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Published on: October 30, 2016
Codon-deoptimized single-round infectious virus for therapeutic and vaccine applications
Takafumi Noguchi1,2, Anju Miyamori1, Takeshi Sugimoto1,2
1Virus Vaccine Group, BIKEN Innovative Vaccine Research Alliance Laboratories, Institute for Open and Transdisciplinary Research Initiatives, The University of Osaka, Suita, Osaka, Japan.
Insights
Scientists engineered a safer Coxsackievirus B3 (CVB3) vaccine by deoptimizing its genes. This approach reduces the virus
Area of Science:
- Virology
- Immunology
- Vaccine Development
Background:
- Coxsackievirus B3 (CVB3) causes severe myocarditis and pancreatitis, especially in neonates, with high mortality.
- Current preventive strategies and treatments for CVB3 infections are lacking.
- Live-attenuated vaccines are promising but require careful control of pathogenicity without sacrificing immunogenicity.
Purpose of the Study:
- To investigate codon deoptimization and defective viral genomes (DVGs) as strategies to modulate CVB3 pathogenicity.
- To preserve the immune-activating capacity of CVB3 while reducing its harmful effects.
- To develop safer and effective live-attenuated vaccine candidates and therapeutic agents against CVB3.
Main Methods:
- Engineered codon-deoptimized CVB3 variants with increased CpG dinucleotide content in the 3CD region.
- Assessed the pathogenicity and immunogenicity of these modified CVB3 strains.
- Generated and evaluated DVGs derived from both codon-deoptimized and wild-type CVB3 (CVB3WT).
Main Results:
- Codon-deoptimized CVB3s showed attenuated pathogenicity, directly correlated with the degree of deoptimization.
- These modified CVB3s successfully induced protective immunity against CVB3WT infection.
- DVGs from codon-deoptimized CVB3 exhibited enhanced viral interference and stimulated greater neutralizing antibody production compared to DVGs from CVB3WT.
Conclusions:
- CpG-enriched genomes and DVGs are effective tools for regulating viral pathogenicity.
- These strategies enhance vaccine safety and immunogenicity for potential live-attenuated vaccines.
- The findings support the development of novel therapeutic strategies against viral infections like CVB3.
Abstract:
Coxsackievirus B3 (CVB3) is a major cause of myocarditis and acute pancreatitis, particularly in neonates, in whom infections result in severe symptoms and high mortality rates. Despite the urgent need for effective preventive strategies, no vaccines or therapeutic agents have been developed. Live-attenuated vaccines hold promise for combating viral infections; however, their pathogenicity must be carefully regulated without compromising immunogenicity. Here, we investigated codon deoptimization and defective viral genomes (DVGs) as strategies to modulate CVB3 pathogenicity, while preserving its immune-activating capacity. Codon-deoptimized CVB3s with increased CpG dinucleotide content in their 3CD region were engineered, leveraging the innate immunostimulatory properties of CpG. These modified CVB3s exhibited attenuated pathogenicity proportional to the level of codon deoptimization and induced protective immunity against wild-type CVB3 (CVB3WT), making them viable live-attenuated vaccine candidates. Additionally, DVGs derived from codon-deoptimized CVB3 demonstrated superior viral interference and enhanced stimulation of neutralizing antibody production compared to DVGs derived from CVB3WT. These findings highlight that CpG-enriched genomes and DVGs are promising tools for regulating viral pathogenicity, enhancing vaccine safety, and developing therapeutic strategies against viral infections.
