Stability of RNA virus attenuation approaches

Kenney, Joan L.; Volk, Sara M.; Pandya, Jyotsna; Wang, Eryu; Liang, Xiaodong; Weaver, Scott C.

doi:10.1016/j.vaccine.2011.01.055

Cited by 32 publications

(38 citation statements)

References 41 publications

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“…Several alternative strategies based on directed manipulation of the alphaviral genome, such as chimeras consisting of two distinct alphaviruses or internal ribosome entry site-dependent translation of structural proteins, have proven to produce stably attenuated, safe, and effective strains in recent studies (17,28,32,51,53,54).…”

Section: Discussionmentioning

confidence: 99%

Attenuation of Chikungunya Virus Vaccine Strain 181/Clone 25 Is Determined by Two Amino Acid Substitutions in the E2 Envelope Glycoprotein

Gorchakov¹,

Wang²,

Leal³

et al. 2012

J Virol

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155

163

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Chikungunya virus (CHIKV) is the mosquito-borne alphavirus that is the etiologic agent of massive outbreaks of arthralgic febrile illness that recently affected millions of people in Africa and Asia. The only CHIKV vaccine that has been tested in humans, strain 181/clone 25, is a live-attenuated derivative of Southeast Asian human isolate strain AF15561. The vaccine was immunogenic in phase I and II clinical trials; however, it induced transient arthralgia in 8% of the vaccinees. There are five amino acid differences between the vaccine and its parent, as well as five synonymous mutations, none of which involves cis -acting genome regions known to be responsible for replication or packaging. To identify the determinants of attenuation, we therefore tested the five nonsynonymous mutations by cloning them individually or in different combinations into infectious clones derived from two wild-type (WT) CHIKV strains, La Reunion and AF15561. Levels of virulence were compared with those of the WT strains and the vaccine strain in two different murine models: infant CD1 and adult A129 mice. An attenuated phenotype indistinguishable from that of the 181/clone 25 vaccine strain was obtained by the simultaneous expression of two E2 glycoprotein substitutions, with intermediate levels of attenuation obtained with the single E2 mutations. The other three amino acid mutations, in nsP1, 6K, and E1, did not have a detectable effect on CHIKV virulence. These results indicate that the attenuation of strain 181/clone 25 is mediated by two point mutations, explaining the phenotypic instability observed in human vaccinees and also in our studies.

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Section: Discussionmentioning

confidence: 99%

Attenuation of Chikungunya Virus Vaccine Strain 181/Clone 25 Is Determined by Two Amino Acid Substitutions in the E2 Envelope Glycoprotein

Gorchakov¹,

Wang²,

Leal³

et al. 2012

J Virol

Self Cite

155

163

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“…Thus far, DNA shuffling has been mainly used to generate chimeric viruses with novel tissue tropism or with broader antigenic representation (5-7). To our knowledge, attenuation of a virus by DNA shuffling has never been done, although virus attenuation by constructing chimeric viruses, which is very different from the DNA-shuffling strategy used in this study, has been reported (8).…”

mentioning

confidence: 96%

Attenuation of Porcine Reproductive and Respiratory Syndrome Virus by Molecular Breeding of Virus Envelope Genes from Genetically Divergent Strains

Opriessnig

Zhou

et al. 2013

J Virol

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bMolecular breeding via DNA shuffling can direct the evolution of viruses with desired traits. By using a positive-strand RNA virus, porcine reproductive and respiratory syndrome virus (PRRSV), as a model, rapid attenuation of the virus was achieved in this study by DNA shuffling of the viral envelope genes from multiple strains. The GP5 envelope genes of 7 genetically divergent PRRSV strains and the GP5-M genes of 6 different PRRSV strains were molecularly bred by DNA shuffling and iteration of the process, and the shuffled genes were cloned into the backbone of a DNA-launched PRRSV infectious clone. Two representative chimeric viruses, DS722 with shuffled GP5 genes and DS5M3 with shuffled GP5-M genes, were rescued and shown to replicate at a lower level and to form smaller plaques in vitro than their parental virus. An in vivo pathogenicity study revealed that pigs infected with the two chimeric viruses had significant reductions in viral-RNA loads in sera and lungs and in gross and microscopic lung lesions, indicating attenuation of the chimeric viruses. Furthermore, pigs vaccinated with the chimeric virus DS722, but not pigs vaccinated with DS5M3, still acquired protection against PRRSV challenge at a level similar to that of the parental virus. Therefore, this study reveals a unique approach through DNA shuffling of viral envelope genes to attenuate a positivestrand RNA virus. The results have important implications for future vaccine development and will generate broad general interest in the scientific community in rapidly attenuating other important human and veterinary viruses.

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“…However, the vaccine causes adverse effects such as headache and fever in approximately 23% of vaccine recipients, while another approximately 18% of recipients do not develop sufficient neutralizing antibody titers [79]. Reversion mutations can explain adverse effects that have been observed with live-attenuated vaccines including TC-83 [80]. Nevertheless, due to its long history of clinical use, the TC-83 represents a logical starting point for proof-of-concept studies, as well as for preparation of improved vaccines against VEEV [80].…”

Section: Dna-launched Vaccines For Alphavirusesmentioning

confidence: 99%

DNA-launched live-attenuated vaccines for biodefense applications

Pushko

Lukashevich

Weaver

et al. 2016

Expert Review of Vaccines

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Summary A novel vaccine platform uses DNA immunization to launch live-attenuated virus vaccines in vivo. This technology has been applied for vaccine development against positive-strand RNA viruses with global public health impact including alphaviruses and flaviviruses. The DNA-launched vaccine represents the recombinant plasmid that encodes the full-length genomic RNA of live-attenuated virus downstream from a eukaryotic promoter. When administered in vivo, the genomic RNA of live-attenuated virus is transcribed. The RNA initiates limited replication of a genetically defined, live-attenuated vaccine virus in the tissues of the vaccine recipient, thereby inducing a protective immune response. This platform combines the strengths of reverse genetics, DNA immunization and the advantages of live-attenuated vaccines, resulting in a reduced chance of genetic reversions, increased safety, and improved immunization. With this vaccine technology, the field of DNA vaccines is expanded from those that express subunit antigens to include a novel type of DNA vaccines that launch live-attenuated viruses.

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Stability of RNA virus attenuation approaches

Cited by 32 publications

References 41 publications

Attenuation of Chikungunya Virus Vaccine Strain 181/Clone 25 Is Determined by Two Amino Acid Substitutions in the E2 Envelope Glycoprotein

Attenuation of Chikungunya Virus Vaccine Strain 181/Clone 25 Is Determined by Two Amino Acid Substitutions in the E2 Envelope Glycoprotein

Attenuation of Porcine Reproductive and Respiratory Syndrome Virus by Molecular Breeding of Virus Envelope Genes from Genetically Divergent Strains

DNA-launched live-attenuated vaccines for biodefense applications

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