Live attenuated strains of foot and mouth disease modified by deoptimization and uses thereof
Inventors
De Los Santos, Teresa B. • Rieder, Aida E. • DIAZ-SAN SEGUNDO, Fayna C. • KLOC, ANNA • Coleman, John R. • Mueller, Steffen • MEDINA, GISSELLE N.
Assignees
US Department of Agriculture USDA • Codagenix Inc
Publication Number
US-11793870-B2
Publication Date
2023-10-24
Expiration Date
2041-05-26
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Abstract
The present disclosure describes deoptimized foot and mouth viruses and their use for prophylactic and therapeutic treatment of mammalian subjects. The recombinant viruses provided herein include alterations in several genomic regions as well as Differentiating Infected from Vaccinated Animals (DIVA) markers.
Core Innovation
Foot-and-mouth disease (FMD) is a highly contagious viral disease affecting cloven-hoofed animals caused by FMD virus (FMDV). The disease leads to severe economic costs and challenges in control, with current vaccines having limitations such as a delayed protective immunity onset and shorter duration than natural infection. Existing attenuated FMDV candidates have faced issues including partial virulence or reversion to virulence, preventing their successful development or implementation as live attenuated vaccines.
The invention describes the generation of stable, viable deoptimized FMDV strains through synonymous codon and codon-pair deoptimization of several genomic regions, including conserved P2 and P3 domains, rather than only capsid regions. These modified viruses contain Differentiating Infected from Vaccinated Animals (DIVA) markers, enabling differentiation. They show attenuation in cell cultures, mice, and swine, with reduced virulence and decreased probability of reversion or recombination with virulent strains, highlighting their potential as modified live attenuated vaccine candidates.
Claims Coverage
The patent includes multiple independent claims focusing on deoptimized foot and mouth disease viruses and methods of eliciting immune responses using these viruses. The claims cover deoptimization of specific genomic regions, compositions with DIVA markers, and administration methods.
Deoptimized genomic regions in FMDV
A deoptimized foot and mouth disease virus comprising a substituted genomic region with at least 95% identity to SEQ ID NOs: 1-7, encoding the same polypeptide sequence or with up to 10 amino acid changes.
Inclusion of DIVA markers
The deoptimized FMDV further comprises DIVA markers involving mutations in the 3B and 3D coding regions enabling differentiation between infected and vaccinated animals.
Codon pair bias reduction in P2 and/or P3 domains
A deoptimized modified FMDV constructed by substituting the P2 and/or P3 domain with codon or codon-pair deoptimized regions encoding the same or slightly altered protein, where the codon pair bias is reduced by 0.05, 0.1, or 0.2 compared to parent virus.
Specific variant strains with P2, P3, or P2/P3 deoptimization
Deoptimized FMDV variants including A24-P2-3B3D, A24-P3-3B3D, and A24-P2/P3-3B3D, each having deoptimized genomic regions as defined.
Method of eliciting immune response by administration of deoptimized virus
A method of eliciting an immune response to FMD by administering the deoptimized modified FMDV to a mammalian subject, including specific dosing ranges (102 to 105 pfu) and prime and boost dose regimens.
The claims collectively define novel recombinant FMDV strains with codon and codon-pair deoptimization in specified genomic regions combined with DIVA markers, and methods of using these strains for immunization, emphasizing the engineered attenuation and differentiation properties.
Stated Advantages
Deoptimized FMDV strains exhibit attenuation in cell culture, mice, and swine, the natural host, reducing virulence while maintaining viability.
Use of codon/codon-pair deoptimization reduces the probability of reversion to virulence and recombination with circulating virulent strains.
Deoptimized viruses contain DIVA markers allowing differentiation of infected animals from vaccinated animals.
The modified viruses can induce strong adaptive immune responses and protective immunity in vaccinated animals.
Documented Applications
Prophylactic and therapeutic treatment of mammalian subjects, including bovids and suids, against foot and mouth disease.
Use as modified live attenuated vaccine candidates for FMDV, enabling immunization with reduced risk of virulence.
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