Evolutionary reversion of live viral vaccines: Can genetic engineering subdue it?

Bull, James J.

doi:10.1093/ve/vev005

Cited by 59 publications

(71 citation statements)

References 71 publications

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“…Fortunately, recent developments in genetic engineering provide considerable improvements in attenuation methods and the promise of reduced scope for reversion. One especially promising method is attenuation by introducing many silent codon changes [7,23,24]. For reasons still not fully understood, some types of silent codon changes reduce fitness slightly, and when dozens to hundreds of such changes are combined in the same genome, fitness can be reduced to arbitrary levels.…”

Section: Discussionmentioning

confidence: 99%

Eradicating infectious disease using weakly transmissible vaccines

et al. 2016

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Viral vaccines have had remarkable positive impacts on human health as well as the health of domestic animal populations. Despite impressive vaccine successes, however, many infectious diseases cannot yet be efficiently controlled or eradicated through vaccination, often because it is impossible to vaccinate a sufficient proportion of the population. Recent advances in molecular biology suggest that the centuries-old method of individual-based vaccine delivery may be on the cusp of a major revolution. Specifically, genetic engineering brings to life the possibility of a live, transmissible vaccine. Unfortunately, releasing a highly transmissible vaccine poses substantial evolutionary risks, including reversion to high virulence as has been documented for the oral polio vaccine. An alternative, and far safer approach, is to rely on genetically engineered and weakly transmissible vaccines that have reduced scope for evolutionary reversion. Here, we use mathematical models to evaluate the potential efficacy of such weakly transmissible vaccines. Our results demonstrate that vaccines with even a modest ability to transmit can significantly lower the incidence of infectious disease and facilitate eradication efforts. Consequently, weakly transmissible vaccines could provide an important tool for controlling infectious disease in wild and domestic animal populations and for reducing the risks of emerging infectious disease in humans.

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Section: Discussionmentioning

confidence: 99%

Eradicating infectious disease using weakly transmissible vaccines

et al. 2016

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“…In principle, on the background of thousands of attenuating mutations, any single-site reversion should yield only a minuscule selective advantage. The most likely path to reversion imaginable under this model is the progressive accumulation of many individual mutations, providing for a slow progression of deattenuation (12)(13)(14).To date, genetic stability studies of large-scale deoptimized viruses have shown that deattenuation, indeed, seems to be low, suggesting that these viruses are genetically stable (6,8,(15)(16)(17)(18)(19)(20)(21). However, an important limitation of these studies is that the deoptimized viruses generally have not been subjected to strong selective pressure that…”

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confidence: 99%

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confidence: 99%

Genetic stability of genome-scale deoptimized RNA virus vaccine candidates under selective pressure

Nouën

McCarty

Brown

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Recoding viral genomes by numerous synonymous but suboptimal substitutions provides live attenuated vaccine candidates. These vaccine candidates should have a low risk of deattenuation because of the many changes involved. However, their genetic stability under selective pressure is largely unknown. We evaluated phenotypic reversion of deoptimized human respiratory syncytial virus (RSV) vaccine candidates in the context of strong selective pressure. Codon pair deoptimized (CPD) versions of RSV were attenuated and temperature-sensitive. During serial passage at progressively increasing temperature, a CPD RSV containing 2,692 synonymous mutations in 9 of 11 ORFs did not lose temperature sensitivity, remained genetically stable, and was restricted at temperatures of 34°C/35°C and above. However, a CPD RSV containing 1,378 synonymous mutations solely in the polymerase L ORF quickly lost substantial attenuation. Comprehensive sequence analysis of virus populations identified many different potentially deattenuating mutations in the L ORF as well as, surprisingly, many appearing in other ORFs. Phenotypic analysis revealed that either of two competing mutations in the virus transcription antitermination factor M2-1, outside of the CPD area, substantially reversed defective transcription of the CPD L gene and substantially restored virus fitness in vitro and in case of one of these two mutations, also in vivo. Paradoxically, the introduction into Min L of one mutation each in the M2-1, N, P, and L proteins resulted in a virus with increased attenuation in vivo but increased immunogenicity. Thus, in addition to providing insights on the adaptability of genome-scale deoptimized RNA viruses, stability studies can yield improved synthetic RNA virus vaccine candidates.negative-strand RNA virus | respiratory syncytial virus | live attenuated vaccine | codon pair deoptimization | genetic stability T he availability and affordability of large-scale custom DNA synthesis opened the new field of synthetic biology (1). The combined approach of sequence design and synthetic biology allows the generation of DNA molecules with extensive targeted modifications. Synonymous genome recoding, in which one or more ORFs of a microbial pathogen are modified at the nucleotide level without affecting amino acid coding, currently is being widely evaluated to reduce pathogen fitness and create potential live attenuated vaccines, particularly for RNA viruses (reviewed in ref.2) (3-7). The main strategies for attenuation by synonymous genome recoding are codon deoptimization (CD), codon pair deoptimization (CPD), and increasing the dinucleotide CpG and UpA content (which is usually the result of CD and CPD) (2).The mechanisms of attenuation by these strategies are currently under intensive research. It has been suggested that the primary effect of CD and CPD is to reduce translation efficiency of pathogen mRNAs, thereby providing attenuation (8). Effects on mRNA stability also can be a factor (9). In addition, recent studies suggested that codon pa...

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“…On the assumption that each codon change has a small fitness effect, full evolutionary reversion should require reversing all the changes and thus be very slow and possibly incomplete. In practice, reversion is faster than predicted and occurs with relatively few changes, but reversions are still acceptably slow [66]. …”

Section: Engineering Fitness Landscapes To Suppress Evolutionmentioning

confidence: 99%

“…However, this method has not proven especially recalcitrant to evolutionary recovery [66]. Genomes are prone to evolve in response to the deletion, offsetting its effect by adjusting gene expression or even by replacing deleted sequences.…”

Section: Engineering Fitness Landscapes To Suppress Evolutionmentioning

confidence: 99%

Arresting Evolution

Bull

Barrick

2017

Trends in Genetics

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Evolution in the form of selective breeding has long been harnessed as a useful tool by humans. However, rapid evolution can also be a danger to our health and a stumbling block for biotechnology. Unwanted evolution can underlie the emergence of drug and pesticide resistance, cancer, and weeds. It makes live vaccines and engineered cells inherently unreliable and unpredictable, and therefore potentially unsafe. Yet, there are strategies that have been and can possibly be used to stop or slow many types of evolution. We review and classify existing population genetics-inspired methods for arresting evolution. Then, we discuss how genome editing techniques enable a radically new set of approaches to limit evolution.

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Evolutionary reversion of live viral vaccines: Can genetic engineering subdue it?

Cited by 59 publications

References 71 publications

Eradicating infectious disease using weakly transmissible vaccines

Eradicating infectious disease using weakly transmissible vaccines

Genetic stability of genome-scale deoptimized RNA virus vaccine candidates under selective pressure

Arresting Evolution

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