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

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Abstract

Attenuated, live viral vaccines have been extraordinarily successful in protecting against many diseases. The main drawbacks in their development and use have been reliance on an unpredictable method of attenuation and the potential for evolutionary reversion to high virulence. Methods of genetic engineering now provide many safer alternatives to live vaccines, so if live vaccines are to compete with these alternatives in the future, they must either have superior immunogenicity or they must be able to overcome these former disadvantages. Several live vaccine designs that were historically inaccessible are now feasible because of advances in genome synthesis. Some of those methods are addressed here, with an emphasis on whether they enable predictable levels of attenuation and whether they are stable against evolutionary reversion. These new designs overcome many of the former drawbacks and position live vaccines to be competitive with alternatives. Not only do new methods appear to retard evolutionary reversion enough to prevent vaccine-derived epidemics, but it may even be possible to permanently attenuate live vaccines that are transmissible but cannot evolve to higher virulence under prolonged adaptation.

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The distribution of fitness effects caused by single-nucleotide substitutions in an RNA virus.

R. Sanjuán, A. Moya, S F Elena (2004)

Little is known about the mutational fitness effects associated with single-nucleotide substitutions on RNA viral genomes. Here, we used site-directed mutagenesis to create 91 single mutant clones of vesicular stomatitis virus derived from a common ancestral cDNA and performed competition experiments to measure the relative fitness of each mutant. The distribution of nonlethal deleterious effects was highly skewed and had a long, flat tail. As expected, fitness effects depended on whether mutations were chosen at random or reproduced previously described ones. The effect of random deleterious mutations was well described by a log-normal distribution, with -19% reduction of average fitness; the effects distribution of preobserved deleterious mutations was better explained by a beta model. The fit of both models was improved when combined with a uniform distribution. Up to 40% of random mutations were lethal. The proportion of beneficial mutations was unexpectedly high. Beneficial effects followed a gamma distribution, with expected fitness increases of 1% for random mutations and 5% for preobserved mutations.

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The Yeast Deletion Collection: A Decade of Functional Genomics

Guri Giaever, Corey Nislow (2014)

The yeast deletion collections comprise >21,000 mutant strains that carry precise start-to-stop deletions of ∼6000 open reading frames. This collection includes heterozygous and homozygous diploids, and haploids of both MAT a and MATα mating types. The yeast deletion collection, or yeast knockout (YKO) set, represents the first and only complete, systematically constructed deletion collection available for any organism. Conceived during the Saccharomyces cerevisiae sequencing project, work on the project began in 1998 and was completed in 2002. The YKO strains have been used in numerous laboratories in >1000 genome-wide screens. This landmark genome project has inspired development of numerous genome-wide technologies in organisms from yeast to man. Notable spinoff technologies include synthetic genetic array and HIPHOP chemogenomics. In this retrospective, we briefly describe the yeast deletion project and some of its most noteworthy biological contributions and the impact that these collections have had on the yeast research community and on genomics in general.

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DNA vaccines: an historical perspective and view to the future.

Margaret A Liu (2011)

This review provides a detailed look at the attributes and immunologic mechanisms of plasmid DNA vaccines and their utility as laboratory tools as well as potential human vaccines. The immunogenicity and efficacy of DNA vaccines in a variety of preclinical models is used to illustrate how they differ from traditional vaccines in novel ways due to the in situ antigen production and the ease with which they are constructed. The ability to make new DNA vaccines without needing to handle a virulent pathogen or to adapt the pathogen for manufacturing purposes demonstrates the potential value of this vaccine technology for use against emerging and epidemic pathogens. Similarly, personalized anti-tumor DNA vaccines can also readily be made from a biopsy. Because DNA vaccines bias the T-helper (Th) cell response to a Th1 phenotype, DNA vaccines are also under development for vaccines against allergy and autoimmune diseases. The licensure of four animal health products, including two prophylactic vaccines against infectious diseases, one immunotherapy for cancer, and one gene therapy delivery of a hormone for a food animal, provides evidence of the efficacy of DNA vaccines in multiple species including horses and pigs. The size of these target animals provides evidence that the somewhat disappointing immunogenicity of DNA vaccines in a number of human clinical trials is not due simply to the larger mass of humans compared with most laboratory animals. The insights gained from the mechanisms of protection in the animal vaccines, the advances in the delivery and expression technologies for increasing the potency of DNA vaccines, and encouragingly potent human immune responses in certain clinical trials, provide insights for future efforts to develop DNA vaccines into a broadly useful vaccine and immunotherapy platform with applications for human and animal health. © 2010 John Wiley & Sons A/S.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101664675

Journal ID (pubmed-jr-id): 44168

Journal ID (nlm-ta): Virus Evol

Journal ID (iso-abbrev): Virus Evol

Title: Virus evolution

ISSN (Electronic): 2057-1577

Publication date Nihms-submitted: 23 March 2016

Publication date (Electronic): 1 January 2015

Publication date (Print): January 2015

Publication date PMC-release: 29 March 2016

Volume: 1

Issue: 1

Electronic Location Identifier: vev005

Affiliations

[1 ]Department of Integrative Biology, The University of Texas at Austin, Austin, TX 78712, USA

[2 ]Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712, USA

[3 ]Center for Computational Biology and Bioinformatics, The University of Texas at Austin, Austin, TX 78712, USA

Author notes

[* ]Corresponding author: bull@ 123456utexas.edu

Article

Manuscript ID: NIHMS771127

DOI: 10.1093/ve/vev005

PMC ID: 4811365

PubMed ID: 27034780

SO-VID: f615005b-5e95-47eb-b342-d4d08c246064

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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

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Vaccines

Most cited references 79

The distribution of fitness effects caused by single-nucleotide substitutions in an RNA virus.

The Yeast Deletion Collection: A Decade of Functional Genomics

DNA vaccines: an historical perspective and view to the future.

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