Extensive genomic recoding by codon-pair deoptimization selective for mammals is a flexible tool to generate attenuated vaccine candidates for dengue virus 2

Stauft, Charles B.; Song, Yinglin; Gorbatsevych, Oleksandr; Pantoja, Petraleigh; Rodríguez, Idia V.; Futcher, Bruce; Sariol, Carlos A.; Wimmer, Eckard

doi:10.1016/j.virol.2019.09.003

Cited by 12 publications

(9 citation statements)

References 26 publications

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“…Lack of detectable viable virus in serum could contribute to the overall lack of antibody induction; however, previous studies have shown induction of neutralizing antibodies without viremia (Diaz-San Segundo et al, 2016). In recent studies with other deoptimized vaccine candidates for other viral disease, i.e., DENV, Stauft et al (2019a) showed that promising candidates initially tested in mice, were also too attenuated to induce a protective immune response when tested in more relevant species (Rhesus macaque). Accordingly, if deoptimization in the P2 and/or P3 regions is to be used as a vaccine backbone, further refinement of the deoptimization parameters to "de-attenuate" the strains used in combination with other well-established attenuating mutations in FMDV NS proteins (Diaz-San Segundo et al, 2012) might be required.…”

Section: Discussionmentioning

confidence: 99%

“…Independently of the "codon bias" concept, synonymous codon-pairs might also be used at frequencies that differ from those statistically predicted, a phenomenon that has been defined as "codon-pair bias" and is species specific (Moura et al, 2007). By applying this technology to recode the nucleotides of polio, influenza, respiratory syncytial and dengue viruses, viable viruses were derived by reverse genetics displaying severe attenuation in vitro and in vivo (Coleman et al, 2008;Mueller et al, 2010;Yang et al, 2013;Le Nouën et al, 2014;Shen et al, 2015;Stauft et al, 2018Stauft et al, , 2019a. Furthermore, applying codon-pair bias deoptimization to other viruses such as, porcine respiratory and reproductive syndrome virus (Park et al, 2020), classical swine fever virus (Velazquez-Salinas et al, 2016), human immunodeficiency type 1 virus (Martrus et al, 2013), Zika virus (Li et al, 2018), or vesicular stomatitis virus (Wang et al, 2015), has also resulted in attenuated strains with potential for LAV development.…”

Section: Introductionmentioning

confidence: 99%

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Use of Synonymous Deoptimization to Derive Modified Live Attenuated Strains of Foot and Mouth Disease Virus

et al. 2021

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Foot-and-mouth disease (FMD) is one of the most economically important viral diseases that can affect livestock. In the last 70 years, use of an inactivated whole antigen vaccine has contributed to the eradication of disease from many developed nations. However, recent outbreaks in Europe and Eastern Asia demonstrated that infection can spread as wildfire causing economic and social devastation. Therefore, it is essential to develop new control strategies that could confer early protection and rapidly stop disease spread. Live attenuated vaccines (LAV) are one of the best choices to obtain a strong early and long-lasting protection against viral diseases. In proof of concept studies, we previously demonstrated that “synonymous codon deoptimization” could be applied to the P1 capsid coding region of the viral genome to derive attenuated FMDV serotype A12 strains. Here, we demonstrate that a similar approach can be extended to the highly conserved non-structural P2 and P3 coding regions, providing a backbone for multiple serotype FMDV LAV development. Engineered codon deoptimized P2, P3 or P2, and P3 combined regions were included into the A24Cruzeiro infectious clone optimized for vaccine production, resulting in viable progeny that exhibited different degrees of attenuation in cell culture, in mice, and in the natural host (swine). Derived strains were thoroughly characterized in vitro and in vivo. Our work demonstrates that overall, the entire FMDV genome tolerates codon deoptimization, highlighting the potential of using this technology to derive novel improved LAV candidates.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Use of Synonymous Deoptimization to Derive Modified Live Attenuated Strains of Foot and Mouth Disease Virus

et al. 2021

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“…were housed and challenged by the intranasal route with tissue homogenates collected on Days 4 and 7 postinfection as described previously 9 according to an animal protocol approved by the Food and Drug Administration IACUC. The hamsters were tested for neutralizing antibodies by a 50% plaque‐reduction neutralization assay 10 just before challenge. A summary of the hamsters used in this study is presented in Table S1 .…”

