunol. 1(2): 102-103, 2000; Green et al. , Vaccine 20:242-248, 2001). Expression vectors encoding the codon-optimized COBRA gene sequence can be used, for example, to produce VLPs containing the COBRA HA.

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Abstract

Described herein is the generation of optimized H5N1 and H1N1 influenza HA polypeptides for printing broadly reactive immune responses against influenza virus isolates. The optimized HA polypeptides were performed through a series of HA protein alignments and subsequently administered to H5N1 and H1N1 influenza isolates to generate consensus sequences. Provided herein are optimized H5N1 and H1N1 influenza HA polypeptides, as well as compositions, fusion proteins and VLPs comprising said HA polypeptides. Also provided herein are codon optimized nucleic acids encoding the HA polypeptides. The present disclosure also provides methods of eliciting an immune response against influenza virus in a subject.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application No. 61 / 617815, filed March 30, 2012, which is incorporated herein by reference in its entirety. technical field [0003] The present disclosure relates to optimized influenza hemagglutinin proteins that elicit broadly reactive immune responses against H5N1 and H1N1 influenza viruses and their use as vaccines. Background technique [0004] Influenza viruses are members of the Orthomyxoviridae family. There are three subtypes of influenza virus, named influenza A, influenza B, and influenza C. The influenza virion contains a segmented negativesense RNA genome encoding the following proteins: hemagglutinin (HA), neuraminidase (NA), matrix (M1), proton ion channel protein ( M2), nucleoprotein (NP), polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2), polymerase acidic protein (PA) and nonstructural protein 2 (NS2). HA, NA, M1 and M2 proteins a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/11C12N15/44A61K39/145A61K31/16
CPCC07K14/005A61K39/00C12N2760/16134C12N2760/16122A61K39/12A61K2039/5258A61K2039/55505A61K2039/55561A61P31/16A61P37/04A61K39/145C12N15/63A61K9/0019B82Y5/00C07K16/1018C07K2317/32C12Q2600/156G01N33/56983G01N2333/11
Inventor T·M·罗斯C·J·科雷瓦D·M·卡特
Owner UNIVERSITY OF PITTSBURGH