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Lassa virus vaccine

A technology of arenaviruses and flaviviruses, applied in the field of vaccines based on chimeric flaviviruses, can solve problems such as inability to expand the technical scale and genetic instability

Pending Publication Date: 2022-07-08
KATHOLIEKE UNIV LEUVEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In addition, the vaccine candidate exhibited genetic instability issues that prevented the technical scale-up required for vaccine production

Method used

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  • Lassa virus vaccine
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0131] Example 1 YFV17D / Lassa Construct

[0132] Lassa glycoprotein precursor (LASV-GPC) from strain Josiah was inserted between YF-E / NS1 to generate two constructs as shown below ( figure 1 ):

[0133] 1) PLLAV-YFV17D-LASV-GPC: Lassa glycoprotein with deletion of N-terminal signal peptide sequence (SSP) and GP2 transmembrane domain (TM). The LASV glycoprotein cleavage site was mutated (R246A) to maintain the precursor GPC (GP1 and GP2 linked). These point mutations R207C and G360C (covalently bound to GP1 and GP2) and E329P (described in Hastie et al. (2017) Science 356, 923-928) were introduced to improve stability. This mutated Lassa-GPC was fused to the transmembrane domains (TM1 and TM2) of WNV to maintain the polyprotein topology required for replication of YFV17D and to allow correct expression of LASV-GPC. In addition, a sequence encoding the first 9 amino acids of YF-NS1 was introduced before the LASV-GPC sequence for proper processing of the antigen.

[0134] 2) ...

Embodiment 2

[0135] Example 2 Construct #1 PLLAV-YFV17D-LASV-GPC

[0136] When PLLAV-YFV17D-LASV-GPC was transfected into BHK21J cells, typical CPE was observed, and the viral supernatant harvested from it formed significantly smaller plaques compared to the plaque phenotype of YFV17D ( figure 2 A). Therefore, the resulting transgenic virus (YFV17D-LASV-GPC) was further attenuated, and the virus yield was at least 10-fold lower compared to YFV17D.

[0137] The stability of PLLAV-YFV17D-LASV-GPC was determined by performing RT-PCR to detect transgene inserts in virus samples harvested during serial passages of YFV17D-LASV-GPC ( figure 2 B). Sequencing of RT-PCR products indicated that the LASV-GPC insert without mutations could be detected in BHK21J cells at least until passage 5.

Embodiment 3

[0138] Example 3 Immunogenicity of PLLAV-YFV17D-LASV-GPC in AG129 mice

[0139] The immunogenicity of PLLAV-YFV17D-LASV-GPC and derived live attenuated virus (LAV) was assessed in AG129 mice. Animals (n=9 / group) were vaccinated with 25 μg of PLLAV-YFV17D-LASV-GPC or 375 PFU of YFV17D-LASV-GPC ( image 3 ). YFV- and LASV-specific antibody responses were quantified by indirect immunofluorescence assay (IIFA), and cell-mediated immune responses were quantified by ELISPOT ( Figure 4 ).

[0140] Vaccinated mice were monitored daily for morbidity / mortality, and blood was collected for serological analysis at baseline and at two-week intervals. The vaccine was safe as no adverse effects were observed in any of the vaccinated mice. Some animals (4 of 9 mice) were boosted two weeks after the first vaccination with PLLAV or LAV YFV17D-LASV-GPC using the same dose and route as the first vaccination ( image 3 ).

[0141] Immunogenicity analysis of YFV17D-LASV-GPC (PLLAV or LAV) sh...

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Abstract

The present invention relates to a polynucleotide comprising a live, infectious, attenuated flavivirus sequence wherein a nucleotide sequence encoding at least a portion of an arenavirus glycoprotein is located in an intergene region between the E gene and the NS1 gene of said flavivirus such that a chimeric virus is expressed, the invention is characterized in that the coding sequences of the C-terminal of the flavivirus E protein and the N-terminal of the signal peptide of the flavivirus NS1 protein comprise the following sequences: another signal peptide of the flavivirus NS1 protein, arenavirus glycoprotein lacking the N-terminal signal sequence and GP2 transmembrane domain, and TM1 and TM2 domains of the flavivirus E protein.

Description

technical field [0001] The present invention relates to chimeric flavivirus-based vaccines. The present invention also relates to vaccines against viruses such as Lassa virus. Background technique [0002] Currently, there is no approved licensed human vaccine against Lassa virus (LASV). Many different vaccine candidates have been generated, involving multiple platform technologies. The most advanced candidates are the VSV-based LASV (VSV-LASV-GPC), Mopeia virus (MOPV) / LASV reassortment virus (clone ML29) and a DNA vaccine called INO-4500 (pLASV-GPC). VSV-based LASV vaccine candidates comprise replication-competent VSV that expresses the glycoprotein of LASV. ML29 is a reassortant between Lassa virus and Mopeia virus, carrying the L segment of MOPV and the S segment (nucleoprotein and glycoprotein) of LASV. INO-4500 is a DNA vaccine encoding the LASV-GPC gene from Josiah f strain from Inovio (pLASV-GPC). [0003] In addition to using different methods described above, y...

Claims

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Application Information

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IPC IPC(8): A61K39/12A61P31/14
CPCA61K39/12A61K2039/5254A61K2039/5256A61K2039/70A61P31/14C12N2760/10034C12N2770/24143Y02A50/30
Inventor K·达迈尔V·莱门斯J·奈茨L·桑切斯费利佩
Owner KATHOLIEKE UNIV LEUVEN
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