Section: Methodsmentioning

confidence: 99%

Long‐term immunity in convalescent Syrian hamsters provides protection against new‐variant SARS‐CoV‐2 infection of the lower but not upper respiratory tract

Stauft

Selvaraj

Lien

et al. 2022

Journal of Medical Virology

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COVID-19 vaccines provide high levels of protection against severe disease and hospitalization due to severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infection. Vaccination may be less effective in preventing shedding of infectious viruses from otherwise immune patients. In this study, we describe breakthrough infections and shedding of infectious viruses in convalescent hamsters without significant replication in the lower respiratory tract following reinfection by Alpha and Delta variants despite high levels of circulating antibodies in sera. Using convalescent hamsters with long-term immunity (up to 1 year) following infection by ancestral SARS-CoV-2, we can model aspects of recurring COVID-19 in the context of preexisting immunity.

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“…The ultimate goal of codon swapping is to increase the number of underrepresented codon pairs in the virus’s genes. The strategy has been implicated in attenuating viruses for making vaccine candidates, including human respiratory syncytial virus [ 83 ], porcine reproductive and respiratory syndrome viruses [ 84 ], enterovirus A71 [ 85 ], and dengue virus 2 [ 86 ], and the list is long. In the present study, we presented both the high occurring codon pairs and low-occurring codons so that the high-occurring pairs may be disrupted with the low-occurring codons.…”

Section: Resultsmentioning

confidence: 99%

A Synthetic Biology Approach for Vaccine Candidate Design against Delta Strain of SARS-CoV-2 Revealed Disruption of Favored Codon Pair as a Better Strategy over Using Rare Codons

Gurjar¹,

Karuvantevida

Rzhepakovsky

et al. 2023

Vaccines

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The SARS-CoV-2 delta variant (B.1.617.2) appeared for the first time in December 2020 and later spread worldwide. Currently available vaccines are not so efficacious in curbing the viral pathogenesis of the delta strain of COVID; therefore, the development of a safe and effective vaccine is required. In the present study, we envisaged molecular patterns in the structural genes’ spike, nucleoprotein, membrane, and envelope of the SARS-CoV-2 delta variant. The study was based on determining compositional features, dinucleotide odds ratio, synonymous codon usage, positive and negative codon contexts, rare codons, and insight into relatedness between the human host isoacceptor tRNA and preferred codons from the structural genes. We found specific patterns, including a significant abundance of T nucleotide over all other three nucleotides. The underrepresentation of GpA, GpG, CpC, and CpG dinucleotides and the overrepresentation of TpT, ApA, CpT, and TpG were observed. A preference towards ACT- (Thr), AAT- (Asn), TTT- (Phe), and TTG- (Leu) initiated codons and aversion towards CGG (Arg), CCG (Pro), and CAC (His) was present in the structural genes of the delta strain. The interaction between the host tRNA pool and preferred codons of the envisaged structural genes revealed that the virus preferred the codons for those suboptimal numbers of isoacceptor tRNA were present. We see this as a strategy adapted by the virus to keep the translation rate low to facilitate the correct folding of viral proteins. The information generated in the study helps design the attenuated vaccine candidate against the SARS-CoV-2 delta variant using a synthetic biology approach. Three strategies were tested: changing TpT to TpA, introducing rare codons, and disrupting favored codons. It found that disrupting favored codons is a better approach to reducing virus fitness and attenuating SARS-CoV-2 delta strain using structural genes.

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Extensive genomic recoding by codon-pair deoptimization selective for mammals is a flexible tool to generate attenuated vaccine candidates for dengue virus 2

Cited by 12 publications

References 26 publications

Use of Synonymous Deoptimization to Derive Modified Live Attenuated Strains of Foot and Mouth Disease Virus

Use of Synonymous Deoptimization to Derive Modified Live Attenuated Strains of Foot and Mouth Disease Virus

Long‐term immunity in convalescent Syrian hamsters provides protection against new‐variant SARS‐CoV‐2 infection of the lower but not upper respiratory tract

A Synthetic Biology Approach for Vaccine Candidate Design against Delta Strain of SARS-CoV-2 Revealed Disruption of Favored Codon Pair as a Better Strategy over Using Rare Codons

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