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RNA virus attenuation by altering mutational robustness

Objective

RNA viruses have extreme mutation frequencies. When a RNA virus replicates, nucleotide mutations are generated resulting in a population of variants. This genetic diversity creates a cloud of mutations that are potentially beneficial to viral survival, but the majority of mutations are detrimental to the virus. By increasing the mutation rate of a RNA virus, viral fitness is reduced because it generates more errors, and attenuates the virus during in vivo infection. Another feature that affects RNA virus fitness is mutational robustness. Mutational robustness is the ability to buffer the negative effects of mutation.
The attenuation of RNA viruses for vaccine production faces problems of genetic instability and reversion to a pathogenic phenotype. The conventional method for attenuation is mostly empirical and specific to the particular RNA virus species.
Hence, it cannot be universally applied to a variety of virus types. We've developed a non-empirical, rational means of attenuating RNA viruses, targeting mutational robustness as modifiable trait.
 We demonstrate that mutational robustness of RNA viruses can be modified without changing a virus' physical and biological properties for vaccine production; yet the virus is attenuated as it becomes victim of its naturally high mutation rate. Specifically, the genome of RNA viruses are modified so that a larger proportion of mutations become lethal Stop mutations. Our technology places the virus one step away from these Stop mutations (1-to-Stop). We succeeded in attenuating two RNA viruses from very different viral families, confirming the broad applicability of this approach. These viruses were attenuated in vivo, generated high levels of neutralizing antibody and protected mice from lethal challenge infection.
The proposal now seeks to complete proof of concept studies and develop commercialization strategies to scale up this new technology to preclinical testing with industrial partners.

Host institution

INSTITUT PASTEUR

Address

Rue Du Docteur Roux 25-28
75724 Paris Cedex 15

France

Activity type

Research Organisations

EU Contribution

€ 150 000

Beneficiaries (1)

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INSTITUT PASTEUR

France

EU Contribution

€ 150 000

Project information

Grant agreement ID: 727758

Status

Closed project

  • Start date

    1 September 2016

  • End date

    28 February 2018

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 150 000

  • EU contribution

    € 150 000

Hosted by:

INSTITUT PASTEUR

France